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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6 March 2024; 8 April 2024; 4 September 2024; 15 January 2025; and 24 July 2025 are acknowledged and considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is 29 words, which is below the range of the range of 50 to 150 words in length. Correction is requested. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in ¶ [0057] lines 8 and 9, ¶ [0068] line 15, and ¶ [0074] line 6. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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.
Claims 1-3, 9, 36-37, 41-42, 48, 52-54 as being obvious over Ishii (JP 2004250347A) in view of Yamamoto et al. ("N- and L-type calcium channels blocker cilnidipine ameliorates neuropathic pain." (793) 66-75. Published December 15, 2016 (IDS (3/6/2024) - #520)). The original and the Google machine translated version of Ishii is provided. The citations discussed below with page, paragraphs, and line numbers are to the corresponding English translated version of Ishii.
Ishii teaches a therapeutic for diseases caused by retinal ischemia (page 1, [Summary]). The therapeutic is cilnidipine, and was taught to inhibit retinal damage in a rat model of transient retinal ischemia. Further, the diseases that may resulting from retinal ischemia are glaucoma, diabetic retinopathy, hypertensive retinopathy, macular degeneration, etc. (page 1, [Solution]). The teachings further describe non-limiting examples of administration of cilnidipine. Oral administration via tablets, pills, emulsions, etc. and parenteral administration via intravenous, sprays, eye drops, eye ointments, etc. (page 4, lines 37-41). Ishii’s teachings also state that glaucoma can cause reduction in visual field due to the death of retinal neuron and that the main cause is organic damage from increases in intraocular pressure caused by impaired aqueous humor outflow. Furthermore, neuronal toxicity can be caused by glutamate released from nerve cell terminals due to retinal ischemia (page 2, lines 40-46). A disease model was described wherein cilnidipine was administered intravenously, 15 min before retinal ischemia. The results showed that cilnidipine treatment inhibited the reduction of thickness of the retinal layers (page 6, lines 41-47) of ischemia induced mice.
Ishii does not explicitly teach cilnidipine alleviating neuropathic pain.
Yamamoto et al. teaches that nerve injury leads to the persistent activation of sensory afferents, which triggers neuropathic pain with symptoms including allodynia and hyperalgesia (page 66, Introduction). Yamamoto et al. states: "Cilnidipine produced potent inhibition of neuropathic pain without affecting normal pain sensation, which was distinct from ω-conotoxin GVIA and nicardipine. The i.t. treatment with cilnidipine (61–203 pmol) dose-dependently attenuated mechanical allodynia and hyperalgesia in spared nerve injury mice (Fig. 1), whereas the mechanical threshold in naïve mice was not affected. In in vivo electrophysiology experiments, spinal application of cilnidipine significantly inhibited the basal C-fiber evoked field potentials in the spared nerve injury rat model (Fig. 7C), but not in naïve animals (Fig. 4A)” (page 72, first column, first indented ¶).
Yamamoto et al. does not explicitly teach administering cilnidipine to the eye of a subject.
Ishii and Yamamoto et al. are considered to be analogous art to the claimed invention because they are in the same field of administering cilnidipine to treat subjects that have eye diseases or neuropathic pain. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) to identify cilnidipine as a treatment for eye pain or eye diseases, through the teachings of Ishii, towards subjects exhibiting neuropathic pain in view of the teachings of Yamamoto et al. A PHOSITA would have had a reasonable expectation of success in applying a method of treating eye pain or eye disease via cilnidipine treatment to the eye of the subject (e.g., by way of eye drops) to achieve reduction in neuropathic pain in said subject.
Regarding claims 1-2, Ishii teaches administering cilnidipine to a subject via administration through the eye by way of eye drops and eye ointments (see above citations). Yamamoto et al. teaches that cilnidipine ameliorates neuropathic pain. It would have been prima facie obvious to a PHOSITA to apply a method of administering cilnidipine to subjects that have eye pain or neuropathic pain.
Regarding claim 3, Ishii teaches that cilnidipine can be used to treat various diseases that occur from retinal ischemia and reperfusion injury, such as glaucoma (see above citations), and that cilnidipine may be administered to the eyes of a subject via eye drops (see above citations).
Regarding claim 9, Ishii teaches that cilnidipine can be administered to the eye of a subject by way of eye drops. Furthermore, Ishii teaches that one of the diseases modeled as a result of ischemia was glaucoma. It would have been prima facie obvious to a PHOSITA to apply a method of administering cilnidipine to treat a subject having glaucoma and have a reasonable expectation of success in treating said subject.
Regarding claims 36-37, Ishii teaches inhibited thickness reduction (or inhibited thinning) of the retina as a result of cilnidipine treatment to ischemia induced mice. Yamamoto et al. teaches that cilnidipine ameliorates neuropathic pain (see above citations). It would have been prima facie obvious to a PHOSITA to expect a reduction in neuropathic eye pain as result of cilnidipine treatment.
Regarding claim 41, Yamamoto et al. teaches that cilnidipine ameliorated neuropathic pain without affecting normal pain sensation (see above citations).
Regarding claim 42, Ishii teaches that cilnidipine is effective in the treatment or prevention of ischemia and was found to inhibit thinning of the retina. It would have been prima facie obvious to a PHOSITA that as a result of cilnidipine treatment visual acuity of a subject would improve because of the inhibition of thinning of the retina of a subject.
Regarding claim 48, Ishii teaches that cilnidipine was diluted to 0.1% prior to administration of a subject (page 6, lines 22-24). Therefore, it would be prima facie obvious to choose a concentration around this percentage to administer to a subject (MPEP §2144.05(I)).
Regarding claims 52 and 54, Ishii teaches that cilnidipine, can be administered topically (page 4, line 40) or as a solution (page 5 lines 28-29).
Claims 4-6 are rejected as being obvious over Ishii (JP 2004250347A), in view of Schwartz (PCT Application Publication No. WO 2010039531 A1).
As discussed above, Ishii teaches a method of administering cilnidipine to subjects having eye diseases (e.g., glaucoma, diabetic retinopathy, hypertensive retinopathy, macular degeneration, etc.). Ishii also teaches that cilnidipine can be administered in combination with other drugs (page 5, lines 35-37).
Ishii does not teach administering cilnidipine to subjects possessing dry eye disease, uveitis, or optic neuritis.
Schwartz teaches compositions of resolvin compounds and methods of treatment for various diseases including ophthalmic conditions (page 5, line 19). The teachings state that the resolvin compounds can be co-administered for ophthalmic conditions with “antiglaucoma drugs” (page 64, line 7). The ophthalmic conditions include, “dry eye disease” (page 61, line 25), “uveitis” (page 62, line 20), and “optic neuritis” (page 62, line 13).
Schwartz does not explicitly teach administering cilnidipine to treat ophthalmic conditions.
Ishii and Schwartz are considered to be analogous art to the claimed invention because they are in the same field of administering treatments to subjects possessing ophthalmic conditions. Therefore, it would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention, to apply a method of administering an anti-glaucoma drug like cilnidipine as taught by Ishii, on subjects possessing dry eye disease, uveitis, and optic neuritis in view of Schwartz. Through the collective teachings a PHOSITA would be motivated to administer cilnidipine as a mono-therapy or combination therapy towards the ophthalmic conditions. Accordingly, claims 4-6 are rendered prima facie obvious.
Claims 7 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii (JP 2004250347A) in view of Sakamoto et al. (“Histological protection by cilnidipine, a dual L/N-type Ca2+ channel blocker, against neurotoxicity induced by ischemia–reperfusion in rat retina” Experimental Eye Research 88 (2009) 974–982. Published 5 May 2009), further in view of Milburn (PCT Application Publication No. WO2006078941 A2 (IDS (1/15/2025) - #92) evidenced by Microvascular Cranial Nerve Palsy (https://web.archive.org/web/20210923184320/https://www.nanosweb.org/files/Patient%20Brochures/English/2021/Microvascular_Cranial_Nerve_Palsy.pdf, accessed 29 January 2026, published 23 September 2021) (“MCNP”).
As discussed above, the teachings of Ishii established cilnidipine as an effective treatment for various forms of diseases that materialize as a result of retinal ischemia reperfusion injury.
Ishii does not teach that cilnidipine is a calcium channel blocker and that it can be used to treat microvascular cranial nerve palsy. Ishii also does not teach intraocular administration of cilnidipine.
Sakamoto et al. teaches that cilnidipine is a dual N-type and L-type calcium channel blocker (page 975, first column, second indented ¶). It also teaches that cilnidipine maybe a useful treatment against retinal diseases which cause neuronal cell death such as glaucoma and central retinal vessel occlusion (Abstract, last sentence). Furthermore, Sakamoto et al. teaches that cilnidipine can be administered via intravitreous injection (Abstract, third sentence).
Sakamoto et al. does not explicitly teach that cilnidipine can be used to treat microvascular cranial nerve palsy.
Milburn teaches that a combination therapy with calcium channel blockers along with their claimed sirtuin activators (page 54, line 23; page 60, lines 17-18) can be administered to treat neurodegenerative disorders including “microvascular cranial nerve palsy” (page 53, line 25). For clarity, Milburn refers to “microvascular cranial nerve palsy” by way of “diabetic neuropathy includes third nerve palsy,” a specific type of microvascular cranial nerve palsy as evidenced by MCNP (page 2).
Milburn does not explicitly teach administering cilnidipine to subjects with neurodegenerative disorders.
Ishii, Sakamoto et al., and Milburn are considered to be analogous art to the claimed invention because they are in the same field of administering treatments to subjects possessing ophthalmic conditions like microvascular cranial nerve palsy. Therefore, it would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention to apply a method of administering a dual N-type and L-type calcium channel blocker, like cilnidipine, intraocularly (or intravitreally) through the collective teachings of Ishii and Sakamoto et al., to subjects possessing microvascular cranial nerve palsy in view of Milburn. A PHOSITA would have had a reasonable expectation of success in administering a dual type calcium channel antagonist like cilnidipine to subjects possessing microvascular cranial nerve palsy in combination with sirtuin activators in view of Milburn. Accordingly, claims 7 and 53 are rendered prima facie obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Ishii (JP 2004250347A) in view of Saunders (WO 2009158646 A1).
As discussed above, the teachings of Ishii established cilnidipine as an effective treatment for various forms of diseases that materialize as a result of retinal ischemia reperfusion injury.
Ishii does not explicitly teach a method of administering cilnidipine for the treatment of hyphema.
Saunders teaches that hyphema can lead to an increase in intraocular pressure (page 67, line 2). Furthermore, Saunders teaches that a combination therapy of histone acetylase transferase (HAT) inhibitors and an effective amount of an agent for treating glaucoma (page 72, ¶ 1, line 7) can be utilized in a particular embodiment to treat or prevent ocular disorders or secondary conditions associated with ocular disorders, which includes hyphema.
Saunders does not explicitly teach administering cilnidipine as agent for treating glaucoma.
Ishii and Saunders are both considered to be analogous art because they are in the same field of a method of administering antiglaucoma compositions to treat a disease like hyphema. Therefore, it would have been prima facie obvious to a PHOSITA to incorporate the teachings of Ishii, to apply a method of administering cilnidipine, in view of the teachings of Saunders, to administer cilnidipine alone or in combination to treat hyphema. Accordingly, claim 8 is rendered prima facie obvious.
Claims 38-39, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii (JP 2004250347A) in view of Sakamoto et al. (“Histological protection by cilnidipine, a dual L/N-type Ca2+ channel blocker, against neurotoxicity induced by ischemia–reperfusion in rat retina” Experimental Eye Research 88 (2009) 974–982. Published 5 May 2009), further in view of Goldstein (EP 3,861,985).
As discussed above, the teachings of Ishii established that cilnidipine is an effective treatment for glaucoma and that one of the risk factors of glaucoma is higher intraocular pressure. Furthermore, it is inherent with the teachings of Ishii that if cilnidipine is an effective treatment for glaucoma, then reduction of eye pain will be present in subjects that take cilnidipine. Sakamoto et al. teaches that cilnidipine is a dual N-type and L-type calcium channel blocker (see above citations).
Ishii and Sakamato et al. do not teach the use of ophthalmic tests to measure the effect of administering cilnidipine to a human subject.
Goldstein teaches the use of biodegradable intracameral implants to treat human subjects wherein, the implants contain an active pharmaceutical ingredient (API). A class of API’s taught are calcium channel blockers (¶ [0288], line 40). The teachings further disclose, applanation tonometry being the method of care to determine intraocular pressure and is the international gold standard when proper technique is used (page 8, ¶ 0063, lines 18 - 20; page 79, ¶ 0492, lines 14-15). The API’s of interest in Goldstein were prostaglandins, which have been shown to lower intraocular pressure (page 2, ¶ [0005], lines 30-32). The implant with the prostaglandin API, elicited a reduction of intraocular pressure by at least 20% (page 31, ¶ [0230], lines 5-14). Goldstein also teaches that best corrected visual acuity is typically tested utilizing Early Treatment Diabetic Retinopathy Study (ETDRS) for subjects prior to performing tests like applanation tonometry (page 76, ¶s 0476-0477 lines 50 - 58; page 77, ¶s 0478-0479, lines 7-16).
Goldstein does not explicitly teach administering cilnidipine to treat subjects having glaucoma.
Ishii and Goldstein are considered analogous art because they are in the same field of measuring the effects of administering a glaucoma treatment. Therefore, it would have been prima facie obvious to a PHOSITA to apply a method of administering cilnidipine to treat a subject with glaucoma as taught by Ishii, and measure the outcome of said treatment through tests like applanation tonometry or ETDRS. In view of the collective teachings, a PHOSITA would be motivated to discern the outcome of cilnidipine treatment through the tests taught by Goldstein. While Goldstein is focused on prostaglandin API’s for delivery to the eye of a human subject, a PHOSITA would have been motivated to try calcium channel blockers in view of the collective teachings of Sakamoto et al. and Goldstein, to treat subjects having glaucoma. A PHOSITA would have had a reasonable expectation of success in reducing intraocular pressure using the calcium channel blocker cilnidipine.
With respect to claims 38-39, Ishii teaches applying a method of administering cilnidipine to ischemia induced subjects and that the outcome of administration, was inhibition of thinning of the retina (see above citations). Goldstein teaches the test of choice to measure the outcome of a treatment is applanation tonometry. It would have been prima facie obvious to a PHOSITA to have a reasonable expectation of success in observing reduction in intraocular pressure through applanation tonometry via administration of cilnidipine to a subject.
With respect to claim 43, Ishii teaches that cilnidipine is effective in the treatment or prevention of ischemia and was found to inhibit thinning of the retina. Goldstein teaches, best corrected visual acuity is typically tested utilizing the ETDRS test (see above citations). It would have been prima facie obvious to a PHOSITA that as a result of cilnidipine treatment, visual acuity of a subject would improve through the teachings of Ishii, and would be motivated to test the efficacy of treatment via the ETDRS test in view of Goldstein.
Additional Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Koganei et al. ("Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage Dependent Calcium Channel Blocker" Biol. Pharm. Bull 32 (10) 1695 - 1700. Published August 5, 2009) teaches that cilnidipine does not impart anesthetic effects on subjects. Cummings (PCT Application Publication No. WO2018031922A1) teaches the use of cilnidipine for treatment with subjects possessing dry eye disease. Abelson (US Patent No. 5,435,998) teaches the treatment of low-tension glaucoma by topical administration of calcium channel blocking agents. Poole (US Patent No. 5,540,227) teaches a method to examine the cornea of a patient’s eye using applanation tonometry.
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623