CTNF 18/690,492 CTNF 97575 The Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION 12-151 AIA 26-51 12-51 Status of Claims Claims 1-4, 6, 8, 10, 11, 15-17, 19-21, 24, 26, 29-31, and 33 are pending and under examination in this office action . Priority The instant application 18/690,492 filed on 03/08/2024, is a 371 of PCT/US2022/043063 filed 09/09/2022, which claims the benefit of priority to U.S. Provisional Application No. 63/242,192 filed 09/09/2021 . U.S. provisional application No. 63/242,192 only disclosed Example 1, verteporfin for glaucoma surgery without detailed experiment and result. Application ‘192 does not disclose any subject matter related to treating fibrosis or reducing risk of developing fibrosis in a subject after an ocular injury. Information Disclosure Statement The information disclosure statements (IDS) submitted on 09/10/2024, is in compliance with the provisions of 37 CFR1.97. Accordingly, the information disclosure statements are being considered by the examiner. Drawing 06-22-03 The drawings are objected to because in Fig. 6, ALK +10ug/mL verteporfin are recited twice in different rows under Procedure. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Claim Rejections - 35 USC § 112(a) 07-30-01 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. 07-31-01 Claims 1, 3, 4, 6, 8, 10, 17, 19-21, 24, 26, 29-31, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors at the time the application was filed, had possession of the full scope of instantly claimed invention. MPEP 2163.02 states “ Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought , the inventor was in possession of the invention, and that the invention, in that context, is whatever is now claimed.” Instant claims are directed to method of treating fibrosis or reducing risk of developing fibrosis or scarring in an eye of a subject after an ocular injury or ocular surgery. Instant specification discloses embodiments wherein verteporfin was administered once and evaluated for reducing scarring in a rabbit model of glaucoma filtration surgery and corneal injury (See Example 5 and 6, Fig 5 and 6). However, instant specification does not disclose any working example with verteporfin treating fibrosis in an eye. Instant Spec does not disclose any working example wherein verteporfin is administered after ocular injury (e.g. chemical exposure) as recited in claim 3 or other ocular surgery as recited in claim 17. Although instant specification discloses administration of verteporfin in general (See [0070-[0071], instant Spec does not disclose any working example wherein verteporfin is administered at multiple dose no more frequently than biweekly as recited in claims 6, 8, 19-21, 26, and 31. In the absence of sufficient working examples of verteporfin administered to different subject , an ordinary skilled in the art would not know if instant claimed multiple administration of verteporfin would be effective for treating fibrosis or reducing the risk of developing fibrosis or scarring after any ocular injury or ocular surgery in full scope. Instant claims 8, 19 and 26 recite the verteporfin is administered no more frequently than biweekly which is considered as negative limitation. Instant specification does not disclose any working example wherein multiple dose of verteporfin are administered with longer period than biweekly or within the period of bi-week. According to MPEP §2173.05(i): “Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims…The mere absence of a positive recitation is not basis for an exclusion. Any claim containing a negative limitation which does not have basis in the original disclosure should be rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.” The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. Claim 1-4, 6, 8, 10, 11, 15-17, 19-21, 24, 26, 29-31, and 33 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 1 recites a method of treating fibrosis or reducing risk of developing fibrosis or scarring in an eye of a subject after an ocular injury or ocular surgery. Claim 26 recite a method of treating fibrosis in ocular tissues comprising identifying a subject who has fibrosis in ocular tissues or is at risk of developing fibrosis or scarring in ocular tissues after a previous ocular surgery or ocular injury. The phrase “risk of developing fibrosis or scarring” is relative and subjective. Instant specification does not disclose quantifiable measurement to identify the risk of developing fibrosis or scarring and quantifiable degree or to what extent would be considered as reducing the risk of developing fibrosis or scarring. The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired. MPEP 2173.05(b) IV states “ A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014)”. Claims 2-4, 6, 8, 10, 11, 15-17, 19-21, 24, 29-31, and 33 are rejected due to dependency on claims 1 and 26, respectively. Claim 11 recites a broad range of “0.001mg to 10mg” of verteporfin , and “0.01mg to 1mg” which is the narrower statement of the range/limitation. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 8, 19 and 26 recite the verteporfin is administered no more frequently than biweekly. It’s not clear what’s the time period between two adjacent verteporfin administration, 3 weeks or 3 month, or 1 year. An ordinary skilled in the art would not know what’s the frequency of administering verteporfin. Claims 15 and 19 recite verteporfin is administered before, during, or after an ocular surgical procedure. The contradictory limitation ‘before” and “after” are confusing. An ordinary skilled in the art would not know what’s the time period of administering verteporfin. Instant claims 24 and 33 recite administration of the verteporfin is performed in conjunction with bleb needling or other manipulation of the conjunctiva. It’s not clear what other manipulation of the conjunctiva refer to. An ordinary skilled in the art would not be appraised the scope of instant claims. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 1 is rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Zhang et al. (J. Cell Mol Med, 2020, 24(21):12390-124002020, Applicant’s IDS dated 09/10/2024, "YAP is essential for TGF-β-induced retinal fibrosis in diabetic rats via promoting the fibrogenic activity of Müller cells") . Zhang discloses a study to investigate the role of Yes-associated protein (YAP)activation and proliferation of retinal Müller cells in the development of TGF-β-induced retinal fibrosis(See whole article). Zhang teaches TGF-β-induced fibrosis can be reversed by inhibiting YAP signaling, suggesting that suppression of YAP can inhibit or reverse retinal fibrosis (See abstract, page 12399, left column). Zhang teaches verteporfin (a YAP inhibitor) is intraperitoneally administered (100 mg/kg) every other day for 4 weeks and verteporfin suppressed retinal fibrogenesis in diabetic rats (See abstract, page 12391, right column). As such, Zhang anticipates instant claimed invention . 07-15 AIA Claim s 1-2, 4, 11, 15-17 and 24 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Stasi et al.(Acta Ophthalmologica Scandinavica, 2006, 84: 661-666, https://doi.org/10.1111/j.1600-0420.2006.00677.x, Photodynamic treatment in a rabbit model of glaucoma surgery) . Stasi discloses a study of postoperative verteporfin photodynamic treatment (PDT) as an adjunct to glaucoma filtration surgery in rabbits, wherein wound healing in glaucoma surgery is modulated with verteporfin (See whole article). Stasi teaches conjunctival blebs in the experimental group administered with verteporfin remained elevated while blebs in the control groups ( e.g. laser without verteporfin) were flat, scarred and vascularize (See page 663, Fig. 3-5). Stasi teaches postoperative administering photosensitizer (i.e. verteporfin) occlude newly formed capillaries, thus delaying or preventing maturation of the scar tissue (See page 664, third column, last para) and concludes PDT can be used to prolong bleb survival in a glaucoma surgery (See page 665, third column, last para). Stasi teaches verteporfin was administered/infused at 0.4mg /mL (2 mg/ml diluted to 5mL)(See page 662, third column, last para) (which reads on instant claim 11). Stasi collectively teaches a method of preventing/reducing the risk of developing scarring with verteporfin photodynamic treatment (PDT) as an adjunct to glaucoma filtration surgery. Thus, Stasi anticipates instant claimed invention . 07-15 AIA Claim s 1-2, 4 and 15-17 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Futakuchi et al. (Invest Ophthalmol Vis Sci, 2018, 59(7):3069-3078, Applicant’s IDS dated 09/10/2024, "YAP/TAZ Are Essential for TGF-β2-Mediated Conjunctival Fibrosis") . Futakuchi teaches Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) is essential in TGF b2–mediated conjunctival fibrosis (See whole article). Futakuchi explicitly teaches verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects on conjunctival fibrosis by suppressing TGF-b2-YAP/TAZ-Smad signaling(See page 3069, Conclusion; page 3073, left and right column; page 3075, left column; Figures 3-6). Futakuchi teaches verteporfin inhibition of YAP/TAZ might prevent conjunctival fibrosis and improve the outcome after glaucoma filtration surgery (See page 3069, Conclusion; page 3077, left column). As such, Futakuchi anticipates instant claimed invention . 07-15 AIA Claim s 1, 3, 4, 6 and 11 are rejected under 35 U.S.C. 102( a)(1) and (a)(2 ) as being anticipated by Mascharak et al. (WO2021021607A2, hereafter “Mascharak’ 607”, published on 02/04/2021) . The applied reference has a common applicant/ assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). Mascharak’ 607 discloses a method for preventing scarring, promoting Engrailed-1 lineage-negative fibroblasts(ENF) mediated healing of a wound in a subject, comprising administering an effective amount of a Yes-Associated Protein YAP inhibitor (e.g. verteporfin) (See abstract, page 2, line 1; page 59, clauses 1-75; claims 1-14). Mascharak’ 607 teaches embodiments wherein the method is to reduce or prevent scarring resulting from burns, scalds, grazes, abrasions, cuts and other incisional wounds, surgery and conditions of fibrotic dermal scarring, hypertrophic scarring, keloid scarring, corneal and other ocular tissue scarring (See page 38, lines 4-10). Mascharak’ 607 teaches En-1 activation was associated with adoption of a pro-fibrotic phenotype, modulating YAP signaling promotes regenerative En-1- negative fibroblasts (ENFs) mediated wound healing, decreases fibrosis and reduces incisional scar formation (See page 52, lines 14-34; page 57, lines 12-32). Regarding the administration limitation of instant claims, Mascharak’ 607 teaches verteporfin-treated wounds demonstrated reduced fibrosis and increased cellularity by 2 weeks (See page 53, line 3-4) and administering multiple doses of YAP inhibitor/verteporfin at an effective amount ( e.g. 0.1mg/ ml to 5 mg/ml) over a period of time, e.g. 14 days, 30 days or more, or 90 days or more (See page 19, lines 2-18; page 7 line 12-13; page 55, lines 1-4). Mascharak’ 607 explicitly teaches verteporfin ( 30ul, 1 mg/ml) was injected locally to the wound(See page 41, line 24, 29). Mascharak’ 607 collectively teaches a method of reducing fibrosis and scarring with verteporfin in ocular tissue. Thus, Mascharak’ 607 anticipates instant claimed invention . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-4, 6, 8, 10, 11, 15-17, 19-21, 24, 26, 29-31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Stasi et al.(Acta Ophthalmologica Scandinavica, 2006, 84: 661-666, https://doi.org/10.1111/j.1600-0420.2006.00677.x, Photodynamic treatment in a rabbit model of glaucoma surgery), in view of Rosa ( US20180236035A1, Applicant IDS dated 09/10/2024) and Visudyne ® label 2016 (verteporfin for injection, revised in April 2016) . The collective teachings of Stasi is elaborated in preceding 102 rejection and applied as before. Stasi collectively teaches a method of wound healing/reducing scarring with verteporfin photodynamic treatment (PDT) as an adjunct to glaucoma filtration surgery. Stasi is silent about ocular injury of claim 3 and multiple administration limitation. Rosa teaches a method of treating or preventing an ocular disease/ disorder or condition (e. g. ocular injury, subretinal fibrosis, etc.), comprising administering a pharmaceutical composition comprising verteporfin to the subject (See abstract, [0011], [0023], [0025], [0171]). Rosa teaches embodiment that prevent or reduce scar formation while simultaneously enhancing ocular healing, wound repair in ocular disease/conditions including ocular injury(e.g. chemical burn)(See [0154], [0157]-[0158]) Regarding instant claim 2, 4 and 15-17, Rosa discloses embodiments wherein the ocular surgery is trabeculectomy (filtering surgery), i. e. glaucoma surgery, and other ocular surgery (See [0168]). Please note glaucoma surgery is considered as an ocular surgery that causes a corneal/conjunctival wound. Regarding claim 3, Rosa discloses embodiment wherein the ocular injury is caused by foreign bodies or a chemical exposure: "Severe scarring is another common result of chemical burns. The therapeutic compositions of the present invention are designed to accelerate the healing of the corneal erosion caused by the chemical burns, to prevent stromal necrosis and infection of the eye, and to reduce corneal scarring and thereby restore/preserve corneal transparency"(See [0151]- [0158]). Regarding claim 10, Rosa teaches various administration route, e.g. topical, subconjunctival, intravitreal, subretinal, or injection into the anterior chamber of the eye of a subject, etc.(See [0014]). Regarding the administration limitation of instant claims 6, 8, 19-21, 26, and 31, Rosa teaches optimization of administration time and frequency to determine whether two injections are more effective (See [0292]), and further teaches administration time and frequency may be adjusted to the individual requirements depending on the disease or disorder being treated, and the extent and severity thereof (See [0272]). Visudyne ® label 2016 teaches verteporfin injection is photosensitizer indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Visudyne ® label teaches reconstituted verteporfin at 2 mg/mL (See Dosage). Visudyne ® label teaches retreatment of age-related macular degeneration (AMD) was allowed every 3 months if fluorescein angiograms showed any recurrence or persistence of leakage (See page 12, Clinical Study). Visudyne ® label 2016 teaches the average number of AMD with photodynamic therapy treatment per year were 3.5 in the first year, 2.4 in the second, 1.3 in the third, 0.4 in the fourth and 0.1 in the fifth year (See page 13). Based on the extension study of verteporfin in photodynamic therapy in pathologic myopia (VIP-PM), the average number of treatments per year were 3.5 in the first year after diagnosis, 1.8 in the second, 0.4 in the third, 0.2 in the fourth and 0.1 in the fifth (See page 13, Pathologic Myopia). It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug. Verteporfin is FDA approved treatment for age-related macular degeneration AMD and other ocular disease with good safety profile. It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to further explore use of verteporfin for other ocular disease/condition, e.g. wound healing/reducing scarring in the eye as taught by Stasi and Rosa, based on the combined teachings of prior art, together with general knowledge of ocular disease /conditions. An ordinary skilled would be motivated to further explore verteporfin use in wound healing following ocular surgery/injury, and reasonably expect verteporfin would reduce risk of scarring based on Stasi’s teaching. Dose adjustment (administration timing, frequency, etc.) based on patient’s condition is routine practice in the art as shown in Visudyne ® label. A skilled artisan would know to evaluate the treatment outcome in the patient and adjust the subsequent verteporfin treatment accordingly. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art and general knowledge of ocular disease /conditions. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary . 07-21-aia AIA Claim s 1-4, 6, 8, 10, 11, 15-17, 19-21, 24, 26, 29-31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Visudyne ® label 2016 (verteporfin for injection, revised in April 2016), in view of Futakuchi et al. (Invest Ophthalmol Vis Sci, 2018, 59(7):3069-3078, Applicant’s IDS dated 09/10/2024, "YAP/TAZ Are Essential for TGF-β2-Mediated Conjunctival Fibrosis") and Rosa ( US20180236035A1, Applicant IDS dated 09/10/2024) . The collective teachings of Visudyne ® label 2016 and Rosa are elaborated in preceding 103 rejection and applied as before. Visudyne ® label 2016 teaches verteporfin for treating AMD and other ocular disease. Visudyne ® label is silent about verteporfin for treating fibrosis and/or reducing risk of fibrosis or scarring in an eye of a subject. As elaborated in preceding 102 rejection and applied as before, Futakuchi explicitly teaches verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects on conjunctival fibrosis by suppressing TGF-b2-YAP/TAZ-Smad signaling. Futakuchi teaches verteporfin inhibition of YAP/TAZ might prevent conjunctival fibrosis and improve the outcome of glaucoma filtration surgery. It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug. Verteporfin is FDA approved treatment for age-related macular degeneration AMD and other ocular disease with good safety profile. It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to further explore use of verteporfin for other ocular disease/condition, e.g. reducing risk of conjunctival fibrosis and/ or scarring taught by Futakuchi and Rosa, based on the combined teachings of prior art, together with general knowledge of ocular disease /conditions. An ordinary skilled would be motivated to further explore verteporfin use in treating/preventing ocular fibrosis /or scarring, and reasonably expect verteporfin would reduce risk of developing fibrosis or scarring after glaucoma filtration surgery or other ocular surgery based on Futakuchi’s teaching. Dose adjustment (administration timing, frequency, etc.) based on patient’s condition is routine practice in the art. A skilled artisan would know to evaluate the treatment outcome in the patient and adjust the subsequent verteporfin treatment accordingly. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art and general knowledge of ocular disease /conditions. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary . 07-21-aia AIA Claim s 1-2, 4, 6, 8, 10, 11, 15-17, 19-21, 24, 26, 29-31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kahook (WO 2013/059095 A1), in view of Futakuchi et al. (Invest Ophthalmol Vis Sci, 2018, 59(7):3069-3078, Applicant’s IDS dated 09/10/2024, "YAP/TAZ Are Essential for TGF-β2-Mediated Conjunctival Fibrosis") and Visudyne ® label 2016 (verteporfin for injection, revised in April 2016) ., Kahook discloses a method of treating glaucoma or other ocular disease comprising administering photosensitizer (i.e. verteporfin) to a subject with damaged ocular cells, wherein trabecular meshwork cells may be targeted to improve fluid outflow or reduce the risk of developing progressive visual field defects (See abstract, page 2, lines 15-26; claims 1- 70). Kahook teaches PDT has been shown to reduce bleb failure by decreasing fibrosis, presumably by targeting local neovascularization in a rabbit model of glaucoma filtration surgery (See page 27, lines 17-18). Kahook teaches administering photosensitizer (i.e. verteporfin) topically or intraocular injection (See page 31, lines 4-5; claims 12 and 13). Kahook teaches various dose of verteporfin (1-25ug/ml) in various cell viability assay (See page 25, lines 13-32). Kahook teaches embodiments wherein verteporfin (2ug/mL 10ug/ml) is administered via intraocular injection(See Example 1) (which reads on instant claim 10 and 11). Kahook further teaches dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. The treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the subject undergo maintenance therapy to prevent the recurrence of the disease state, wherein the compound is administered in maintenance doses, once or more daily (page 40, lines16-30). Kahook is silent about verteporfin for treating conjunctival fibrosis. As elaborated in preceding 102 rejection and applied as before, Futakuchi explicitly teaches verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects on conjunctival fibrosis by suppressing TGF-b2-YAP/TAZ-Smad signaling. Futakuchi teaches verteporfin inhibition of YAP/TAZ might prevent conjunctival fibrosis and improve the outcome after glaucoma filtration surgery. It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug. Verteporfin is FDA approved treatment for age-related macular degeneration AMD and other ocular disease with good safety profile. It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to further explore use of verteporfin for other ocular disease/condition, e.g. reducing risk of conjunctival fibrosis and/ or scarring by Futakuchi, based on the combined teachings of prior art, together with general knowledge of ocular disease /conditions. An ordinary skilled would be motivated to further explore verteporfin use in treating/preventing ocular fibrosis, and reasonably expect verteporfin would reduce risk of developing fibrosis after glaucoma filtration surgery or other ocular surgery based on Futakuchi’s teaching. Dose adjustment (administration timing, frequency, etc.) based on patient’s condition is routine practice in the art. A skilled artisan would know to evaluate the treatment outcome in the patient and adjust the subsequent dose of verteporfin treatment accordingly. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art and general knowledge of ocular disease /conditions. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary . Conclusion No claims are allowed. 07-96 AIA The prior art made of record and not relied upon is considered pertinent to applicant's disclosure : Strong et al. (US 9226917B2) Strong teaches a method of photodynamic therapy comprising administering verteporfin for treatment of eye conditions characterized by unwanted choroidal neovasculature CNV (e.g. wet age-related macular degeneration) (See abstract, Col. 3 and 4; claims 1-21). Strong teaches the therapy is repeated multiple times following first treatment depending on the assessment, e.g. about every 55 days, about every three months , or at least once twice or three times for a period for about at least 6 months or more (e.g. 12month) (See Col. 25, lines 11-26; Examples 1- 3; Col. 31, claims 8-10 and 12). Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /L.M./Examiner, Art Unit 1628 /JARED BARSKY/Primary Examiner, Art Unit 1628 Application/Control Number: 18/690,492 Page 2 Art Unit: 1628 Application/Control Number: 18/690,492 Page 3 Art Unit: 1628 Application/Control Number: 18/690,492 Page 4 Art Unit: 1628 Application/Control Number: 18/690,492 Page 5 Art Unit: 1628 Application/Control Number: 18/690,492 Page 6 Art Unit: 1628 Application/Control Number: 18/690,492 Page 7 Art Unit: 1628 Application/Control Number: 18/690,492 Page 8 Art Unit: 1628 Application/Control Number: 18/690,492 Page 9 Art Unit: 1628 Application/Control Number: 18/690,492 Page 10 Art Unit: 1628 Application/Control Number: 18/690,492 Page 11 Art Unit: 1628 Application/Control Number: 18/690,492 Page 12 Art Unit: 1628 Application/Control Number: 18/690,492 Page 13 Art Unit: 1628 Application/Control Number: 18/690,492 Page 14 Art Unit: 1628 Application/Control Number: 18/690,492 Page 15 Art Unit: 1628
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