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. DETAILED ACTION The office acknowledges Applicants filing of the response on 12/18/2025 in regards to the restriction election requirement dated 6/18/2025. Applicants have elected N-{4-[2-(2-chloro-3-flu or ophenyl)acetamido]pyridine-2-yl}-N-(4-fluoropheny1)aceta m ide and ocular pain as species for examination. Applicants argue that multiple groups can be searched and examined together without undue burden. In response, this application is a 371 international application and Applicants are reminded that search burden is not relevant in a national stage application. The restriction requirement is made final. For the sake of compact prosecution, allowable subject matter was discussed with Attorney of record, Peter Corless on Jan 16 2026 and 2/10/2026 and an agreement was reached. Applicants requested additional time to file some documents and none has been filed to date. Hence this office action is being mailed. Claims 1-14, 17-20 are pending. Claims 12, 18 are withdrawn from further consideration pursuant to 37 C.F.R. 1.142(b), as being drawn to non-elected subject matter. Claims 1-11, 13, 14, 17, 19-20 are examined based on the merits herein. that multiple groups can be sear Application Priority This application filed 12/22/2022 is a National Stage entry of PCT/EP2021/ 067714, International Filing Date: 06/28/2021, PCT/EP2021/067714 Claims Priority from Provisional Application 63202797, filed 06/24/2021, claims foreign priority to 20183306.8, filed 06/30/2020, claims foreign priority to 21151884.0, filed 01/15/2021. Information Disclosure Statement The information disclosure statement(s) (IDS) filed on 12/12/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner. Claim Rejections - 35 USC § 112 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. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: 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 of carrying out his invention. Claims 1-11, 13, 14, 17, 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for the synthesis of compounds of claim 2, its use in the treatment of conditions with the P2X4 inhibitors by providing in vitro data with assays does not reasonably provide enablement for the prophylaxis of the conditions as claimed . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims. The instant specification fails to provide information that would allow the skilled artisan to practice for the prevention of lung injury as claimed. To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated: The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 ( BdApls 1986) at 547 the court recited eight factors: the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention, 5) the state of the prior art, 6) the relative skill of those in the art, 7) the predictability of the art, and 8) the breadth of the claims. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons: (1), (4) The breadth of the claims: The instantly claimed method is directed to: The dependent claims are limited to the use of specific P2X4 inhibitors of formula 1 , its stereoisomers, a tautomer, N-oxide, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and the mammal being human. The claims are broad in scope in regards to ( i ) the P2X4 inhibitors (ii) conditions to be treated (iii) subjects to be treated (can be any mammal). As per claim 2, the instant method use P2X4 compounds, its stereoisomers, a tautomer, N-oxide, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. (2),(3): The nature of the invention, state and relative skill level: The instant specification teach “ The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/immune processes specifically including monocytes, macrophages, mast cells and microglia cells ”. “ Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain ” . [0004]. EP2597088A1 describes P2X4 receptor antagonists and a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain [0005]. There is no reference in the state of the art about the use of P2X4 antagonists for the treatment of for the treatment or prophylaxis of dry eye syndrome and in particular dry eye, ocular neuropathic pain, ocular trauma and post-operative ocular pain, and particularly the use of substituted N- phenylacetamides of general formula (I) as described and defined herein [0007]. Dry eye syndrome, also known as dry eye disease, is a common condition characterized by insufficient tear production or rapid evaporation of tears, leading to symptoms such as burning, itching, and a gritty feeling in the eyes. Dry eye is a condition that affects your tear film, the three layers of tears that cover and protect the surface of your eyes (See Cleveland Clinic, https://my.clevelandclinic.org/health/ diseases/24479-dry-eye 2025). Neuropathic or nociplastic ocular pain (NOP) is a condition characterized by a group of long-lasting eye pain symptoms that are caused by nerve problems (See NORD, 2026, Neuropathic/ Nociplastic Ocular Pain - Symptoms, Causes, Treatment | NORD ). According to Cleveland Clinic, eye pain can be caused by various factors including infections, contact lenses, allergies, toxins, inflammation, increased eye pressure etc. (See https://my.clevelandclinic.org/health/symptoms/17796-eye-pain , 2022). Ocular trauma is a major cause of ocular morbidity and a leading cause of monocular visual loss. It is estimated that over 2 million eye injuries occur in the USA each year (See Retina (Fifth Edition), Volume Three, 2013, Page 1647). Ocular trauma includes any damage to the eye or the structures around it. This can range from a minor scratch on the surface of the eye to a serious injury that threatens your sight (See https://marlton.refocuseyedoctors.com/article/ocular-trauma/ , 2026). The relative skill of those in the art is high, that of an MD or PHD. (5) Predictability of the art: Despite the advanced training of practitioners in the art, it is still impossible to predict from the specification and prior art that dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain can be prevented completely from occurring again. It is noted that prophylaxis is defined as ‘ action taken to prevent disease, especially by specified means or against a specified disease ‘. Applicants define in the specification, prevention, i.e. prophylaxis (See printed publication, [0353]). The examiner maintains that absent demonstration from applicant demonstrating prevention of the claimed eye conditions one would not be able to ascertain if indeed said prevention occurs. Prevention requires the recited method to be completely effective in all patients at all times. It is respectfully pointed out that a method of preventing the diseases or disorders claimed means that the compounds or compositions are administered to subjects that do not have such diseases or disorders. The purpose is to prevent the condition before occurring but not to treat after it has occurred. Furthermore, the definition of "to prevent" and the “act of preventing" embraces the complete 100% inhibition. Thus, the burden of enablement in the assertion of this claim is much higher than would be the case of enabling the treatment of the condition and is not achieved. The claim is very broad insofar as they suggest that the subject will not experience the disease or disorder ever again when taking the claimed agent; that should one get the disease, it will not worsen; or that following its treatment, it will not recur. While such "prevention" might theoretically be possible under strictly controlled laboratory conditions, as a practical matter it is nearly impossible to achieve in the "real world" in which patients live. It is well established that "the scope of enablement various inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839 (1970). Absent a mechanistic link between the method steps and the observed effect, the pharmaceutical and medical treatment arts are highly unpredictable. Most progress is established through empirical and anecdotal evidence as to the efficacy of certain treatments. Once a mechanistic link has been established between the method and the mechanism of action become more predictable. However, many uncertainties can still exist even when the mechanism of action is known. For example, factors such as the bioavailability, pharmacokinetic profile, and potency of a compound can still be uncertain even if it can be expected to be active in disease models. It is not predictable from the prior art or from the specification’s teachings that dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain will not occur in the subjects treated with the P2X4 inhibitors or its composition as claimed. (6)/(7) The amount of direction or guidance provided and the presence or absence of working examples: The specification provides guidance towards synthesis of compounds of claim 2 and in vitro data towards P2X4 inhibition using HEK cell F LIP R assay , F LIPR Method for Rat P2X4 1321N1 a strocytoma c ells with select compounds of claim 2 (Table 10). T here is no guidance in the specification or in the art for the prophylaxis of dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain. 8) The quantity of experimentation necessary: Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the agents as claimed can be useful in the prophylaxis of dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain as inferred by the claims and contemplated by the specification. To practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success. Claim Rejections - 35 USC § 112 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. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: 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 of carrying out his invention. Claims 1-11, 13, 14, 17, 19-20 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 inventor(s), at the time the application was filed, had possession of the claimed invention. The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated: "To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir.1997); In re Gostelli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966." Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398. Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents" of the University of California v. Eli Lilly & Co. the court stated: "A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers , 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398. The MPEP states that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli , the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli , 872, F.2d at 1012, 10 USPQ2d at 1618. The Guidelines for Examination of Patent Applications Under 35 USC 112, "Written Description" Requirement (Federal Register, Vol. 66, No. 4, pg. ll05, column 3), in accordance with MPEP § 2163, specifically state that for each claim drawn to a genus the written description requirement may be satisfied through sufficient description of a representative number of species by a) actual reduction to practice; b) reduction to drawings or structural chemical formulas; c) disclosure of relevant, identifying characteristics (i.e. structure) by functional characteristics coupled with a known or disclosed correlation between function and structure. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention (Federal Register, Vol. 66, No. 4, p. ll05, 3rd column, 3rd paragraph). Below is such comparison. Scope of claims: The scope is very broad in regards ( i ) the P2X4 inhibitors (ii) conditions to be treated (iii) subjects to be treated (can be any mammal). The dependent claims are limited to the use of specific P2X4 inhibitors of compound of formula 1 , its stereoisomers, a tautomer, N-oxide, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and the mammal being human. Scope of disclosure and reduction to practice : As per the specification , “ The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/ immune processes specifically including monocytes, macrophages, mast cells and microglia cells ”. “ Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain ” [0004]. EP2597088A1 describes P2X4 receptor antagonists and a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain [0005]. There is no reference in the state of the art about the use of P2X4 antagonists for the treatment of for the treatment or prophylaxis of dry eye syndrome and in particular dry eye, ocular neuropathic pain, ocular trauma and post-operative ocular pain, and particularly the use of substituted N- phenylacetamides of general formula (I) as described and defined herein [0007]. The specification provides guidance and in vitro data towards synthesis of compounds of claim 2 and P2X4 inhibition using HEK cell FLIPR assay, FLIPR Method for Rat P2X4 1321N1 Astrocytoma Cells with select compounds of claim 2 (Table 10). The state of the art teach in regards to the conditions to be treated as follows: Dry eye syndrome, also known as dry eye disease, is a common condition characterized by insufficient tear production or rapid evaporation of tears, leading to symptoms such as burning, itching, and a gritty feeling in the eyes. Dry eye is a condition that affects your tear film, the three layers of tears that cover and protect the surface of your eyes (See Cleveland Clinic, https://my.clevelandclinic.org/health/ diseases/24479-dry-eye 2025). Neuropathic or nociplastic ocular pain (NOP) is a condition characterized by a group of long-lasting eye pain symptoms that are caused by nerve problems (See NORD, 2026, Neuropathic/ Nociplastic Ocular Pain - Symptoms, Causes, Treatment | NORD ). According to Cleveland Clinic, eye pain can be caused by various factors including infections, contact lenses, allergies, toxins, inflammation, increased eye pressure etc. (See https://my.clevelandclinic.org/health/symptoms/17796-eye-pain , 2022). Ocular trauma is a major cause of ocular morbidity and a leading cause of monocular visual loss. It is estimated that over 2 million eye injuries occur in the USA each year (See Retina (Fifth Edition), Volume Three, 2013, Page 1647). Ocular trauma includes any damage to the eye or the structures around it. This can range from a minor scratch on the surface of the eye to a serious injury that threatens your sight (See https://marlton.refocuseyedoctors.com/article/ocular-trauma/ , 2026). As to N-oxide, an amine oxide, also known as amine-N-oxide and N-oxide, is a chemical compound that contains the functional group R3N+-0-, an N-0 coordinate covalent bond with three additional hydrogen and/or hydrocarbon side chains attached to N. Applicants’ do not provide guidance or support in the specification for making of the N-oxide compounds of formula 1. In summary, the scope of the P2X4 inhibitors used is very large. As per claim s 2, 13 the instant method use P2X4 compounds, its stereoisomers, tautomer , N-oxide, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Representative number of Examples: The data provided is limited to the synthesis of compounds of claim 2 (See Tables 8-9) and in vitro data of select compounds of formula 1 of claim 2 towards P2X4 inhibition using HEK cell FLIPR assay, F LIPR Method for Rat P2X4 1321N1 a strocytoma c ells with select compounds of claim 2 (Table 10). There is no evidence of using representative samples of all types of P2X4 inhibitor compounds as they include all types of agents including antibodies, a miRNA, a ribozyme, an aptamer etc. Further there is no guidance or data or examples for making and using of the N-oxides of any of the P2X4 compounds of formula 1 in the specification. Correlation between structure and function: The structure is the P2X4 inhibitor and the function is the treatment or prophylaxis of dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain in a mammal in need thereof. P2X4 inhibitor encompasses hundred s of chemical compounds and other entities, for example: antibodies ( US 20170166634 ) or a siRNA, a shRNA, a miRNA, a ribozyme, an aptamer, an antisense nucleic acid molecule, a small molecule and modified versions of these inhibitors (See US 20240075036 ). I t is not understood what specific structures of the P2X4 inhibitor(s) will lead to the treatment/prophylaxis of the disorders as claimed. The chemical, physical and pharmacological properties of the compounds or other agents are influenced based on the structural differences. A correlation between structure and function in achieving the property of wherein administration of the compound or agent or pharmaceutical therapeutic composition of P2X4 in the treatment of dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain . Even with select P2X4 listed in instan t claim 2, the chemical structures vary . There is substantial variation within the genus of the P2X4 inhibitors to be used and one must describe a sufficient variety of species to reflect the variation within the genus. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved". See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Due to the unpredictable nature in the pharmaceutical arts, one of ordinary skill in the art cannot predict from the in vitro data provided in the specification for select compounds of claim 2 or from the prior art that a ny P2X4 inhibitor or its pharmaceutical composition and/or it N-oxide will treat the claimed disorders. A skilled artisan would not be able to extrapolate from the in vitro data provided for select compounds of formula 1 of claim 2 to in vivo for any and all P2X4 compounds or its N-oxides in treating the disorders claimed in any mammal subject in need thereof. Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.” The specification provides insufficient written description to support the genus encompassed by the claim, Vas-Cath Inc. Mahurkar , 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Thus, the specification fails to provide adequate written description for the use of the P2X4 compounds or its N-oxides in the treatment of dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma or post-operative ocular pain as claimed and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT UMAMAHESWARI RAMACHANDRAN whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-9926 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F- 8:30-5:00 PM (PST) . 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, FILLIN "SPE Name?" \* MERGEFORMAT Kortney Klinkel can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 5712705239 . 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. /Umamaheswari Ramachandran/ Primary Examiner, Art Unit 1627