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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application is a 371 of PCT/KR2021/009824 filed on 07/28/2021, which claims domestic benefit to US provisional application no. 63/057,992 filed on 07/29/2020.
Status of the Claims
The claim amendments and remarks filed on 01/05/2026 is acknowledged. Claims 1, 5, and 8 are amended. Claims 2, 6, and 9 are cancelled.
Accordingly, claims 1, 3-5, 7-8, and 10-12 are pending and being examined on the merits herein.
Withdrawn Rejections
The 35 USC 102 rejection over Elmfeldt for claims 1-2, 4-8, and 11-12 and over Ferrari for claims 1-3, 8, 10, and 12 are withdrawn because these rejections relied upon administering felodipine, however felodipine is now removed from the recited list of compounds in the amended claims. Furthermore, the cancellation of claims 2 and 6 renders the rejection over these claims moot.
The 35 USC 103 rejection over Gidari for claims 1-2, 8-9, and 12 because this rejection relied upon administering cyproterone acetate, however cyproterone acetate is now removed from the recited list of compounds in the amended claims. Furthermore, the cancellation of claim 9 renders the rejection over this claim moot.
The nonstatutory double patenting rejecting over copending Application No. 18/262,721 for claims 1-12 are withdrawn because this rejection relied upon substituting the recited compounds in ‘721 with feldopine, however felodipine is now removed from the recited list of compounds in the amended claims. Furthermore, the cancellation of claims 2, 6, and 9 renders the rejection over these claims moot.
The following grounds of rejection are new as necessitated by Applicant’s amendments.
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, 3-5, 7-8, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhuo et al. (PNAS, 2012 in PTO-892) in view of Lee et al. (Journal of Neurochemistry, 2009 in PTO-892) and Sakamoto et al. (Experimental Eye Research, 2009 in PTO-892).
Zhuo discloses that Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with a maternal inheritance that is characterized by degeneration of retinal ganglion cells and the optic nerve with sudden onset and usually severe bilateral loss of central vision (see second paragraph left column first page). Zhuo discloses several proposed pathogenetic mechanisms including complex I dysfunction with decreased ATP synthesis, elevated levels of oxidative stress, and impaired glutamate transport, all leading to retinal ganglion cell (RGC) dysfunction and ultimately apoptotic cell death (see last paragraph left column first page).
Zhuo discloses a mouse model of LHON, in which oxidative stress rather than energy deficiency appeared to be an important factor contributing to LHON (see last paragraph left column through first paragraph middle first page, and FIG. 1). As seen in FIG. 1 and disclosed by Zhuo, the flow of electrons that normally pass along the electron transport chain may be disturbed in LHON, leading to the generation of superoxides that cause oxidative stress and lead to biomolecule damage and ultimate RGC death and optic neuropathy (see second paragraph left column second page). Zhuo discloses that oxidative damage has been proposed to participate in the pathophysiology of several neurodegenerative diseases, such as Parkinson disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and age-related macular degeneration (see first paragraph middle paragraph second page). Zhuo therefore suggests treatments to reduce oxygen toxicity such as using antioxidants including Vitamins D and E, co-enzyme Q10, Trolox, and others for slowing, preventing, or restoring vision loss in LHON (see last paragraph middle column through first paragraph right column second page).
Although Zhuo suggests the use of antioxidant compounds to reduce oxidative stress in LHON, Zhuo does not disclose the use of one of the recited compounds in the instant claims such as cilnidipine.
Lee discloses the neuroprotective effect of cilnidipine by scavenging free radicals and activating the phosphatidylinositol 3-kinase pathway (see Abstract).
Lee discloses that oxidative stress is a common mechanism implicated in neuronal cell death, making it an important factor in several neurological disorders (see second paragraph left column page 91).
Lee demonstrates in FIGS 2-4 (pages 94-95) that treatment with cilnidipine increased the viability of H2O2-injured neuronally differentiated PC12 (nPC12 cells) in a concentration-dependent manner and reduced free radical levels in H2O2-injured nPC12 cells in a dose-dependent manner. Furthermore, Lee demonstrates in FIG. 5 (pages 96-97) that in addition to reducing oxidative stress, cilnidipine may also have additional protective effects by activating the PI3K pathway. Here, Cilnidipine treatment increased the expression of p85aPI3K (phosphatidylinositol 3-kinase) phosphorylated Akt, phosphorylated glycogen synthase kinase-3 (pGSK-3b), and heat shock transcription factor (HSTF-1) which are proteins related to neuronal cell survival, and decreased levels of cytosolic cytochrome c, activated caspase 3, and cleaved poly (ADP-ribose) polymerase (PARP), which are associated with neuronal cell death, in H2O2-injured nPC12 cells (see Abstract).
Lee concludes that cilnidipine mediates its neuroprotective effects by reducing oxidative stress, enhancing survival signals (e.g., PI3K, phosphorylated Akt, pGSK-3b, and HSTF-1), and inhibiting death signals from cytochrome c release, caspase 3 activation, and PARP cleavage. Here, the neuroprotection effects of cilnidipine disclosed by Lee meets the limitation of enhancing cell viability, reducing mitochondrial ROS, intracellular ROS, and mitochondrial stress recited in instant claims 1 and 10, as well as increasing lifespan and enhancing neuronal activity recited in instant claims 4 and 11 because Lee demonstrates that cilnidipine enhances cell viability of neuronal PC12 cells and scavenges free radicals which reduces oxidative stress within the mitochondrial of the neuronal cells.
Sakamoto discloses the histological protection by cilnidipine against neurotoxicity induced by ischemia-reperfusion in rat retina (see Abstract).
Sakamoto discloses that cell death of retinal ganglion cells and inner retinal neurons is a characteristic of retinal ischemia-reperfusion injury and while mechanisms of cell death induced by retinal ischemia are not completely understood, endogenous substances such as glutamate, oxygen free radicals, nitric oxide, and calcium are among the pathological causes of ischemia-reperfusion injury (see first paragraph left column page 974). Sakamoto discloses that glutamate is the principal excitatory neurotransmitter in the central nervous system, including retina, and that stimulation of glutamate receptors such as N-methyl-D-aspartate (NMDA) by excessive amounts of glutamates is toxic and is thought to be one of the mechanisms of neuronal cell death induced by glaucoma (see right column page 974).
Sakamoto discloses that while cilnidipine was shown to have neuroprotective effects, its utility against retinal diseases such as glaucoma or central retinal vein occlusion are not clear (see third paragraph left column page 975). Therefore, Sakamoto tested the effects of cilnidipine on retinal injury. Here, Sakamoto demonstrates in FIG. 2-3 on pages 977-978, FIG. 7 on page 980, and FIG. 9 on page 981 that morphometric evaluation at 7 days after ischemia reperfusion showed that treatment with cilnidipine (100 mg/kg, i.v. or 0.5 pmol/eye, intravitreous injection) prior to ischemia dramatically reduced the retinal damage. Furthermore, treatment with cilnidipine (100 mg/kg, i.v.) reduced the retinal damage induced by intravitreous NMDA, but not NOC12.
Sakamoto concludes that cilnidipine reduces Ca2+ influx via N-type Ca2+ channels after NMDA receptors activation and then protects neurons against ischemia–reperfusion injury in the rat retina in vivo, and that cilnidipine may be useful as a therapeutic drug against retinal diseases which cause neuronal cell death, such as glaucoma and central retinal vessel occlusion (Abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to have treated the LHON disclosed in Zhuo by administering an effective amount of cilnidipine as disclosed in Lee and Sakamoto to arrive at the claimed invention. One of ordinary skill in the art could have combined these prior art elements according to known methods to yield predictable results because Zhuo discloses that oxidative stress is an important factor contributing to LHON and suggests treatments to reduce oxygen toxicity for slowing, preventing, or restoring vision loss in LHON. Furthermore, Lee demonstrates that cilnidipine can reduce oxidative stress by scavenging ROS in neuronal cells, and Sakamoto demonstrates that cilnidipine significantly reduced retinal damage from ischemia-reperfusion and suggests its use as a therapeutic in retinal diseases.
Lastly, any of the enhancing mitochondrial function events recited in instant claims 3-4, 10, and 11 would also flow naturally from following the suggestions of the prior art because the combined teachings described above provide guidance to administer an effective amount of cilnidipine to treat the same patient population (LHON patients), and as demonstrated in FIGS 1-2 and FIGS. 5-6 of the instant specification, cilnidipine provides these effects when administered to SH-SY5Y cells (FIGS 1-2), in a mitochondria stress assay (FIG. 5), and through TMRE-mediated mitochondrial membrane potential (FIG. 6).
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Response to Arguments
Applicant’s arguments filed on 01/05/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant presents arguments against Elmfeldt, Ferrari, and Gidari. However, these references are not cited in the new rejection, rendering Applicant’s arguments moot.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-5, 7-8, and 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18/262,721 (‘721) in view of Zhuo et al. (PNAS, 2012 in PTO-892), Lee et al. (Journal of Neurochemistry, 2009 in PTO-892), and Sakamoto et al. (Experimental Eye Research, 2009 in PTO-892).
The claims of ‘721 recite the same limitations as the instant application except the administered compounds of the instant invention. Furthermore, the claims of ‘721 do not recite the enhancing mitochondrial function event recited in instant claims 4 and 11.
The independent teachings of Zhuo, Lee, and Sakamoto are as described above.
It would have been prima facie before the effective filing date of the claimed invention to have substituted any one of the claimed compounds recited in ‘721 with the cilnidipine as disclosed by the combined teachings of Zhuo, Lee, and Sakamoto described above to arrive at the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because the claims of ‘721 recite the use of compounds for treating LHON by enhancing mitochondrial function such as enhancing cell viability and/or reducing mitochondrial ROS or intracellular ROS, and the combined teachings of Zhuo, Lee, and Sakamoto described above also suggests the use of cilnidipine for treating LHON by enhancing the same mitochondrial functions as described above. See MPEP 2144.06 section II.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed on 01/05/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant presents arguments against the secondary references (Elmfeldt and Gidari) used in the nonstatutory double patenting rejections. However, these references are not cited in the new rejection, rendering Applicant’s arguments moot.
Conclusion
No claim is found allowable.
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.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693