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 .
Claim Status
Applicant’s claim amendments in the response filed 26 January 2026 are acknowledged.
Claims 4, 9, 13, & 16-25 are pending.
Claims 1-3, 5-8, 10-12, 14 & 15 are cancelled.
Claim 4 is amended.
Claims 9, 13 & 23-25 are withdrawn.
Claims 4 & 16-22 are under consideration.
Examination is to the extent of the following species:
Further substances-antioxidants.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file. The effective filing date of the instant application is 29 June 2018.
Maintained Rejections
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 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 4 & 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over Bouchemal [US 2015/0151005; IDS-12/23/2020; previously cited; as evidenced by Pietrangelo (WO 2005/085293; Published 09/15/2005; previously cited)], in view of Michalicova [(Plos One. September 8, 2017; previously cited); as evidenced by Hyaluronic Acid (Published: 02/21/2023; previously cited)] and Huerta-Angeles (Carbohydrate Polymers 111 (2014) 883–891; Published: 2014; previously cited).
With regard to claims 4 & 16-22, and the elected species, Bouchemal in Example 12 teaches a method for preparation of a fatty acid-grafted hyaluronic acid [0632]. Bouchemal teaches mixing hyaluronic acid with dichloromethane (i.e. an aprotic, nonpolar solvent as evidenced by Pietrangelo-pg. 7 as applied to claims 4 & 17) and palmitic acid chloride (i.e. a saturated C16 linear fatty acid chloride) contained in a flask ([0632]). Hence, a person of ordinary skill in the art before the effective filing date would have found it obvious to add the hyaluronic acid to the dichloromethane solvent followed by adding the fatty acid chlorides because any sequence of addition of ingredients to a mixture is prima facie obvious (MPEP 2144.04. IV. C.). Selection of any order of mixing ingredients is prima facie obvious. In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930). Additionally, a person of ordinary skill in the art would have found it obvious to make a dispersion of the hyaluronic acid in the dichloromethane solvent because having the hyaluronic acid dispersed would allow the hyaluronic acid to react to completion with the fatty acid chlorides. Bouchemal in Example 12 teaches the flask is placed under reflux under continuous magnetic stirring for 5 days at 30° C (i.e. allowing the fatty acid chlorides to esterify with hyaluronic acid under reaction conditions sufficient to form a fatty acid-grafted hyaluronic acid; [0632]). With regard to claim 4, Bouchemal in Example 12 teaches the solid is recovered under sintered glass (i.e. isolating the fatty acid-grafted hyaluronic acid in solid form; [0632]). With regard to claim 22, Bouchemal teaches the degree of substitution of the polysaccharide (i.e. hyaluronic acid) with hydrophobic groups (i.e. fatty acid) is from 0.001 to 100%, in particular from 0.05 to 50% [0058]. Bouchemal in Example 12 teaches characterization of their hyaluronic acid grafted with palmitic acid by infrared spectroscopy [0632]. Bouchemal in Example 12 teaches O-palmitoyl-hyaluronic acid is an ester [0633]. Bouchemal teaches the compositions of their invention may be a part of an encapsulation system in which antioxidants are encapsulated [0264].
Bouchemal does not teach the steps of “dispersing native hyaluronic acid in an aqueous solution to obtain an aqueous dispersion, freeze-drying the aqueous dispersion to produce a freeze dried hyaluronic acid and dispersing the freeze dried hyaluronic acid in an organic solvent…” Nor does Bouchemal teach the step of contacting the isolated fatty acid grafted hyaluronic acid in solid form with an aqueous solution to obtain fatty acid-grafted hyaluronic microspheres by self-aggregation in which the fatty acid grafted hyaluronic acid microspheres consist of the fatty acid-grafted hyaluronic acid.
In the same field of invention, Michalicova teaches hyaluronan (i.e. hyaluronic acid) is applied to drug delivery systems (Introduction-pg. 13). Michalicova teaches hyaluronan is a highly hydrophilic polymer and a strategy to use it with hydrophobic drugs is to hydrophobize hyaluronan (Introduction-pg. 13). Michalicova teaches hydrophobic patches exist in hyaluronan that are protected by a hydration shell (pg. 2) Michalicova teaches a freeze-drying method to open the hydration shell and support hydrophobic interaction between the hyaluronan chain and non-polar species (pg. 2). With regard to claim 4, Michalicova teaches the method step of preparing a stock solution of hyaluronic acid in deionized water, the hyaluronan stock solution was added to freeze drying flasks, homogenized, frozen, and transferred to a freeze dryer (pg. 4). Michalicova teaches the method of freeze-drying hyaluronan can be considered as a technique for supporting interactions between native hydrophilic biopolymer hyaluronan and hydrophobic species (pg. 10). With regard to claim 4, the different molecular weights of hyaluronan examined were 106 kDa to 1.46 MDa with a molecular weight of 800 kDA found optimal (pg. 9). With regard to claim 4, this corresponds to 265 to 3,640 repeat units, with 1,995 repeat units found optimal [(Molecular weight of repeat unit of hyaluronan = 401 g/mol; 106,000/401 = 264; 1,460,000/401 =3640); pg. 9]. With regard to claim 16, Michalicova teaches hyaluronan is a chain (i.e. fiber; pg. 2). With regard to claim 16, as evidenced by Hyaluronic Acid, hyaluronic acid is a fiber (pg. 2).
In a same field of invention of esterification of hyaluronan with fatty acids, Huerta-Angeles teaches full characterization of sodium oleyl hyaluronate in D2O by NMR to determine the structure of the hyaluronate esters and the degree of substitution (i.e. heavy water; C18 fatty acid; abstract, Figure 5; pg. 889-col. 1). Huerta-Angeles teaches aggregation of the hydrophobic domains in the sample that underwent NMR analysis (pg. 889). To determine the size and shape of micellar of hyaluronate esters that self-assembled in water, Cryo SEM analysis was used and a hydrophobic dye was used to visualize the samples (pg. 885). Cryo-SEM analyses indicated formation of spherically shaped vehicles with average diameter size about 60 nm (i.e. 0.060 microns; microspheres; Fig. 7). Since the spherically shaped vesicles self-assemble in water, the sodium oleyl hyaluronate in the water used for the NMR characterization necessarily self-assembles into spherically shaped aggregates (i.e. microspheres consisting of fatty acid grafted hyaluronic acid; pg. 889). Huerta-Angeles further teaches “[t]he amphiphilic HA derivatives self-aggregate in aqueous solution while forming spherical vehicles…” (pg. 890).
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Here, at least rationale (G) may be employed in which it would have been prima facie obvious to the ordinary skilled artisan before the effective filing date to have modified Bouchemal’s method by substituting Bouchemal’s hyaluronic acid with Michalicova’s freeze dried hyaluronic acid (i.e. a hyaluronic acid with a backbone of 265 to 3,640 repeat units) made by the steps of “dispersing native hyaluronic acid…freeze-drying the aqueous dispersion to produce freeze-dried hyaluronic acid” because Bouchemal and Michalicova are directed to hyaluronic acid and its interaction with hydrophobic chemicals. The ordinary skilled artisan would have been motivated to do so, with an expectation of success, in order to improve the interaction of the hyaluronic acid with the fatty acids and other non-polar substances by opening hyaluronic acid’s hydration shell through freeze drying. It would also have been prima facie obvious to the ordinary skilled artisan before the effective filing date to have modified Bouchemal’s method by adding the method step of characterization of Bouchemal’s Example 12 O-palmitoyl-hyaluronic acid by NMR [i.e. contacting the solid O-palmitoyl-hyaluronic acid with heavy water thereby obtaining fatty acid grafted hyaluronic acid microsphere formed through self-aggregation consisting of O-palmitoyl-hyaluronic acid] as taught by Huerta-Angeles because Bouchemal and Huerta-Angeles are both directed to characterization of hyaluronate fatty acid esters and it is obvious to modify similar methods in the same way. The ordinary skilled artisan would have been motivated to do so, with an expectation of success, in order to determine the structure of the O-palmitoyl-hyaluronic acid and its degree of substitution through NMR as taught by Huerta-Angeles.
With regard to the recited number of repeating disaccharide units, the number of carbon atoms in the fatty acid, and degree of modification of hyaluronic acid with fatty acid, the combined teachings of Bouchemal, Michalicova and Huerta-Angeles teach these parameters with values which overlap with the claimed ranges. 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). It is obvious to optimize within prior art conditions or through routine experimentation. 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).
Response to Arguments
Applicant argues their present disclosure provides a safe dermal filler (reply, pg. 5 & 11). Applicant reiterates this argument as it pertains to the Bouchemal reference, stating Bouchemal is directed toward drug delivery but their invention is related to a dermal filler (reply, pg. 7-8). Applicant argues that a person of ordinary skill in the art would neither rely on the teaching of Bouchemal nor combine the teachings of Bouchemal, Pietrangelo, Michalicova, Davis and/or Michalicova when faced with the task of developing a safe hyaluronic acid-based dermal filler formulation providing sufficient lifting capacity and longevity while remaining easily injectable through fine needles (reply, pg. 11).
This is not persuasive. The claims are directed to a process of making/preparing fatty acid-grafted hyaluronic acid microspheres. In other words, Applicant is arguing an invention not under examination (i.e. a method of using a dermal filler) instead of the invention as claimed (i.e. method of making microspheres of fatty acid graft hyaluronic acid).
In the traverse of the rejection of claims 4 and 16-22 under 35 USC 103 over Bouchemal, Michalicova and Huerta-Angeles, Applicant argues the prior art references do not teach a manufacturing process that is spontaneously capable of forming microspheres by self-aggregation which show improved rheological properties without use of toxic crosslinkers (reply, pg. 6-7).
This is not persuasive. The combined teachings of Bouchemal, Michalicova and Huerta-Angeles teach the recited methods steps, and using the recited reagents. As a result the microspheres formed by the process suggested by the combined teachings of Bouchemal, Michalicova and Huerta-Angeles do not contain toxic crosslinkers and necessarily spontaneously form microspheres by self-aggregation (see Huerta-Angeles teachings) and have improved rheological properties. "Products of identical chemical composition can not have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant argues the Bouchemal reference individually, arguing that the Example 12 hyaluronic acid which was esterified with palmitic acid chloride was later used in Example 30 where it is complexed with alpha-cyclodextrin (reply, pg. 7).
This is not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Bouchemal teaches the step of hyaluronic acid is mixed with dichloromethane (i.e. organic solvent) and palmitic acid chloride. Bouchemal’s Example 30 is a teaching not relied upon; Applicant is arguing a rejection not made.
Applicant argues Bouchemal does not teach fatty acid-grafted microspheres that self assemble (reply, pg. 8).
This is not persuasive. Huerta-Angeles teaches characterizing fatty acid grafted hyaluronic acid by dispersing the fatty acid-grafted hyaluronic acid in solid form in aqueous solutions. It would be obvious to add Huerta-Angeles’ method step to Bouchemal’s method because Bouchemal teaches characterizing their fatty acid grafted hyaluronic acid and Huerta-Angeles’ method step is a method to characterize fatty acid grafted hyaluronic acid.
Applicant argues their claimed invention is “not obvious in view of Bouchemal at least because Bouchemal fails to disclose (i) the use of high-molecular-weight hyaluronic acid having a hyaluronic acid backbone of 1,250 to 12,500 repeating disaccharide units, (ii) a freeze-drying pretreatment of native hyaluronic acid followed by dispersion in an organic solvent, and (iii) a step of contacting the isolated fatty acid grafted hyaluronic acid in solid form with an aqueous solution to obtain self-aggregated microspheres consisting of fatty acid-grafted hyaluronic acid” (reply, pg. 8).
This is not persuasive. Michalicova teaches the method steps of use of high molecular weight hyaluronic acid which corresponds to 265 to 3,640 repeat units, with 1,995 repeat units found optimal. Michalicova teaches the method steps of freeze-drying pretreatment of native hyaluronic acid to open the hydration shell and expose the hydrophobic domains. Bouchemal in Example 12 teaches the solid is recovered under sintered glass (i.e. isolating the fatty acid-grafted hyaluronic acid in solid form; [0632]). Bouchemal in Example 12 further teaches characterization of their hyaluronic acid grafted with palmitic acid by infrared spectroscopy [0632]. Huerta-Angeles teaches characterization of fatty acid grafted hyaluronic acid by adding it an aqueous solution and that it forms vesicles that are microspheres.
Applicant reiterates Pietrangelo’s teachings (reply, pg. 8).
Pietrangelo is an evidentiary reference used to show dichloromethane is a non-polar solvent.
Applicant argues the Michalicova reference individually (pg. 9). Applicant argues Michalicova requires a co-solvent which is tert-butanol in the freeze-drying solution (reply, pg. 9 & 10). Applicant argues Michalicova teaches away from freeze-drying an aqueous solution of hyaluronan (reply, pg. 10).
With regard to the arguing the claims individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With regard to the argument that Michalicova requires a co-solvent, the claims recite “comprising” as the transitional phrase. The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).
Also, tert-butanol is soluble and miscible in water, as such Michalicova teaches an aqueous solution.
Applicant argues Michalicova’s reference uses native, non-modified hyaluronic acid and presents its approach as an alternative to chemical modification strategies (reply, pg. 10). Applicant further argues Michalicova does not teach that freeze-drying could enhance chemical grafting reactions (reply, pg. 10).
This is not persuasive. Michalicova teaches the method steps of dispersing native hyaluronic acid in an aqueous solution to obtain an aqueous dispersion, freeze-drying the aqueous dispersion to produce a freeze-dried hyaluronic acid.
With regard to the argument that Michalicova does not teach that freeze-drying could enhance chemical grafting reactions, The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is ... a person of ordinary creativity, not an automaton."). In the instant case, ” Bouchemal and Michalicova are directed to hyaluronic acid and its interaction with hydrophobic chemicals. Michalicova teaches freeze drying the hyaluronic acid opens the hydration shell, to expose the hydrophobic domains. A person of ordinary creativity would freeze dry to the hyaluronic acid, to expose its hydrophobic domains, making it more available to interact with fatty acids.
Applicant reiterates Davis’s teachings (reply, pg. 11).
The examiner notes that Davis is an evidentiary reference used to show that hyaluronic acid is a fiber.
Applicant summarizes Huerta-Angeles’ teachings (reply, pg. 11) . Applicant argues Huerta-Angeles, alone or in any combination with the cited art, does not provide any teaching or motivation for a skilled person to arrive at the process of the present claims (reply, pg. 11).
This is not persuasive. Bouchemal and Huerta-Angeles are both directed to characterization of hyaluronate fatty acid esters and it is obvious to modify similar methods in the same way. The ordinary skilled artisan would have been motivated to do so, with an expectation of success, in order to determine the structure of the O-palmitoyl-hyaluronic acid and its degree of substitution through NMR as taught by Huerta-Angeles.
Applicant argues none of the cited art provides any incentive or motivation, to modify its disclosure in a manner that would result in the claimed process for preparing fatty acid grafted hyaluronic acid microspheres (reply, pg. 11).
This is not persuasive. Huerta-Angeles teaches fatty acid grafted hyaluronic acid forms vesicles when dispersed in water. It would have been obvious to modify Bouchemal’s method by adding the step of contacting the fatty acid-grafted hyaluronic acid in solid form with an aqueous solution, thereby obtaining the fatty acid-grafted hyaluronic acid microspheres by self-aggregation as taught by Huerta-Angeles to characterize the structure of the O-palmitoyl-hyaluronic acid and its degree of substitution. The ordinary skilled artisan would have been motivated to do so, with an expectation of success, in order to determine the structure of the O-palmitoyl-hyaluronic acid and its degree of substitution through NMR as taught by Huerta-Angeles since Bouchemal teaches characterization of their fatty acid grafted hyaluronic acid.
Applicant argues picking and choosing has occurred using from Applicant’s disclosure as a guide (reply, pg. 12).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, automaton."). In the instant case, Bouchemal and Michalicova are directed to hyaluronic acid and its interaction with hydrophobic chemicals. Michalicova teaches freeze drying the hyaluronic acid opens the hydration shell, to expose the hydrophobic domains. A person of ordinary creativity would freeze dry to the hyaluronic acid, to expose its hydrophobic domains, making it more available to interact with fatty acids. Bouchemal also teaches characterization of the fatty acid grafted hyaluronic acid and Huerta-Angeles teaches fatty acid grafted hyaluronic acid forms vesicles when dispersed in water in the process of characterizing them by NMR.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LORI K MATTISON whose telephone number is (571)270-5866. The examiner can normally be reached 9-7 (M-F).
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/LORI K MATTISON/ Examiner, Art Unit 1619
/NICOLE P BABSON/ Primary Examiner, Art Unit 1619