DETAILED ACTION This office action is in response to applicant’s filing dated November 1 0 , 202 5 . 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. Status of Claims Claims 1-29 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed November 1 0 , 202 5 . C laims 30-116 were previously canceled . Election/Restrictions Applicant’s election of (i) compound 18: as the elected compound species; (ii) graft versus host disease (GVHD) as the elected acute inflammatory condition species; and IL-6 as the elected pro-inflammatory cytokine species in the reply filed on November 10, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Compound 18 is a compound of formula (I) wherein X is O; L is –(CH 2 ) m Y(CH 2 ) p -, Y is S(O) q , wherein m is 0, p is 1, and q is 0; R 1 is a C 6 aryl, phenyl, substituted with R a and R b , wherein one of R a and R b is hydrogen and the other is –(CH 2 ) r CO 2 R x , wherein r is 1 and R x is hydrogen; R c is -CN; and R d is 5-membered heteroaryl, thienyl . Claims 5, 6, 16, 17, 19, 23, 26, 28, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 10, 2025. Claims 1-4, 7-15, 18, 20-22, 24, 25, and 27 are presently under examination as they relate to the elected species: (i) compound 18: (ii) graft versus host disease (GVHD) ; and (iii) IL-6 . Priority The present application claims benefit of priority to US Provisional Application 63/346,193 filed on May 26, 2022. Information Disclosure Statement The information disclosure statement (IDS) submitted on September 18, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where marked with a strikethrough. Drawings Acknowledgement is made of the drawings received on May 24, 2023. These drawings are accepted. Specification The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided. Claim Rejections - 35 USC § 112 (a) Scope of Enablement 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- 4, 7- 15, 18, 20-22, 24, 25, and 27 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 a method of treating graft versus host disease comprising administering Compound 18, does not reasonably provide enablement for a method of treating any acute inflammatory condition in a subject comprising administering any compound of Formula (I). 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. This is a scope of enablement rejection . To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that: 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 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). As pointed out by the court in In re Angstadt , 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation". The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands , 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman , 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors: 1- 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. The nature of the invention, state and predictability of the art, and relative skill of those in the art The invention relates to a method of t reating an acute inflammatory condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I). Claim s 2 -4, 7 -15 and 18 narrow the limitations of the compound of formula (I). Claims 20-22 narrow the scope of the acute inflammatory condition. Claims 24, 25, and 27 narrow the scope of the method to the intended result of reducing a pro-inflammatory cytokine. The relative skill of those in the art is high, generally that of a D.V.M. or Ph.D. The artisan using Applicant’s invention would generally be a veterinarian with a V.M.D. degree and several years of experience. The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher , 166 USPQ 18, at 24 (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); Nationwide Chemical Corporation, et. al. v. Wright, et. al ., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Brannon et al ( Nat Rev Mater , 2022; 7 : 796 - 813) ; Varela et al ( Inflammation, 2018; 41 ( 4 ):1115-1127) ; and Zhang et al ( Inflammation Research, 2025; 74:74 pp. 1-21) . Brannon teaches a cute inflammation is essential for initiating and coordinating the body’s response to injuries and infections ; h owever, in acute inflammatory diseases, i nflammation is not resolved but propagates further, which can ultimately lead to tissue damage such as in sepsis, acute respiratory distress syndrome and deep vein thrombosis ; c urrently, clinical protocols are limited to systemic steroidal treatments, fluids and antibiotics that focus on eradicating inflammation rather than modulating it ; s trategies based on stem cell therapeutics and selective blocking of inflammatory molecules, despite showing great promise, still lack the scalability and specificity required to treat acute inflammation (abstract). Brannon teaches i nflammation plays an essential part in the immune response against harmful stimuli and injury through recognition and containment of invading pathogens and toxins ; o verly responsive or uncontrolled inflammation can lead to tissue damage and organ dysfunction, and is associated with numerous human disorders, such as acute lung and liver injury, sepsis, asthma, inflammatory bowel disease, rheumatoid arthritis and neurodegenerative diseases ; a cute inflammation, regulated by the innate immune system, is responsible for the initial recognition of an inflammatory stimulus and focuses on the rapid containment of the offending pathogen or injury ; s uch a response aims at accelerating inflammatory resolution and typically lasts on a scale of hours to days ; i f the acute inflammation response is excessive or fails to contain the inflammatory stimulus, the response is shifted to a chronic (pathological) phase characterized by prolonged inflammatory episodes and can last on a scale of weeks to years (page 796, left, 1 st paragraph). Brannon teaches a cute inflammation is initiated by either pathogenic infections or exogenously by mechanical trauma, ischaemia-reperfusion or chemicals (page 796, right, 1 st paragraph). Brannon teaches c ytokine- and antibody-based therapy ; p roteins can be designed to target cytokines, such as TNF, IL-1 and IL-6, or to dampen systemic inflammation in patients with immune disorders, by blocking antibodies or by inhibiting cytokines through receptor binding ; c ytokine inhibitors have shown excellent efficacy in treating inflammation in clinical trials (page 799, left, 2 nd paragraph); h owever, cytokine-targeting therapeutics lack specificity, with reduced haematopoiesis as one of the most common side effects, ultimately leading to increased infections owing to reduced WBC populations (page 799, left, 3 rd paragraph). Varela teaches i nflammation is an adaptive process to the noxious stimuli that the human body is constantly exposed to ; f rom the local inflammatory response to a full-blown systemic inflammation, a wide complex sequence of events occurs ; p ersistent immunosuppression and catabolism may ensue, until multiple organ failure finally sets in ; a nd since clinically useful and specific biomarkers are lacking, diagnosis may come late ; a thorough understanding of these events (how they begin, how they evolve, and how to modulate them) is imperative, but as yet poorly studied (abstract) . Varela teaches t he inflammatory process has been best studied in response to infectious stimuli, particularly bacterial infections ; i t is not clear whether most of the principles studied in infection-induced inflammation apply to other causes (page 1115, right, last paragraph); r eleased pro-inflammatory cytokines create a proinflammatory loop that can break away from the injured tissue and enter the bloodstream, leading to what has been called the “ cytokine storm ”; o rgan-specific receptors are activated by these cytokines and a systemic reaction ensues ; t his systemic reaction is called the acute-phase response ; t he purpose of each of these changes in protein quantity has not yet been fully clarified, but scavenging pathogens and modulation of the inflammatory response and its consequences may be an important goal (page 1117, left, 1 st paragraph). Varela teaches m uch remains to be known about inflammation and how its progresses thought the different phases presented ; a n understanding of this progress in a continuum would allow for future therapies to modulate the transition between these phases ; a lso, current treatments simply rely on catching up with the damages the inflammatory process is dealing (page 112, left, 2 nd paragraph). Moreover, Zhang teaches s epsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and associated with significant morbidity and mortality, posing a critical challenge to global public health ; a mong its complications, sepsis frequently causes acute respiratory distress syndrome (ARDS), which has a high incidence and mortality rate, particularly in intensive care units (ICUs) ; c urrently, the management of sepsis-induced ARDS is largely limited to supportive care, as no specific pharmacological treatments are available (abstract) . Zhang establishes that even in the development of drugs for a single acute inflammatory condition is extremely unpredictable. Thus, Brannon, Varela, and Zhang establish that the art of developing therapeutics for treating acute inflammatory conditions is extremely unpredictable. 2. The breadth of the claims Claims 1-4, 7-15, 18, 20-22, 24, 25, and 27 are broad in terms compounds claimed to be useful for the claimed methods and the conditions claimed to be treated. Claims 13-15 and 18 are narrow in terms of compounds claimed to be useful for treating any acute inflammatory condition. Moreover, t he instant claims do not require that an individual is in need of treating an acute inflammatory condition. 3. The amount of direction or guidance provided and the presence or absence of working examples The specification provides examples wherein Compound I-18 increase QPRT expression; compounds I-17 and I-18 restore NAD + biosynthesis; Compound I-18 increases expression of SIRT-1 in Kupffer cells and SIRT-3 in HK2 primary tubule cells; compounds I-17 and I18 activate SIRT1 in primary hepatocytes; Compound I-18 increases STAT3 and IL-10 expression; compounds I-17 and I18 decrease IL-6 expression. The Examiner notes that the specification discloses CLP-induced sepsis model; LPS-induced sepsis model; acute pancreatitis model; acute hepatic injury model; acute graft versus host disease model. However, in a review of the disclosure of these experimental models, disclosure of the compounds administered was not identified. The specification does not provide any data that shows that any of the claimed compounds treat any acute inflammatory condition. 4. The quantity of experimentation necessary Because of the known unpredictability of the art (as discussed supra ) and in the absence of experimental evidence commensurate in scope with the claims , the skilled artisan would not accept that any compound of formula (I) could be predictably be used to treat any acute inflammatory condition. Determining if a particular compound of formula (I) will treat any acute inflammatory condition wo uld require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. Accordingly, the inventions of claims 1-4, 7-15, 18, 20-22, 24, 25, and 27 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention 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 (b) Indefinite 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. Claim 12 is 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. Claim 12 recites the limitation "wherein n is 0." There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite n, and thus there is insufficient antecedent basis for this limitation. Claim Rejections - 35 USC § 102 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. 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 – (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. Claims 1-4 , 7-9, and 20-22 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Pellicciari et al (WO 2020/104456 A1) . While the examination has not been expanded beyond the elected species: Compound 18 (as the compound of formula (I) species), the following rejection is made to further prosecution with regards to the claims which read on the elected species, and that are being anticipated by the prior art ( Pellicciari ) with regard to the broader genus of “ Compounds of Formula (I) ”. Pellicciari teaches a method of treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD+) levels comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD+ levels a therapeutically effective amount a compound or a pharmaceutically acceptable salt thereof (claim 43), wherein the disease is liver transplant associated graft versus host disease (claim 45) , and a compound is Compound I-1 (claim 38): Compound I-1 is a compound of formula (I) wherein X is O; L is –(CH 2 ) m Y(CH 2 ) p -, Y is S(O) q , wherein m is 0, p is 1, and q is 0; R 1 is a C 6 aryl, phenyl, substituted with R a and R b , wherein one of R a and R b is hydrogen and the other is –(CH 2 ) r CO 2 R x , wherein r is 1 and R x is C 2 alkyl, ethyl; R c is -CN; and R d is 5-membered heteroaryl, thienyl. Thus, the teachings of Pellicciari anticipate the method of claims 1-4 and 20-22. Claim Rejections - 35 USC § 103 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. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 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. Claims 1-4, 7-15, 18, 20-22, 24, 25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Pellicciari et al (WO 2020/104456 A1). Pellicciari teaches a method of treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD+) levels comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD+ levels a therapeutically effective amount a compound of ( I I), or a pharmaceutically acceptable salt thereof (claim 43), wherein the disease is liver transplant associated graft versus host disease (claim 45) . Pellicciari teaches a compound of Formula (I) (claim 2): Pellicciari does not explicitly teach a compound of formula (I) is the elected compound, Compound 18. However, Pellicciari does teach Compound I-1 (claim 38): and Compound I- 4 (claim 3 8 ): Compound I-1 differs from the instantly elected compound in that Compound I-1 contains a hydrogen and –(CH 2 )CO 2 Et in the positions corresponding to instantly claimed R a and R b , while Compound 18 contains a hydrogen and –(CH 2 )CO 2 H. Compound I- 4 differs from the instantly elected compound in that Compound I- 4 contains a -OCH 3 in the position corresponding to instantly claimed X, while Compound 18 contains a n O. Moreover, Pellicciari teaches X is alternatively O, OH, or OR h , and R h is C 1 -C 4 alkyl (claim 2). Pellicciari teaches R 7 is A, wherein A is –(C(R 6 ) 2 ) r CO 2 R x , wherein R x is alternatively H or C 1 -C 6 alkyl (claim 2). Thus, Pellicciari teaches O and -OCH 3 are alternatively useful in the position corresponding to instantly claimed X and –(CH 2 )CO 2 H and –(CH 2 )CO 2 Et are alternatively useful in the position corresponding to R a and R b for produ cing compounds useful in the claimed methods. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to arrive at the elected compound for use in a method of treating liver transplant associated graft versus host disease with a reasonable expectation of success from the teachings of Pellicciari. Taken together, all this would result in the practice of the method of claims 1-4, 7-15, 18, and 20-22 with a reasonable expectation of success. Regarding claims 24, 25, and 27 , Pellicciari teaches a compound of Formula (I) are administered at different time points [00664] and secondary endpoints include markers of inflammation including IL-6 [00666]. With regard to the limitation wherein the method reduces a pro-inflammatory cytokine ( instant claim 24 , wherein the pro-inflammatory cytokine is IL-6, Pellicciari renders obvious a method of treating liver transplant associated graft versus host disease comprising the elected compound and suggests measuring IL-6 . In regard to "wherein” clauses, MPEP 2111.04 states: The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina , 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). In Hoffer v. Microsoft Corp. , 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc. , 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. In the instant case, the wherein clause is directed to the intended result (i.e. reducing pro-inflammatory cytokine, IL-6 ) of the process step positively recited (i.e. administering a compound of formula (I), elected compound 18 to treat graft versus host disease ). Taken together, all this would result in the practice of the method of claims 24, 25, and 27 with a reasonable expectation of success. Conclusion Claims 1-4, 7-15, 18, 20-22, 24, 25, and 27 are rejected. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT RAYNA B RODRIGUEZ whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-7088 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 8am-5:00pm, Monday - Thursday . 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 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. /Rayna Rodriguez/ Primary Examiner, Art Unit 1628