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 .
Applicants' arguments, filed July 13, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims
Claim Rejections - 35 USC § 103 – Obviousness (Maintained Rejections)
1) Claims 16-33 are rejected under 35 U.S.C. 103 as being unpatentable over Wirostko (US 2015/0157563) in view of Griesser et al. (Polymers, 2018).
Wirostko disclose an ocular composition comprising a polymer matrix and an antibiotic dispersed in the polymer matrix. The ocular composition may be formulated into an ocular insert, solution, film (meeting instant claim 17) or gel. The polymer matrix may comprise a thiolated hyaluronic acid (HA). The thiolated HA includes thiolated carboxymethyl hyaluronic acid cross-linked with a poly(ethylene glycol) diacrylates (interpreted as nonactivated). The hyaluronic active film comprises 10%, 12% and 16% of the film. Actives that are delivered by polymer matrix includes those that treat glaucoma. Glaucoma agents may be added to the compositions and include Latanoprost, Bimatopost, Travaprost, Timolol, Betaxalol, Dorzolamide, Brinzolamide, and Briminodine. The therapeutic agents comprise 0.01 to about 0.5% and 0.2% to about 10% of the composition. Additional ingredients can be added to the HA bioerodible polymer to improve a variety of polymeric properties such as mucoadhesiveness, flexibility, and the like. Non-limiting examples of such ingredients include methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl-pyrrolidone, alginic acid, chitosan, xanthan gum, carrageenan, poly(acrylic) acid, or a derivative thereof (instant claim 31).
Wirostko differs from the instant claims insofar as it does not disclose the preactivated thiomer of hyaluronic acid or the nonactivated thiomers of hyaluronic acids of the instant claims.
Griesser et al. disclose thiolated hyaluronic acid as a versatile mucoadhesive polymer. Due the ability of disulfide bond formation within the polymer itself as well as with biological materials, certain properties such as mucoadhesive, gelling, enzyme inhibitory, permeation enhancing and release controlling properties are improved (Abstract).The composition may be used for drug delivery to the eye and used to treat ocular wounds. The hyaluronic acid is thiolated at the carboxyl group. The thiol group is further protected with 6-mercaptonicotinamide. Via this pre-activation with 6 mercaptonicotinamide the free thiol groups are oxidized to disulfide bonds. As free thiol groups from thiolated HA are sensitive towards oxidation and rapidly react with the cysteine-rich domains in the mucus, S-protection (pre-activation) plays a major role in the improvement of mucoadhesiveness, cohesiveness as well as stability against degradation. Thiolation of HA leads to an even 12-fold augmentation in mucoadhesion on buccal mucosa. Thiolated HA preactivated with 6-mercaptonicotinamide demonstrated a 4-fold improved adhesion time compared to thiolated HA. The unprotected polymers have a cysteine side chain (instant claim 23). The polymers are crosslinked (3.2). Crosslinking causes a higher stability.
It would have been obvious to one of ordinary skill in the art prior to filing the instant application to have use the pre-activated thiolated hyaluronic acids in conjunction with or as the thiolated hyaluronic acids of Wirostko motivated by the desire to produce a film with an improved mucoadhesiveness, cohesiveness as well as stability against degradation.
It would have been obvious to one of ordinary skill in the art prior to filing the instant application to have made the films of Wirostko with a combination of the activated and nonactivated thiolated hyaluronic acids of Griesser et al. motivated by the desire to obtain different mucoadhesiveness by combining polymers with different adhesive properties.
In regards to the amounts recited in claim 32, the preactivated thiomer of hyaluronic acid is a result effective variable because it controls that adhesiveness of the system that is applied to the eye. It would have taken no more than the relative skill of one of ordinary skill in the art to have adjusted the amount of preactivated thiomer of hyaluronic acid to obtain the desired therapeutic effect. See MPEP 2144.05.
In regards to claim 33, the composition of Wirostko may be used to deliver glaucoma actives either alone or in combination. Therefore, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have used the delivery systems of Wirostko modified with Griesser et al. to deliver the glaucoma drugs to treat glaucoma because they are suitable for delivering glaucoma therapeutic agents.
In regards to claim 18, the protection of the cysteine hyaluronic acid of Griesser et al. with 6-mercaptonicotinamide would yield one of the compounds of instant claim 18.
In regard to instant claim 20, the moles of 6-mercaptonicotinamide would control how much of the hyaluronic acid is protected, making it a result effective variable. It would have been in the relative skill of one of ordinary skill in the art to have adjusted the micromole/g of 6-mercaptonicotinamide in order to arrive at the desired substitution on the hyaluronic acid. See MPEP 2144.05.
Response to Arguments
The Examiner submits that in regards to Griesser, Griesser discloses preactivated thiomer of HA leads to longer adhesion. It is specifically disclosed that “[t]hrough thiolation of HA properties such as mucoadhesiveness, swelling capacity, stability and biocompatibility could be improved. The protection of thiol groups via crosslinking or preactivation forming disulfide bonds generates more stable and effective drug delivery systems as the properties of thiomers are further improved”. Therefore, Griesser provides motivation to use a preactivated thiomer of HA in the composition of Wirostko. In regards to using other fields such as buccal and vaginal delivery, mucosal surfaces found in different parts of the body use overlapping agents when formulating compositions to use in those areas. Further, Griesser discloses using thiolated HA in the eye. It also states “[m]oreover, further applications, various drug delivery systems (buccal, vaginal, and ocular) and finally product developments are discussed.” Therefore, one would reasonably conclude that the compounds disclosed therein may be used in the eye. In regards to the restraints for ocular delivery systems, one would be motivated to use a preactivated HA because it is more stable and would therefore be more suitable to withstanding the constraints of the ocular environment. Therefore, one of ordinary skill in the art would reasonably conclude that the good adhesion properties reported by Griesser would be suitable for ocular delivery. In regards to combining the references, both references disclose ocular delivery systems. Further, both references disclose thiolated HA and Griesser teaches how preactivated thiolated HA are more stable. Therefore, this is motivation to use the preactivated thiolated HA in the composition of Wirostko. In regard to the molecular weight, one of ordinary skill in the art would recognize that the molecular weight would affect the mucoadhesive properties. It would have taken no more than the relative skill of one of ordinary skill in the art to have adjusted the amount of preactivated thiomer of hyaluronic acid to obtain the desired therapeutic effect. See MPEP 2144.05. Therefore, the combination of references make obvious the instant claims.
2) Claims 16-22 and 24-33 are rejected under 35 U.S.C. 103 as being unpatentable over Wirostko (US 2015/0157563) in view of Nowak et al. (Inter. J. of Pharm., 2015).
Wirostko disclose an ocular composition comprising a polymer matrix and an antibiotic dispersed in the polymer matrix. The ocular composition may be formulated into an ocular insert, solution, film (meeting instant claim 17) or gel. The polymer matrix may comprise a thiolated hyaluronic acid (HA). The thiolated HA includes thiolated carboxymethyl hyaluronic acid cross-linked with a poly(ethylene glycol) diacrylates (interpreted as nonactivated). The hyaluronic active film comprises 10%, 12% and 16% of the film. Actives that are delivered by polymer matrix includes those that treat glaucoma. Glaucoma agents may be added to the compositions and include Latanoprost, Bimatopost, Travaprost, Timolol, Betaxalol, Dorzolamide, Brinzolamide, and Briminodine. The therapeutic agents comprise 0.01 to about 0.5% and 0.2% to about 10% of the composition. Additional ingredients can be added to the HA bioerodible polymer to improve a variety of polymeric properties such as mucoadhesiveness, flexibility, and the like. Non-limiting examples of such ingredients include methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl-pyrrolidone, alginic acid, chitosan, xanthan gum, carrageenan, poly(acrylic) acid, or a derivative thereof (instant claim 31).
Wirostko differs from the instant claims insofar as it does not disclose the preactivated thiomer of hyaluronic acid or the nonactivated thiomers of hyaluronic acids of the instant claims.
Nowak et al. disclose preactivated hyaluronic acid as a potential mucoadhesive. Mucoadhesive polymeric excipients were developed for vaginal drug delivery systems. Hyaluronic acid (HA) was thiolated and subsequently preactivated with 6-mercaptonicotinamide (HA-CYS–MNA) (encompassing 6-mercaptonicotinamide cysteine, instant claim 18) to enhance stability and mucoadhesive properties on vaginal mucosa. Modifying HA-CYS with MNA resulted in higher stability (3.6-fold prolonged disintegration time compared to unmodified hyaluronic acid) and prolonged mucoadhesion time (Abstract). The thiol and disulfide were present exhibiting 218.87 micromole per game of HA and 173.8 micromole per gram respectively (3.1).
Although Nowak et al. disclose virginal mucosa, this can be translated to develop delivery of therapeutics to the mucosa of the eye. Therefore, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have used the pre-activated thiolated hyaluronic acids in conjunction with or as the thiolated hyaluronic acids of Wirostko motivated by the desire to produce a film with higher stability.
In regards to the amounts of in claim 32, the preactivated thiomer of hyaluronic acid is a result effective variable because it controls the stability and the adhesiveness of the system that is applied to the eye. It would have taken no more than the relative skill of one of ordinary skill in the art to have adjusted the amount of preactivated HA in order to obtain the desire stability and residence time for delivery of the active to the eye. See MPEP 2144.05.
In regards to claim 33, the composition of Wirostko may be used to deliver glaucoma actives either alone or in combination. Therefore, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have used the delivery systems of Wirostko modified with the preactivated HA of Nowak et al. to deliver the glaucoma drugs to treat glaucoma because they are suitable for delivering glaucoma therapeutic agents.
In regard to instant claim 20, the moles of 6-mercaptonicotinamide would control how much of the hyaluronic acid is substituted with the 6-mercaptonicotinamide, making it a result effective variable. It would have been in the relative skill of one of ordinary skill in the art to have adjusted the micromole/g of 6-mercaptonicotinamide in order to arrive at the desired substitution on the hyaluronic acid. See MPEP 2144.05.
Response to Arguments
The Examiner submits that Nowak cures the deficiencies of Wirostko by disclosing that a preactivated thiomer of hyaluronic acid has a higher stability and prolonged mucoadhesion time compared to HA and HA-CYS. Therefore, one would be motivated to use the preactivated thiomer of HA to make the ocular delivery system of Wirostko more stable and prolong the mucoadhesion of the delivery system. In regard to Nowak not disclosing an anti-glaucoma drug, Wirostko discloses the anti-glaucoma drug. In regards to the type of mucosa, one of ordinary skill in the art would recognize that components used in mucosal compositions often may be used on mucosal surfaces in different parts of the body. Therefore, one would conclude that a component for the vaginal mucosa may also be used on the ocular mucosa. Further, Nowak discloses that HA may be administered using different routes including an ophthalmic route. Due to the increased stability if a preactivated HA, one would be motivated to use the preactivated HA in an ophthalmic composition because of the constraints. One would reasonably conclude that this would keep the delivery system in place for a longer period of time. In regard to looking to other art, one would look to art encompassing mucoadhesives. One would have a reasonable expectation that mucoadhesives that work in one moist area of the body would more than likely also work in other moist areas such as the eye. In regard to the molecular weight, one of ordinary skill in the art would recognize that the molecular weight would affect the mucoadhesive properties. It would have taken no more than the relative skill of one of ordinary skill in the art to have adjusted the amount of preactivated thiomer of hyaluronic acid to obtain the desired therapeutic effect. See MPEP 2144.05. Therefore, the combination of references make obvious the instant claims.
Obvious-Type Double Patenting
Claims 16-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-31 of copending Application No. 17/796,183 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are coextensive insofar as they both recite a mucoadhesive delivery system comprising a preactivated thiomer polymer. The instant claims differ from the copending claims insofar as they recite hyaluronic acid as the polymer. However the copending claims recite that hyaluronic acid may be the polymer in dependent claim 15. Therefore the instant claims are obvious over the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants respectfully defer these issues until the application is otherwise in condition for allowance. Since this has not occurred, the rejection is maintained.
Conclusion
Claims 16-33 are rejected.
No claims 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 LEZAH ROBERTS whose telephone number is (571)272-1071. The examiner can normally be reached Monday-Friday 11:00-7:30.
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/LEZAH ROBERTS/ Primary Examiner, Art Unit 1612
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