FINAL 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 .
Status of the Claims
This action is in response to papers filed 12/29/2025 in which claims 2-4 and 13 were previously canceled; and claims 8-12 were previously withdrawn.
Claims 1, 5-7 and 14-15 are under examination.
Maintained Rejection
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.
Claim(s) 1, 5-7, and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karlsson et al (US 2016/0145357 A1) in view of Mutschler et al (Chemistry of Materials, 2017, 29(7): 3195-3201; previously cited), and Nibbering et al (US 2016/0075749 A1; previously cited).
Regarding claims 1 and 14, Karlsson teaches a crosslinked hyaluronic acid hydrogel comprising hyaluronic acid, wherein the hyaluronic acid is crosslinked with a crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE) to form an ether linkage and the crosslinked hyaluronic acid is negatively charged (Abstract; [0002], [0012]-[0044], [0049]-[0054], [0065]-[0073], [0086]-[0095], [0107]-[0108]; claims 1-30), thereby meeting the claimed crosslinked with a crosslinking agent at the level of the hydroxyl moieties while the carboxyl moieties of hyaluronic acid remain free and said hyaluronic acid remains negatively charged. It is further noted that the crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE) as taught in Karlsson also meets the generically claimed “the crosslinking agent is a reagent enabling the formation of covalent bonds or ionic bonds between two HA molecules.”
Karlsson teaches the molecular weight of hyaluronic acid is in the range of 0.5-10 MDa ([0068], [0072]), which overlaps or falls within the claimed molecular weight between 150 kDa and 3000 kDa. It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when 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 similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the molecular weight of hyaluronic acid would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Karlsson teaches a medical device comprising the crosslinked hyaluronic acid ([0051]).
Karlsson teaches the crosslinked hyaluronic acid is load with active substance so as to form a drug delivery device ([0054] and [0112]).
However, Karlsson does not teach the positively charged antimicrobial peptide that is loaded in the hydrogel of claim 1.
Regarding the positively charged antimicrobial peptide of claim 1, Mutschler teaches cationic peptide such as polyarginine is known to react with hyaluronic acid via electrostatic interaction to provide strong antimicrobial properties (Mutschler: Abstract; Introduction; pages 1-5), and Nibbering teaches that suitable carrier for cationic peptide such as a homopolymer of arginine includes hydrogels, in which the cationic peptide can be incorporated in or on the surface of the carrier hydrogel so as to provide slow release of the cationic peptide from the hydrogel carrier (Nibbering: Abstract; [0026]-[0187]).
It would have been obvious to one of ordinary skill in the art to load the cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel of Karlsson, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Karlsson indicated that any active substance can be loaded in the hyaluronic acid hydrogel so as to form a desired drug delivery device, and Mutschler and Nibbering provided the guidance and reasonable expectation of loading cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel so as to form a hydrogel product that provide slow release of the cationic peptide from the hydrogel. Thus, an ordinary artisan seeking to provide an antimicrobial hydrogel which provides controlled or slow release of a cationic peptide such as polyarginine would have looked to loading the polyarginine in the hyaluronic acid hydrogel of Karlsson so as to provide an antimicrobial hydrogel which provides slow release of the polyarginine per guidance from Mutschler and Nibbering, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claim 5, Mutschler provides the guidance for using polyarginine having 30 arginine residue as the polyarginine, as Mutschler teaches that cationic peptide such as polyarginine is known to react with hyaluronic acid via electrostatic interaction to provide strong antimicrobial properties (Mutschler: Abstract; Introduction; pages 1-5). Thus, an ordinary artisan seeking to provide a hyaluronic acid hydrogel with enhanced antimicrobial properties, would have looked to using polyarginine having 30 arginine residue as the active substance in the hydrogel of Karlsson in view of Nibbering, per guidance from Mutschler, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claim 6, as discussed above, Karlsson teaches the molecular weight of hyaluronic acid is in the range of 0.5-10 MDa, which overlaps or fall within the claimed molecular weight of between 800 and 850 kDa. Thus, as discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when 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 similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed parameters, the optimization of the molecular weight of hyaluronic acid would have been obvious before the effective filing date of applicant's invention. See MPEP §2144.05 (I)-(II).
Regarding claim 7, as discussed above, Karlsson teaches the crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).
Regarding claim 15, Nibbering teaches and provides the guidance for using cationic peptide loaded hydrogel in medical device such as wound dressing so as to treat wound infections (Nibbering: Abstract; [0005], and [0026]-[0187]).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant argues:
“The form of hyaluronic acid described in Mutschler- non-crosslinked multilayers-is fundamentally incompatible with Karlsson's crosslinked hydrogel. Karlsson uses crosslinked hyaluronic acid to contain a substance within a hollow container, without any mention of interaction between the hyaluronic acid and said substance. In contrast, the antimicrobial effect described by Mutschler specifically requires interaction between the peptide and non-crosslinked hyaluronic acid, namely the diffusion of the peptide through multilayers of hyaluronic acid. Mutschler's mechanism depends on the ability of polyarginine chains to diffuse within the film, a property that would not be expected in a crosslinked hydrogel structure as taught by Karlsson. Indeed, crosslinking would be expected to impede the diffusion of polyarginine chains, thereby destroying the very mechanism that Mutschler relies upon for antimicrobial activity. Thus, a person of ordinary skill in the art would not have had a reasonable expectation of success in achieving the antimicrobial effect of Mutschler's system in Karlsson's crosslinked hydrogel.” (Remarks, page 6, last paragraph to page 7).
In response, the Examiner disagrees. First, it is noted that claim 1 only requires that the peptide is not covalently linked to the hydrogel and thus, does not exclude electrostatic interaction of the peptide with the hyaluronic acid when the peptide is loaded in the hyaluronic acid hydrogel. Applicant is noted that the electrostatic interaction would occur when polyarginine is loaded in the hyaluronic acid hydrogel, as polyarginine is cationic and the hyaluronic acid is anionic. Second, Nibbering provided the guidance and reasonable expectation of success that the cationic peptide such as homopolymer of arginine (polyarginine of Mutschler is a homopolymer of arginine) can be loaded in a hydrogel (see 103 rejection, pages 4-5 of this office action). Thus, the obviousness analysis is not drawn to combining the structures of Mutschler with the structures of Karlsson. Rather, the analysis is to how it would have been obvious to load the cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel of Karlson. As such, Applicant is noted that "I[i]t is well-established that a determination of obviousness based on teachings from multiple references does not require an actual, physical substitution of elements." In re Mouttet, 686 F.3d 1322, 1332, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012) (citing In re Etter, 756 F.2d 852, 859, 225 USPQ 1, 6 (Fed. Cir. 1985) (en banc)) ("Etter's assertions that Azure cannot be incorporated in Ambrosio are basically irrelevant, the criterion being not whether the references could be physically combined but whether the claimed inventions are rendered obvious by the teachings of the prior art as a whole."). See also In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981) ("The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art."); In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) ("[I]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review."); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) ("Combining the teachings of references does not involve an ability to combine their specific structures.").
Accordingly, as discussed in the standing 103 rejection, Mutschler and Nibbering provided the guidance and reasonable expectation of loading cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel so as to form a hydrogel product that provide slow release of the cationic peptide from the hydrogel. Thus, an ordinary artisan seeking to provide an antimicrobial hydrogel which provides controlled or slow release of a cationic peptide such as polyarginine would have looked to loading the polyarginine in the hyaluronic acid hydrogel of Karlsson so as to provide an antimicrobial hydrogel which provides slow release of the polyarginine.
Applicant argues:
“While the Examiner has also cited Nibbering to teach that cationic peptides can be incorporated in hydrogels for controlled release, Nibbering does not cure the deficiency in the proposed combination. Nibbering's teaching of generic hydrogel carriers does not address the specific interaction between polyarginine and hyaluronic acid that Mutschler relies upon for antimicrobial activity. Notably, Nibbering teaches a different peptide (P10, SEQ ID NO:1) and does not teach or suggest that polyarginine would provide antimicrobial activity when loaded into a crosslinked HA hydrogel. See Nibbering, paragraphs [0026]-[0027]. Accordingly, a person of ordinary skill in the art would not have been motivated to use Mutschler's peptide in combination with Karlsson's crosslinked hydrogel, as the teachings of these references are directed to fundamentally different structures with different mechanisms of action.” (Remarks, page 7).
In response, the Examiner disagrees. As discussed above in the 103 rejection, the claimed cationic peptide was structurally taught by Mutschler. See 103 rejection, page 4 of this office action.
As discussed above, Nibbering was used for providing guidance and reasonable expectation of success that the cationic peptide such as homopolymer of arginine (polyarginine of Mutschler is a homopolymer of arginine) can be loaded in a hydrogel (see 103 rejection, pages 4-5 of this office action). Thus, the obviousness analysis is not drawn to combining the structures of Mutschler with the structures of Karlsson. Rather, the analysis is to how it would have been obvious to load the cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel of Karlson. As such, Applicant is noted that "I[i]t is well-established that a determination of obviousness based on teachings from multiple references does not require an actual, physical substitution of elements." In re Mouttet, 686 F.3d 1322, 1332, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012) (citing In re Etter, 756 F.2d 852, 859, 225 USPQ 1, 6 (Fed. Cir. 1985) (en banc)) ("Etter's assertions that Azure cannot be incorporated in Ambrosio are basically irrelevant, the criterion being not whether the references could be physically combined but whether the claimed inventions are rendered obvious by the teachings of the prior art as a whole."). See also In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981) ("The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art."); In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) ("[I]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review."); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) ("Combining the teachings of references does not involve an ability to combine their specific structures.").
Accordingly, as discussed in the standing 103 rejection, Mutschler and Nibbering provided the guidance and reasonable expectation of loading cationic peptide such as polyarginine as the active substance in the hyaluronic acid hydrogel so as to form a hydrogel product that provide slow release of the cationic peptide from the hydrogel. Thus, an ordinary artisan seeking to provide an antimicrobial hydrogel which provides controlled or slow release of a cationic peptide such as polyarginine would have looked to loading the polyarginine in the hyaluronic acid hydrogel of Karlsson so as to provide an antimicrobial hydrogel which provides slow release of the polyarginine.
As a result, for at least the reason discussed above, claims 1, 5-7 and 14-15 remain rejected as being obvious and unpatentable over the combined teachings of Karlsson, Mutschler, and Nibbering in the standing 103 rejection as set forth in this office action.
Conclusion
No claim is 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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/DOAN T PHAN/Primary Examiner, Art Unit 1613
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