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 .
Non-Final Rejection
The Status of Claims:
Claims 1, 10, 13, 19, 24, 31, 32, 35, 48, 54, 72-77 are pending.
Claims 1, 10, 13, 19, 24,, 31, 32, 35, 48, 54, 72-77 are rejected.
DETAILED ACTION
1. Claims 1, 10, 13, 19, 24, 31, 32, 35, 48, 54, 72-77 are under consideration in this Office Action.
Priority
2. It is noted that this application is a 371 of PCT/US2022/075640 08/30/2022 , which has a priority of 63392917 07/28/, which has a priority of 63345202 05/24/2022 ,which has a priority of 63239195 08/31/2021.
Drawings
3. The drawings filed on 2/29/24 are accepted by the examiner.
IDS
4. The IDS filed on 12/08/25 are reviewed by the examiner.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-2,10,13, 19, 24, 31-33, 35, 48, and 54) on 7/28/26 is acknowledged. Claims 54-56 ,58, 67-71 are withdrawn and cacncelled from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups II-III, there being no allowable generic or linking claim.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 10, 13, 19, 24, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Shibagaki.et al (US 2009/0042962 A1) in view of Wikipedia ( Corticosteroid, 24 February 2019, pages 1-12).
Determination of the scope and content of the prior art
Shibagaki.et al discloses a method for treating a keratoconjunctival disorder such as keratitis comprising administering to a patient a therapeutically effective amount of a compound such as losartan in the followings:
12. A method for treating a keratoconjunctival disorder comprising administering to a patient a therapeutically effective amount of a compound represented by the following formula (I)
or a salt thereof:
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wherein X represents
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the ring Y represents a substituted or unsubstituted nitrogen-containing heterocyclic ring; R.sup.1 represents a carboxy group or a substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring; and R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkylcarbonyl group (see page 7, claim 12)
21. The treatment method according to claim 12, wherein 2-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-- 4-yl]methyl]-imidazole (losartan) is a compound of formula (1) which is administered.
22. The treatment method according to claim 12, wherein the keratoconjunctival disorder is dry eyes, corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, corneal epithelial defects, conjunctival epithelial defects, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis or filamentary keratitis .
23. The treatment method according to claim 12, wherein the dosage form is an eye drop or an ophthalmic ointment (see page 9, Claims 21 & 23).
Furthermore, regarding the dose of the present compound, it can be properly selected depending on the symptoms, age, dosage form and the like. In the case of an eye drop, it may be instilled once to several times a day as in claim 13 at a concentration of from 0.00001 to 5% (w/v), preferably from 0.001 to 3% (w/v). In the case of an oral preparation, it may be administered once or divided into several times at a dose of generally from 0.1 to 5000 mg per day, preferably from 1 to 1000 mg per day(see page 4, a paragraph#0072).
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By altering the amount of Compound C to be added, an eye drop at a concentration of 0.003% (w/v), 0.01% (w/v), 0.03% (w/v), 0.05% (w/v), 0.3% (w/v), 1 % (w/v)or 3% (w/v) can be prepared (see page 6, example 3, a paragraph#0095).
Also, it teaches 2-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-- 4-yl]methyl]-imidazole monopotassium salt (hereinafter referred to as "Compound C")(see page 5, a paragraph#0077), which is known as losartan.
In addition, examples of the dosage form include eye drops, ophthalmic ointments, injections, tablets, capsules, granules, powders and the like. In particular, eye drops are preferred. These can be prepared using any of generally used techniques. For example, the eye drops can be prepared using a tonicity agent such as sodium chloride or concentrated glycerin, a buffer such as sodium phosphate or sodium acetate, a surfactant such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil, a stabilizer such as sodium citrate or sodium edetate, a preservative as in claim 31 such as benzalkonium chloride or paraben as needed. The pH of the eye drops is permitted as long as it falls within the range that is acceptable as an ophthalmic preparation, but is preferably in the range of from 4 to 8 (see page 4 , a paragraph#0069).
The current invention, however, differs from the prior art in that the concentration of losartan in terms of mg/ml and the use of eyedrop container and corticosteroid and the subject being a human are not specified in the prior art.
Wikipedia teaches the use of corticosteroids as in claim 19 in medical conditions such as uveitis and keratoconjunctivitis (see page 3, the first paragraph).
Ascertainment of the difference between the prior art and the claims
The difference between the instant application and the applied Shibagaki.et al art is that the applied Shibagaki et al art does not expressly teach the concentration of losartan in terms of mg/ml and the use of eyedrop container and corticosteroid and the subject being a human. The deficiencies of Shibagaki.et al are partially cured by Wikipedia.
The difference between the instant application and the applied Wikipedia art is that the applied Wikipedia art does not expressly teach the method of treating a subject with a corneal injury or scar by losartan and the concentration of losartan in terms of mg/ml and the use of eyedrop container and corticosteroid and the subject being a human. The deficiencies of Wikipedia are partially cured by Shibagaki et al.
Resolving the level of ordinary skill in the pertinent art.
Regarding the instant Claim 1 with respect to the lack of disclosing the
concentration of losartan in terms of mg/ml, Shibagaki.et al does teach that the amount of Compound C (100mg) (losartan) to be added, an eye drop at a concentration of 0.003% (w/v), 0.01% (w/v), 0.03% (w/v), 0.05% (w/v), 0.3% (w/v), 1 % (w/v)or 3% (w/v) can be prepared (see page 6, example 3, a paragraph#0095). From this information, it seems reasonable for the skilled artisan in the art to be able to estimate the concentration of losartan in terms of mg/ml. Therefore, the prior art is still relevant to the claimed invention.
Regarding the instant Claim 10 and 24 with respect to the lack of disclosing the
use of an eyedrop container and the subject being a human, the prior art are silent about them. However, Shibagaki.et al does mention the preparation of an eye drop at a concentration of 0.003% (w/v), 0.01% (w/v), 0.03% (w/v), 0.05% (w/v), 0.3% (w/v), 1 % (w/v)or 3% (w/v) (see page 6, example 3, a paragraph#0095). This passage can imply indirectly the use of the eye drop container for the different concentrations of the compound C. Therefore, the prior art does teach inherently the use of the eyedrop container.
Furthermore, regarding the subject being a human, the prior art are silent about the subject being a human, the prior art does mention that male SD rats were employed for the test for therapeutic effect on corneal damage (see page 5 , a paragraph#0075). This means in the future that it can be possible to use the eye treatment for the therapeutic effect on the human subject having corneal damage. Therefore, the prior art does teach indirectly the possibility of the eye treatment for the human with the corneal damage.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Shibagaki.et al discloses a method for treating keratitis comprising administering to a patient a therapeutically effective amount of losartan and water along with a preservative.
Although Shibagaki.et al does not teach the use of corticosteroid for treating keratitis, Wikipedia does teach that corticosteroid can be used for the medical condition such as keratoconjunctivitis (see page 3, the first paragraph).
So, if the skilled artisan in the art had desired to improve the efficiency of the treatment of keratitis, it would have been obvious to the skilled artisan in the art before the effective filing date of the claimed invention to be motivated to combine Wikipedia’s corticosteroid with losartan in the Shibagaki et al treatment-method. The is because the skilled artisan in the art would expect such combined methods to be feasible and successful as guidance shown in the prior art.
6. Claim(s) 32, 35, 48, 54, 72-77 are rejected under 35 U.S.C. 103 as being unpatentable over Rodgers et al (WO 2014/179440) in view of Wang et al ( The FASEB Journal. 2020;34:10505–10515).
Determination of the scope and content of the prior art
Rodgers et al discloses a method comprising delivering a system to a human subject as in claim 48 (see page 16, aparagraph#1) wherein said subject has an eye that comprises a corneal injury as in claims 32 and 77 (partially) (see page 1, paragraph#4) (clear corneal full-thickness tunnel was created in the same manner as in human phacoemulsification surgery) (see page 17, a paragraph# 2) in the following procedure:
Animals are allocated to the treatment group were treated with 1 drop (approximately 50 pl) of the active drug (0.03%1 or 0.3°- Nle3 A(l-7) in 2% hydroxyethyl cellulose in 0.05 M phosphate buffer, pH 6.5) under investigation instilled into the conjunctival sac daily (using a dropper) as in claims 35 and 75 throughout the follow-up period(see page 17, a paragraph# 2) and a drug agent (an amount effective of an angiotensin peptide being administered at a concentration of about 0.01 %, to about 1'% or about 0.03% to about 03%) on a weight (mg)/volume (ml) basis (see page 3 ,a paragraph#4) to treat the eye injury (see page 1, a paragraph# 3) and water (a topical formulation is selected from the group consisting of hydrogels (water)( see page 3, a paragraph# 1 ) and an active agent selected from the group consisting of artificial tears as in claim 54 (soothing agent) (see page 3 , a paragraph#3),
The current invention, however, differs from the prior art in that a drug agent being losartan and an existing, stromal and posterior corneal scar are unspecified in the prior art.
Wang et al teaches that losartan treatment as in claim 32 (partially) can partially reverse pro-inflammatory activity in ACE2 depleted corneal epithelial cells (see page 8, figure 7). Also, Wang et al does disclose treating a corneal injury with a composition comprising an ACE2 receptor antagonist (treatment of corneal epithelial cells with the AT1R antagonist, losartan could rescue the phenotype (see page 8, column 1, a paragraph# 2).
Ascertainment of the difference between the prior art and the claims
The difference between the instant application and the applied Rodgers et al art is that the applied Rodgers et al art does not expressly teach losartan as the drug agent and an existing, stromal and posterior corneal scar . The deficiencies of Rodgers et al is partially cured by Wang et al.
The difference between the instant application and the applied Wang et al art is that the applied Wang et al art does not expressly teach the method of treating a subject with an existing, stromal and posterior corneal scar by losartan and the use of eyedrop container and water and soothing agent and a human subject. The deficiencies of Wang et al are partially cured by Rodgers et al.
Resolving the level of ordinary skill in the pertinent art.
Regarding the instant Claims 72-74, 76 with respect to the lack of disclosing the existing, stromal and posterior corneal scar, the prior art is silent about them. However, Rodgers et al does teach generally the method comprising delivering a system to a subject with the corneal injury (see page 17, a paragraph# 2). It is well-known knowledge in the art that a corneal injury can cause a scar in the stroma (the middle and thickest layer) and the posterior (back) layers of the cornea. When a deep injury, sharp trauma, or severe infection damages past the outer surface, the eye heals with irregular tissue. This creates a lasting cloudy spot or scar. Furthermore, the existing corneal scar is the long-term consequence or healed result of a prior corneal injury, infection, or surgery, rather than an active injury itself.
So, if the skilled artisan in the art had desired to apply the method comprising delivering a system to a subject with the existing, stromal and posterior corneal scar by using losartan, It would have been obvious to one of ordinary skill in the art at the time to combine the composition of Rodgers formulated for topical delivery to the cornea with Wang’s corneal scar treatment comprising the ACE2 receptor antagonist losartan for the advantage of preventing corneal scarring with soothing eyedrops.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Rodgers et al expressly discloses the method comprising delivering a system to a human subject having the corneal injury by using an amount effective of an angiotensin peptide in the eyedrop sac or container.
Although Rodgers et al does not disclose losartan as an ACE2 receptor antagonist, Wang does teach treating a corneal injury with a composition comprising losartan as an ACE2 receptor antagonist (treatment of corneal epithelial cells with the AT1R antagonist. It
could rescue the phenotype(see page 8, Column 1, a paragraph# 2).
Both prior art are closely related to each other with respect to the method comprising: delivering a system to a human subject with the corneal injury by using the angiotensin peptide vs. the method of treating a corneal injury with a composition containing losartan.
So, if the skilled artisan in the art had desired to apply the method comprising delivering a system to a subject with the corneal injury including a corneal scar by using losartan as an alternative to the angiotensin peptide, it would have been obvious to the skilled artisan in the art before the effective filing date of the claimed invention to be motivated to incorporate Wang’s corneal scar treatment comprising the ACE2 receptor antagonist losartan into the composition of Rodgers formulated for the topical delivery to the cornea for the advantage of preventing corneal scarring with soothing eyedrops. The is because the skilled artisan in the art would expect such combined methods to be feasible and successful as guidance shown in the prior art.
Conclusion
Claims 1, 10, 13, 19, 24,, 31, 32, 35, 48, 54, 72-77 are rejected.
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/TAYLOR V OH/Primary Examiner, Art Unit 1625 8/20/2026
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