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. Election/Restrictions 2. Applicant’s election without traverse of Group I , claims 1-3, 5, 6, 8, 12, 18, 24-31, 33, 35, 36, 39-43, and 45-48 , drawn to a method of treating an ophthalmic condition , in the reply filed on December 22, 2025, is acknowledged with appreciation. 3. Claims 49-50 ( Group II , drawn FILLIN "Enter claim identification information" \* MERGEFORMAT to a method of reducing an immune response ), are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. 4. Applicant additionally made the following species elections: (1) 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one as the single Bruton’s Tyrosine Kinase inhibitor compound (claim 2) ; (2) dry eye disease as the single ophthalmic condition to be treated; (3) microemulsion as the single dosage form; (4) IL-1 b as single inflammatory cytokine to be reduced; and (5) rheumatoid arthritis as the single autoimmune or inflammatory disease. 5. The non-elected species are presently withdrawn as directed to non-elected subject matter , i.e., claims 5, 8, 12 , and 26 also withdrawn . 6. Claims 1 -3, 6, 18, 24 , 25, 27- 31, 33, 35, 36, 39-43, and 45-48 are under examination with the elected species and are the subject of this office action. Information Disclosure Statement 7. The information disclosure statement (IDS) submitted on December 22, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith. Claim Rejections - 35 USC § 112(b) 8. 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. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the appl icant regards as his invention. 9. Claim s 24, 25, 27 , 28-31 and 47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 10. Claim 24 is rejected for reciting “ wherein the compound is administered as nanoparticles comprising the compound ,” because it is not clear if the claim refers to the BTK inhibitor compound itself in the form of nanoparticles or if Applicant is attempting to expand claim 1 to embrace a formulation comprised of nanoparticles that each comprise the BTK inhibitor compound. 11. Claim 2 5 is rejected for reciting “ wherein the compound is in a dosage form selected from a solution, suspension, emulsion, microemulsion, ointment, gel, hydrogel, drug delivery device, tablet, or capsule ,” because it the claim is attempting to expand claim 1 to embrace a dosage form compris ing the BTK inhibitor compound . 12. Claims 27 and 28 are rejected as being dependent upon and including all of the limitations of claim 25. 13. Claim 28 is rejected for reciting , “ wherein the sustained release, extended release, or controlled release dosage form comprises a pegylated BTK inhibitor ,” because it is not clear if the claim is referring to the BTK inhibitor of claim 1, or an additional as-yet unrecited BTK inhibitor. 14. Claim 29 is rejected for reciting “ wherein the compound is administered as particles that self-aggregate into a depot upon administration,” because it is not clear if the claim refers to the BTK inhibitor compound itself in the form of particles or to a formulation comprised of particles that each comprise the BTK inhibitor compound. 15. Claims 30 and 31 are rejected as being dependent upon and including all of the limitations of claim 29. 16. Claim 47 is rejected for reciting, “[t] he method of claim 46, wherein the auto-immune disease or inflammatory disease is … s pondyloarthropathy (such as HLA-B27 associated spondyloarthropathy) .” T he phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim Rejections - 35 USC § 112 (a) 1 7 . 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. 18 . Claim s 1 , 3, 6, 18, 24 , 25, 27 -31, 33, 35, 36, 39-43, and 45-48 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 , regarding the scope of Bruton’s Tyrosine Kinase inhibitors embraced by the claims . The claims contain 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. In particular, support cannot be found for the full scope of Bruton’s Tyrosine Kinase (BTK) inhibitors , as instantly recited in the claims . 1 9 . The MPEP §2163 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. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co. , 119 F.3d 1559 (Fed. Cir. 1997), cert. denied , 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[ i ]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” ( Id. ), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar , 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the Applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result, i.e., “ Bruton’s Tyrosine Kinase (BTK) inhibitor.” But the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” 20 . I t is evident that the genus of drugs embraced by the claims has substantial variance , i.e., the scope of “ BTK inhibitor” as presently recited by claim 1 encompasses the entire class of compounds that inhibit the enzyme BTK , a crucial part of the B-cell receptor signaling pathway, including dozens of compound species, and potentially hundreds or thousands of compound species, including approved first generation (ibrutinib), approved second generation (acalabrutinib, zanubrutinib ), and approved third generation ( pirtobrutinib ) , as well as the 138 BTK inhibitor species listed in Table 1 (Specification at pages 11-35) . Further, the generic recitation of BTK inhibitor reaches through and embraces any future compounds possessing BTK antagonistic ability. Thus, the recite d genus embrace s hundreds or thousands of potential BTK inhibitor compounds that bear no structural resemblance to one another what-so-ever. It is noted that while the instant Specification lists 138 BTK inhibitors in Table 1, but fails to disclose the activity of any BTK inhibitor compounds whatsoever . 21 . While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re 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 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the instant disclosure does not adequately describe a genus embracing hundreds o r thousands of possible compounds . That is, the Specification does not disclose a sufficient variety of species to reflect the breadth of the possible compound selections recited in the claims . 22 . 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”) . Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of BTK inhibitor compounds and their salts, prodrugs, or derivatives thereof recited in the claims 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. As such, claim s 1 , 3, 6, 18, 24-31, 33, 35, 36, 39-43, and 45-48 are rejected. 23 . 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. 24 . Claims 1 - 3, 6, 18, 24 , 25, 27 -31, 33, 35, 36, 39-43, and 45-48 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of reducing inflammation in the eye and/or treating dry eye disease in a subject in need thereof comprising administering the BTK inhibitor 1-(4-(((6-amino-5- (4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one , and those embodied by the instant Specification, is not considered enabled for treating the full scope of ophthalmic conditions embraced by the claims comprising administering any/ all of the other compound species encompassed by “ Bruton’s tyrosine kinase i nhibitor . ” The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. 25 . The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde , 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands , 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below 26 . Nature of the Invention : As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claimed invention is drawn to a method of treating any ophthalmic condition in a human subject in need thereof , comprising administering any BTK inhibitor to the human subject . 27 . The Relative Skill of those in the Art: Those practitioners who treat ophthalmic conditions (s) of any type (medical clinicians, ophthalmologists, pharmacists and/or pharmaceutical chemists) presumably would be highly skilled in the art. 28 . The State of the Prior Art and the Level of Predictability in the Art : As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” 2 9. As discussed above, the instantly claimed invention is drawn to a method of treating any ophthalmic condition in a human subject in need thereof , comprising administering any BTK inhibitor to the subject. 30 . At the time the instant application was filed, it would have been known by those of ordinary skill in the art that “ BTK inhibitor” includes the entire class of compounds that inhibit the enzyme BTK, a crucial part of the B-cell receptor signaling pathway, including dozens of compound species, and potentially hundreds or thousands of compound species, including approved first generation (ibrutinib), approved second generation (acalabrutinib, zanubrutinib ), and approved third generation ( pirtobrutinib ), as well as the 138 BTK inhibitor species listed in Table 1 (Specification at pages 11-35) . 31 . T he state of the art is that BTK inhibitors have demonstrated a wide range of therapeutic effects in benign and malignant hematological disorders with growing application in autoimmune disorders. “ However, overcoming resistance to BTKis remains a major issue. The three commonly used BTKis, namely ibrutinib, acalabrutinib, and zanubrutinib , work with covalent and irreversible binding with the downstream BTK domain. One of the common mechanisms of resistance to the covalent BTKis is through the C481 mutation. The non-covalent inhibitors offer hope for bypassing this resistance mechanism ,” ( Fares et al., Bruton’s Tyrosine Kinase Inhibitors: Recent Updates, International Journal of Molecular Sciences, p. 10, under “7. Future Discussions”). 32. The state of the art is that “ophthalmic conditions” encompasses a wide range of diseases and disorders that can affect vision, eye structure, and overall eye health , including cataracts ; glaucoma ; age-related macular degeneration ; diabetic retinopathy ; retinitis pigmentosa ; dry eye disease (s) including aqueous-deficient dry eye disease , hyperevaporative dry eye disease , or mixed aqueous-deficient and hyperevaporative dry eye disease , and Meibomian Gland Dysfunction (MGD) ; blepharitis ; conjunctivitis ; corneal injuries ; color vison deficiencies ; red eye ; uveitis (including non-infectious uveitis , anterior uveitis , posterior uveitis , and panuveitis ); ocular inflammation (including post-operative); corneal transplant ; ocular GVHD ; allergy ; allergic conjunctivitis ; non-allergic conjunctivitis; or infectious conjunctivitis. 33 . In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic effects of the above listed ophthalmic conditions , whether or not the ophthalmic condition is affected by the inhibition of Bruton’s Tyrosine Kinase would make a difference. As such, the Specification fails to enable the skilled artisan to use the instant method to treat the full scope of the ophthalmic conditions presently encompassed by the claim s . 34 . Even though certain of the instant compounds (specifically ibrutinib, acalabrutinib, Zanubrutinib, pirtobrutinib , and flixebrutinib (the compound of claim 2) ) may have been identified as having inhibitory activity against BTK , as a practical matter their use as therapeutic agents for reducing viability across the broad range of recited types of ophthalmic conditions as claimed, remains extremely unpredictable. It is noted that the pharmaceutical art generally is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court in In re Fisher , 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) held that, “in cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.'' In other words, the more unpredictable an area the more specific enablement is needed in order to satisfy the statute. In the instant case, it has not yet been established in the art that BTK inhibitory activity would be effective, or even desirable, across the broad range of recited ophthalmic conditions . 35 . Hence, in the absence of a showing of correlation between the full scope of treating any ophthalmic condition in a subject , currently encompassed by the language of claim 1, as capable of being treated by any BTK inhibitor, one of skill in the art is unable to fully predict possible results from the recited method for treating the broad scope of ophthalmic conditions recited in claim 1. There is no question that certain of Applicant’s instant compounds may play a role in future methods of treating some of the aforementioned ophthalmic conditions (specifically dry eye disease ). What is disputed is the claim that the full scope of recited BTK inhibitors could be taken by one skilled in the art at the time of filing and used as treatment for the full scope of ophthalmic conditions as embraced by the claims without undue experimentation. There is simply not enough evidence to be found in the literature suggesting tha t any/all BTK inhibiting compounds are capable of being used in the manner recited in claim 1, to treat each and every possible ophthalmic condition that is encompassed by the claim language. In essence, there is no absolute predictability in pharmacology, even with compounds whose properties have been determined, despite the extraordinarily high skill possessed by the ordinary artisan. 36 . The Amount of Direction Provided by the Inventor / Existence of Working Examples : The amount of direction provided by the Applicant is determined by the Specification and the working examples . In the instant case, the Specification fails to demonstrate in vitro or in vivo efficacy studies or the administration of any BTK inhibitor to treat any ophthalmic condition. 37 . The Scope or Breadth of the Claims : As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus , as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification 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 (Fed. Cir. 1993) (emphasis added). 38 . At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt , 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner , 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art. 39 . Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims . " Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd . (Fed. Cir. 1991). As noted by the court in In re Fisher , 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac , 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore , 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”. 40 . As to the first inquiry, as discussed above, the claims are drawn to a method of treating any ophthalmic condition in a human subject comprising administering any BTK inhibitor to the subject . Considering that the generic recitation of BTK inhibitor reaches through and embraces any future compounds possessing BTK antagonistic ability, it is evident that the claims are broad. T hus, the recite d genus embrace s hundreds or thousands of potential BTK inhibitor compounds that bear no structural resemblance to one another what-so-ever. It is noted that while the instant Specification lists 138 BTK inhibitors in Table 1, but fails to disclose the activity of any BTK inhibitor compounds whatsoever . 4 1 . T he various types of ophthalmic conditions have different causative agents, involve different cellular mechanisms, and differ in treatment protocol , even if they each occur in or around the eye . The argument that the ophthalmic conditions recited as treatable by the Applicants are all treat ed by inhibiting BTK activity is insufficient support that the claimed method of administering a BTK inhibitor has specific efficacy in current available form for treating all of the conditions presently encompassed by claim 1 . Applicant has simply not demonstrated that they have sufficient support for the treatment of the recited ophthalmic conditions comprising administering any compound that happens to have BTK inhibito ry activity. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below. 4 2 . Amount of Experimentation Necessary : In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims embrace administering any BTK inhibitor treat any ophthalmic conditions in a subject. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case , this complexity is exacerbated by the broadness of “ BTK inhibitor ” and the scope of ophthalmic conditions recited with respect to the disclosure since compounds that inhibit BTK encompasses hundreds or thousands of compound species (for example those listed in Table 1) , whereas the instant Specification fails to demonstrate wherein any compound species exert s the disclosed activity for treating any ophthalmic condition . Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds o r thousands of compounds encompassed by “ BTK inhibitor ” would exert the alleged activity based on the limited disclosure. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. 43 . After applying the Wands factors and analysis to claims 1 - 3, 6, 18, 24, 25, 27-31, 33, 35, 36, 39-43, and 45-48 , in view of the Applicant’s entire disclosure and the state of the art, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. It is suggest ed to limi t the scope of the ophthalmic conditions to be treated to those that are enabled by Applicants' disclosure, as well as limiting the scope of BTK inhibitors such that they bear a reasonable correlation with the disclosure . Claim Rejections - 35 USC § 103 44 . 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. 45 . 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. 46 . 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. 47 . Claims 1 -3, 6, 18, 25, 39-4 2 , 43, 45, and 4 6 -48 are rejected under 35 U.S.C. 103 as being unpatentable over FILLIN "Insert the prior art relied upon." \d "[ 2 ]" Babler et al., U.S . 2015/0182530 A1 in view of Hodous et al ., 2014/0162983 A . Claim 1 is drawn to a method of treating an ophthalmic condition (more specifically d ry eye disease ( claim 6 )) in a human subject in need thereof comprising: administering to the human subject an amount of a Bruton's Tyrosine Kinase (BTK) inhibitor compound effective to treat the ophthalmic condition in the human subject , more specifically the BTK inhibitor 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one , or a pharmaceutically acceptable salt thereof ( claim 2 )), wherein administering the BTK inhibitor reduces inflammation in an eye of the human subject ( claim 3 ) , a nd wherein the administering comprises topical administration to an eye of the human subject, intraocular injection to an eye of the human subject, intravitreal injection to an eye of the human subject, periocular administration to the human subject, oral administration to the human subject, or intravenous injection to the human subject ( claim 18 ) . 48 . Babler et al . teach a method of treating dry eye disease (an ophthalmic conditio n) in a patient in need thereof comprising topically administering a BTK inhibitor compound of Formula (I) to said patient: “… provided is a method of treating dry eye disease in a patient in need of such treatment comprising topically administering to the eye of said patient a BTK inhibitor. In one embodiment, a therapeutically effective amount of the BTK inhibitor is topically administered to the eye of the patient. ” (see paragraph [0007]). Babler et al . teach that dry eye disease is characterized by ocular surface inflammation (see paragraph [0002]), and autoimmunity: “[ i ] ncreasing evidence now indicates that chronic inflammation and autoimmunity play important roles in the pathogenesis and symptoms of DED ,” (see paragraph [0003]). Babler et al . teach that the BTK inhibitor compounds according to Formula (I), (column 36), and demo nstrate BTK kinase inhibitory activity of over 100 compounds according to Formula (I) in the Table in Example 1 (pages 60-61). 49 . Babler et al. do not teach the administration of Applicant’s instantly recited compound, 1-(4-((( 6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one , or a pharmaceutically acceptable salt thereof. 50 . Yet, Hodous et al. teach the administration of BTK inhibitors for the treatment of autoimmune diseases in humans (paragraph [0001]) and specifically teach the BTK inhibitor Compound A225: which is the same as Applicant’s instantly recited compound of claim 2 (see paragraph [0454]). 51 . As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to modify the method of Babler et al. by substituting Compound A225 for the BTK inhibitor of Formula (I), for the treatment of dry eye disease in a human subject in need thereof, with a reasonable expectation of success. And, as noted by the court in In re Font, 675 F.2d 297 (CCPA 1982), an express suggestion to substitute one equivalent component (i.e., an equivalent BTK inhibitor) for another is not necessary to render such substitution obvious. In the instant case, ( 1 ) the prior art element of Babler et al . performs the function specified in the claim with only insubstantial differences (administration of a BTK inhibitor for treating DED, characterized by inflammation and autoimmunity, in a subject in need thereof) ; ( 2 ) the claimed component (i.e. , Compound A225 aka flixebrutinib ) and its function was known in the art (BTK inhibitory activity) ; ( 3 ) a person of ordinary skill in the art would have recognized the interchangeability of the elements and could have substituted one known element for another; and ( 4 ) the results of the substitution would have been predictable , i.e., successful treatment of dry eye disease in a human subject in need thereof . 52. Regarding claim 3, wherein administering the BTK inhibitor reduces inflammation in an eye of the human subject , one of skill in the art before the effective filing date of the claimed invention would have reasonably expected that by administering the BTK inhibitor A225 for treating DED in a human subject in need thereof, wherein DED is characterized by inflammation, the symptom of inflammation is thereby treated. And, treating any disease is ipso facto treating the symptoms of said disease . Thus claims 1-3, 6, and 18 are prima facie obvious. Claim 25 is drawn to claim 1 and limits wherein the compound is in a dosage form selected from a solution, suspension, emulsion , microemulsion, ointment, gel, hydrogel, drug delivery device, tablet, or capsule . 53 . Babler et al . additionally teach dosage forms, i.e., “[t]he compounds of this disclosure will be administered in a topical formulation which can be liquids, suspensions, emulsion s, a nd the like, ” (see paragraph [0479]) . 54 . Thus, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat dry eye disease in a human subject in need thereof comprising administering a dosage form in the form of a suspension or emulsion comprising the BTK inhibitor A225 to the human subject in need of treatment, with a reasonable expectation of success. As such, claim 25 is prima facie obvious. Claim 39 is drawn to claim 1, wherein administering the compound reduces levels of inflammatory cytokines , wherein the inflammatory cytokines are selected from IL- 1 b , IL-6, INF- g , TNF- a , or a combination thereof ( claim 40 ). Claim 43 is drawn to claim 1, wherein the human subject has a marker of an ophthalmic condition selected from elevated inflammatory cytokines, elevated chemokines, elevated matrix metalloproteinases (MMPs), elevated toll-like receptor 2 (TLR2), elevated nuclear factor-kappa B (NF-KB), elevated tumor necrosis factor alpha (TNF- a ), or combinations thereof , more specifically wherein the inflammatory cytokines are selected from IL-1 b , IL-6, INF- g , TNF- a , or a combination thereof ( claim 45 ). Claim 41 is drawn to claim 1, wherein administering the compound reduces ocular surface APCs, maturation of APCs, or both , wherein the APCs are monocytes, macrophages, dendritic cells, B cells, or combinations thereof ( claim 42 ) . 55 . Babler et al . additionally teach that dry eye disease (DED) is characterized by elevated levels of inflammatory cytokines: “[ i ] ncreasing evidence now indicates that chronic inflammation and autoimmunity play important roles in the pathogenesis and symptoms of DED. It is thought that ocular surface inflammation is sustained by the ongoing activation and infiltration of pathogenic immune cells …. The dessication of the ocular surface creates a stress response that results in the secretion of inflammatory cytokines, such as IL-1 , TNFα and IL-6 , which in turn facilitate the activation and migration of resident antigen presenting cells ( APC ) toward the draining lymph nodes ” (see paragraph [0003]). 56 . Thus one of skill in the art before the effective filing date of the claimed invention would reasonably expect that DED is characterized by elevated levels of inflammatory cytokines including IL- 1, IL-6, and TNF- a , and that by administering the BTK inhibitor A225 to treat dry eye disease in a subject in need thereof, the levels of said inflammat ory cytokines are thereby reduced, which in turn results in a reduc tion of the ocular surface APCs that are activated by said inflammatory cytokines . And, treating any disease is ipso facto treating the symptoms of said disease . Therefore it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to treat DED in a human subject in need thereof, wherein said treatment resulted in a reduction of IL- 1, IL-6, and TNF- a , as well as ocular surface APCs in said subject. As such, claims 39 -42 are prima facie obvious. Claim 46 is draw to claim 1, wherein the human subject has an autoimmune disease or an inflammatory disease in addition to the ophthalmic condition, (more specifically wherein the auto-immune disease or inflammatory disease is rheumatoid arthritis ( claim 47 )). 57 . Hodous et al . additionally teach that the BTK inhibitors of the invention are intended for treating chronic inflammatory diseases, specifically naming rheumatoid arthritis (see paragraph s [0151] -[0152] ). 58 . As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer the BTK inhibitor compound A225 to treat dry eye disease in a human subject in need thereof, wherein the human subject is also suffering from rheumatoid arthritis, and would have had a reasonable expectation of success in said treatment. As such, claims 46 and 47 are prima facie obvious. C laim 48 is drawn to claim 1 and limits wherein the administering occurs at a frequency of three times a daily, twice daily, once daily, every other day, three times a week, twice a week, weekly, every two weeks, twice a month, monthly, every two months, or every three months 59 . Hodous et al. additionally teach administration: “[w] hen treating or preventing … inflammation or other proliferative diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage …, preferably given as a single daily dose…. This dosage regimen may be adjusted to provide the optimal therapeutic response , ” (see paragraph [0164]). 60 . And, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Optimization of parameters such as frequency of administration is a routine practice that would be obvious for a person of ordinary skill in the art to employ . 61 . Therefore it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to treat dry eye disease comprising administering the BTK inhibitor compound A225 to the human subject in need thereof, once daily, with a reasonable expectation of success. As such, claim 48 is prima facie obvious. 62 . Claims 24 and 27 -31 are rejected under 35 U.S.C. 103 as being unpatentable over FILLIN "Insert the prior art relied upon." \d "[ 2 ]" Babler et al., U.S . 2015/0182530 A1, in view of Hodous et al ., 2014/0162983 A, as applied to claims 1 -3, 6, 18, 25, 39-42, and 46-48 , above, and further in view of Meza-Rios et al ., Ophthalmol Ther (published May 7, 2020). Claim 1 is addressed in detail, above. Claim 24 is drawn to claim 1, wherein the compound is administered as nanoparticles comprising the compound , wherein the particles that self-aggregate into a depot upon administration ( claim 29 ), wherein the particles further comprise a polymer , wherein the polymer is selected from the group consisting of chitosan, gelatin, sodium alginate, albumin, poly-L-lactide (PLLA), poly(lactic acid) (PLA), poly(glycolic acid)(PGA), poly(lactic co-glycolic acid) (PLGA), polycaprolactone, poly(lactide co- caprolactone), poly(methyl methacrylates ), poloxamer, poly(ethylene glycol) (PEG), PEG-PLLA, PEG- PLGA, poly(methyl vinyl ether/maleic anhydride), cellulose acetate phthalate, and combinations thereof ( claim s 30- 31 ). Claim 27 is drawn to claim 1 and limits wherein the dosage form is a sustained release form, an extended - release form, a controlled release form, or a combination thereof , more specifically wherein the sustained release, extended release, or controlled release dosage form comprises a pegylated BTK inhibitor ( claim 28 ). 63 . Babler et al. in view of Hodous et al. suggest the treatment of dry eye disease in a human subject in need thereof comprising administer the BTK inhibitor compound A225 to said human subject, but do not teach wherein the compound is administered as nanoparticles that self-aggregate into a depot upon administration and wherein the particles further comprise a polymer . 64 . Yet, Meza-Rios et al . teach the advantages of employing nano particles for eye drug delivery, i.e ., “[ n ] an oparticles increased the solubility of hydrophobic drug, provided sustained drug release with reduced toxicity and improved efficacy, prolonged drug retention time, and enhancement of drug penetration through ocular barriers. ” (see Text Box on page 401). Meza-Rios et al . teach that in particular , polymeric n anomicelles are self-aggregating and are suitable for controlled and sustained drug delivery: “ Nanomicelles : Generated by the dispersion of amphiphilic molecules, consisting of hydrophobic and hydrophilic components in solution. Micelles are formed through self-assembly. They have relatively high stability, minimal cytotoxicity, and suitability for controlled and sustained drug delivery. Hydrophobic drugs may be incorporated into the cores of micelles. Polymeric micelles favor targeted therapy and sustained drug delivery owing to the high drug loading capacity of the inner core. ” (see Table 1 at page 405). 65 . Meza-Rios et al. go on to teach that the nanoparticles that are formed by self-assembly of a modified polymer comprising poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) , i.e ., comprising a PEG polymer chain attachment (pegylated), which meets the limitation of claim 28 : “ The general design was based in photo-targeted NPs that are formed by self- assembly of a chemically modified poly(ethylene oxide)–poly(D,L-lactic acid) (PEG-PLA) ,” (see page 410, left column, lines 6-9). 66 . As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to formulate the BTK inhibitor compound A225 in a dosage form comprising n an oparticles , in particular self-assembling nanomicelles , with the expected advantages of increased solubility, sustained drug release with reduced toxicity and improved efficacy, prolonged drug retention time, and enhancement of drug penetration through ocular barriers , for administration to a human subject suffering from dry eye disease , with a reasonable expectation of success. As such, claims 24 and 27-31 are prima facie obvious. 67 . Claims 33, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over FILLIN "Insert the prior art relied upon." \d "[ 2 ]" Babler et al., U.S . 2015/0182530 A1, in view of Hodous et al ., 2014/0162983 A, as applied to claims 1 -3, 6, 18, 25, 39-42, and 46-48 , above, and further in view of Pflugfelder et al. , J Ocul Pharmacol . Ther . (2017) . Claim 1 is addressed in detail, above. Claim 33 is drawn to claim 1, wherein T-cells in an eye of the human subject overexpress lymphocyte function-associated antigen (LFA-1) and administering the compound decreases the expression of LFA-1 . Claim 35 is drawn to claim 1, wherein the compound inhibits intercellular adhesion molecule 1 (ICAM-1) in an eye of the human subject. 68 . Babler et al. in view of Hodous et al. suggest the treatment of dry eye disease in a human subject in need thereof comprising administer the BTK inhibitor compound A225 to said human subject, but do not teach wherein T-cells in an eye of the human subject overexpress lymphocyte function-associated antigen (LFA-1) . 69 . However, Pflugfelder et al . teach that the LFA-1/ICAM-1 receptor-ligand pair is implicated in dry eye disease (DED) , wherein expression of LFA-1 is elevated (see Figure 2 at page 7) and suggest inhibiti on of the LFA-1/ICAM-1 interaction as s therapeutic targ et for the treatment of dry eye disease (DED): “ The LFA-1/ICAM-1 integrin receptor–ligand pair may play an important role in the cell-mediated immune response and inflammation associated with DED. Research findings support potential functions of the LFA-1/ICAM-1 interaction in both the afferent and efferent arms of the DED immunoinflammatory pathway, and based on the available evidence, inhibition of LFA-1/ICAM-1 interaction represents a rational targeted approach in treating DED .” (see page 10, left column, under Conclusions). 70 . As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat dry eye disease in a human subject in need thereof comprising administering the BTK inhibitor compound A225 to said human subject, and would reasonably expect that T-cells in the eye of the human subject overexpress LFA-1 . 71 . Claim s 33 and 35 are drafted in terms of the intended outcome of the administration of the compound of claim 1: “... wherein administering the compound decreases the expression of LFA-1 , and inhibits intercellular adhesion molecule 1 (ICAM-1) in an eye of the human subject , wherein the administration of the emulsion causes reduced pain on injection.” However, even though a particular benefit of the administration of a claimed compound recited by Applicant is not expressly disclosed in the prior art , i t is the differences in fact in their respective properties which are determinative of nonobviousness. Even if administering the BTK inhibitor of claim 1 to treat dry eye disease does in fact result in a n additional benefit/outcome that is not recognized in the prior art, Applicant’s recognition of the benefit /outcome is not in itself sufficient to distinguish the method of treatment recited in claim 1 from the prior art . See In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1991). That is, the fact that Applicant 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. See Ex parte Obiaya , 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As such, claims 33 and 35 are prima facie obvious. Claim 36 is drawn to claim 35, wherein the ICAM-1 is present on antigen- presenting cells (APCs) in the eye of the human subject, on vascular endothelial cells in the e y e of the human subject, or on corneal epithelial cells in the e y e of the human subject. 72 . Pflugfelder et al. additionally teach that “ increased protein expression of ICAM-1 was demonstrated in conjunctival biopsy samples taken from patients with SS or non-SS DED on conjunctival epithelial cells, vascular endothelial cells, and infiltrating lymphocytes in the substantia propria. 7 ” (page 9, left column, last paragraph). 73 . As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat dry eye disease in a human subject in need thereof comprising administering the BTK inhibitor compound A225 to said human subject, and would reasonably expect that ICAM-1 is present in at least vascular endothelial cells in the eye of the human subject . As such, claim 36 is prima facie obvious. Conclusion 74. Claims 1-3, 5, 6, 8, 12, 18, 24-31, 33, 35-36, 39-43, and 45-50 are present in the application. Claims 8, 12, 26, 49 and 50 are withdrawn from consideration as directed to nonelected subject matter. C laims 1 -3, 6, 18, 24 , 25, 27- 31, 33, 35, 36, 39-43, and 45-48 are rejected. No claim is currently allowed. 75. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Enter examiner's name" \* MERGEFORMAT JANET L COPPINS whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0680 . The examiner can normally be reached FILLIN "Work schedule?" \* MERGEFORMAT Monday-Friday 8:30AM-5PM EST . 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 Amy L Clark can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 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 unp