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 .
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.
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 1-9, 11-14, 16, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan (US 2010/0279951) A1, Wan (Topical Cyclosporine in the Treatment of Allergic Conjunctivitis: A Meta-analysis, Ophthalmology, 2013, 120(11), 2197-2203) and Meyer (A step-care approach to the management of seasonal allergic conjunctivitis. South African Family Practice, 2004, 46(7), 45–46) in view of Theisinger (WO 2011/073134) and Beier (WO 2018/115097).
The amended claims are directed to the treatment of ocular allergy and its symptoms associated with conjunctival inflammation, specifically seasonal allergic conjunctivitis, perennial allergic conjunctivitis, or contact dermatoconjunctivitis, in patients who do not have dry eye disease as a co-morbidity. The method comprises topical administration of cyclosporine to the eye. The cyclosporine is dissolved in 1-(perfluorobutyl)pentane at a concentration of about 0.5 to 1 mg/ml and administered at a dose of 10-12 ml per eye one or two times per day.
The prior art of Morgan, Wan, and Meyer teaches treating ocular allergy with topical ophthalmic cyclosporine
Multiple prior art references suggest that cyclosporine is effective to treat ocular allergy, including seasonal allergic conjunctivitis and perennial allergic conjunctivitis, and in patients who do not also suffer from dry eye disease.
Morgan teaches a method of treating an allergic conjunctivitis, the method comprising topically administering to an eye affected with such a condition a composition comprising cyclosporin, to an eye of a subject having allergic conjunctivitis, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis. The patients do not have dry eye disease as a co-morbidity (claims 1-2; paragraphs [0004]-[0009]). Morgan is directed to low dose formulations of cyclosporine (0.001-0.01% (w/v), which corresponds to 0.01-0.1 mg/ml) (paragraph [0002]). However, Morgan teaches that a low-dose formulation of 0.01% (0.1 mg/ml) is as effective as the commercial cyclosporine composition (0.05% (0.5 mg/ml)) at delivering the drug to the conjunctiva (paragraph [0103]), which is the site of inflammation in ocular allergy (paragraph [0006]). In other words, the data presented by Morgan et al. demonstrate that the higher, commercial dose of cyclosporine when topically administered to the eye, penetrates the conjunctiva (Table 1, (Figures 1-3).
Wan discloses a meta-analysis of topical cyclosporine in the treatment of allergic conjunctivitis (abstract). The meta-analysis includes studies covering the spectrum of ocular allergy, including seasonal allergic conjunctivitis or perennial allergic conjunctivitis (p. 2198, col 2). Wan concludes that topical cyclosporine is effective in alleviating the signs and symptoms of allergic conjunctivitis and reducing the use of topical steroid eye drops in steroid-dependent patients, while maintaining similar safety profile as compared with placebo (p. 2200, col 2). Wan concludes that the results are effective regardless of dosage (abstract) and includes studies administering 0.05 % and 2 % cyclosporine (Table 1; corresponds to 0.5 mg/ml and 2 mg/ml).
Meyer et al. report the use of topical cyclosporine in serious cases of seasonal allergic conjunctivitis (Figure; Section 6).
The prior art of Morgan, Wan, and Meyer does not teach a 1-perfluorobuyl-pentane carrier or dose of 10-12 ul per eye one or two times per day
Neither Morgan, Wan, nor Meyer teach that the cyclosporine is dissolved in 1-perfluorobutyl-pentane at a concentration of about 0.5 to about 1 mg/ml and administered at a dose of about 10-12 ml per eye one or two times per day.
The prior art of Theisinger and Beier teaches topical ophthalmic cyclosporine using compositions at a concentration of about 0.5 to 1 mg / ml in 1-perfluorobuyl-pentane carrier or dose of 10-12 ul per eye one or two times per day
The prior art of Theisinger and Beier are directed to the development of semifluorinated alkane carriers for topical ophthalmic delivery of cyclosporine. The references present these carriers as alternatives to and improvements of commercially available emulsions such as Restasis for the treatment of eye diseases (e.g. Beier, p. 2).
Theisinger teaches a method of topical administration of an ophthalmic pharmaceutical composition comprising cyclosporine dissolved in 1-(perfluorobutyl)pentane (F4H5) at a concentration of about 0.5 mg/ml to about 1 mg/ml (Examples 4 and 6).
Beier teaches a method of topical administration of an ophthalmic pharmaceutical composition comprising cyclosporine dissolved in 1-(perfluorobutyl)pentane at a concentration of about 0.5 mg/ml to about 1 mg/ml (p. 2, lines 10-15). Beier teaches administration of a volume of 10 ml (p. 19, line 15) and a daily dose of 5 or 10 mg when administered once per day, and a daily dose of 10 or 20 mg when administered twice per day (p. 63).
Obviousness Rationale: Simple substitution of one known element for another to obtain predictable results
The prior art contained a method which differed from the claimed method by the substitution of some element with other elements: The prior art of Morgan, Wan, and Meyer teach the same patient population (seasonal allergic conjunctivitis and perennial allergic conjunctivitis, and in patients who do not also suffer from dry eye disease), the same active ingredient (cyclosporine), and the same administration route (topical to the eye) as the instant claims. The prior art of Morgan also acknowledges the presence of conjunctival inflammation as part of these conditions. The prior art of Morgan teaches lower concentrations than the claims but also teaches that the claimed concentration, which is also taught by Wan, delivers cyclosporine to the conjunctiva. These references differ from the claimed method by the substitution of the topical ophthalmic cyclosporine emulsions such as the commercial product Restasis with cyclosporine in a 1-perfluorobuyl-pentane carrier at a dose of 10-12 ml per eye one or two times per day.
The substituted elements and their functions were known in the art: Topical ophthalmic compositions of cyclosporine in a 1-perfluorobuyl-pentane carrier are taught in the prior art of Beier and Theisinger. In addition, Beier teach a dose of 10-12 ml per eye one or two times per day. The function of the 1-perfluorobuyl-pentane carrier is to dissolve the poorly-soluble cyclosporine and to deliver a therapeutically-effective amount of the drug to the eye by a topical route.
Ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable: One of ordinary skill in the art would have substituted the cyclosporine in the 1-perfluorobuyl-pentane carrier of Beier and Theisinger for the cyclosporine in the carrier taught by Morgan, Wan, and Meyer. One of ordinary skill in the art would predict, based on Theisinger, that 1-(perfluorobuytl)pentane carrier would dissolve cyclosporine, be well tolerated by the eye, have a refractive index that is compatible with vision, and have the ability to form small droplets (pp. 13-14; pp. 15-16). In addition, one of skill in the art would predict, based on Theisinger and Beier, that the formulation can deliver cyclosporine to the eye via topical administration given that these references are entirely directed to ophthalmic topical administration s (e.g. Beier, p. 2). One of ordinary skill in the art would predict that the ocular allergy, including conjunctival inflammation, taught by Morgan, Wan, and Meyer would be treated given that the active agent is the same in these references as in Theisinger and Beier.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art.
The resulting method satisfies all of the limitations of claims 1-2 and 16.
With respect to claims 3 and 13, Morgan teaches that symptoms include inflammation of the conjunctiva, lacrimation, tearing, conjunctival vascular dilation, itching, papillary hyperlasia, chemosis, eyelid edema, and discharge from the eye (paragraph [0006]).
With respect to claims 4-8, Theisinger teaches an ophthalmic pharmaceutical composition comprising cyclosporine dissolved in 1-(perfluorobutyl)pentane (F4H5) and 1 wt% ethanol at a concentration of about 0.5 mg/ml to about 1 mg/ml (Examples 4 and 6).
With respect to claims 9 and 20, Theisinger teaches that the composition is clear and does not contain water or a preservative (Example 4).
With respect to claims 11 and 21, Beier teaches administration of a volume of 10 ml (p. 19, line 15) and a daily dose of 5 or 10 mg when administered once per day, and a daily dose of 10 or 20 mg when administered twice per day (p. 63).
With respect to claims 12 and 22, Beier teaches a daily dose of 5 or 10 mg when administered once per day, and a daily dose of 10 or 20 mg when administered twice per day (p. 63), which fall within the claimed ranges.
With respect to claims 14, Morgan teaches that the patient may have eyelid edema (paragraph [0006]).
Response to Arguments
Applicant's arguments filed December 10, 2025, have been fully considered but they are not persuasive.
The rejection is based on the analysis that it would have been obvious to substitute topical ophthalmic cyclosporine emulsions such as the commercial product Restasis in methods of treating ocular allergy taught by Morgan, Wan, and Meyer with cyclosporine in a 1-perfluorobuyl-pentane carrier taught by Beier and Theisinger. In doing so, POSITA would look to the teaching of Beier and Theisinger, not to Morgan, Wan, and Meyer, for the administration and dosage information for the substituted formulation. POSITA would see that Beier teaches that for cyclosporine in a 1-perfluorobuyl-pentane carrier, the effective dose is 10-12 ml per eye one or two times per day, which is the claimed administration and dose. Applicant argues that there is no expectation of success because this dose, useful for dry eye disease, is less than the dose taught by Morgan, Wan, and Meyer for ocular allergy. In making this argument, Applicant appears to be equating the amount of cyclosporine administered in the aqueous suspension to the amount of cyclosporine administered in the 1-perfluorobuyl-pentane carrier. Instead, POSITA would consider the relevant teaching to be in Beier, which discloses how to administer the substituted formulation. POSITA would not use the dosage information for an aqueous suspension from Morgan, Wan, and Meyer to determine how to administer the cyclosporine in a 1-perfluorobuyl-pentane carrier. This information is provided by Beier. The data in the specification from a human clinical shows that a 20 ug per eye daily dose of cyclosporine is effective, which is consistent with the teaching of Beier that for cyclosporine in a 1-perfluorobuyl-pentane carrier, the effective dose is 10-12 ml per eye one or two times per day.
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654