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 RESPONSE TO ELECTION/RESTRICTION Applicant’s election of group I, drawn to compounds of the formula I and simple compositions thereof and elected species: in the reply filed on 1/26/2026 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 § 818.03(a)). The requirement is still deemed proper and is therefore made FINAL . Claims 96-97,103,106-109,113-119 , and 122-125 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. An action on the merits of claims 89-95,98-102,104-105,110-112 , and 120-121 is contained herein. Applicant’s elected species was found free of the art and the search extended to cover a proper Markush grouping wherein the TYK2 ligand consists of FORMULA 1-1E and L = -NH . Priority This application is a 371 of PCT/CN2021/130434 , filed 11/12/2021 , which claims benefit to foreign application PCT/CN2020/128350 , filed 11/12/2020. Information Disclosure Statement The examiner has considered the references cited in the information disclosure statement filed of record . Specification Applicant is reminded of the proper content of an Abstract of the Disclosure, see MPEP 608.01(b). In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g. , "The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics." Exemplification of a species could be illustrative of members of the class. For processes, the type reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary. It is recommended that the structure of Formula I be inserted into the abstract to accurately illustrate the claimed invention. Additionally t he abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. Claim Objections Claim s 99 and 105 are objected to because of the following informality: The language “FORMULAE 7A to 7BJ” in claim 105 should be written as “FORMULAE 7A,7B,7C,etc.” for clarity and to be consistent with other claims (e.g. claim 104). Correction is required. Additionally, claim 99 recites the chemical embodiment “cPr” which is not recognized by those skilled in the art but whose definition appears to be synonymous with the group “cyclopropyl” in the instant disclosure (see page 61, line 3). The examiner objects to this abbreviation and the group “cyclopropyl” should be incorporated into the claim itself for completeness. Claim Rejections - 35 USC § 112 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 applicant regards as his invention. Claim s 89-95,98-102,104-105,110-112 , and 1 2 1 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 pre-AIA the applicant regards as the invention. In the instant claim 89 (see variables R EV 5 , Z E for example ), the 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). Thus the claim and claims dependent on it which do not rectify the issue are indefinite. Correction is required throughout where necessary. Additionally claim 89 recites language for the TYK2 ligand “comprises a moiety of FORMULA 1-1E”. The language comprises suggests that the structure is not limited to that of the recited formula and may encompass other structural features not clearly articulated in the claims. Thus the scope is not entirely clear in regards to the claimed structure. The examiner suggests removal of this language and/or the claim amended to clearly recite all structural features intended to be claimed. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of 35 U.S.C. 112 (pre-AIA), fourth paragraph: Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA)], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claim s 99-100 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim s 99-100 do not further limit claim 89 with respect to variables R 22,23 having deuterated alkylene groups (see NHCD 3 and SO 2 CD 3 ) s ince claim 89 does not recite any “deuterated” derivatives thereof for these or any other variables. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections – Improper Markush Grouping Rejection Claims 89-95,98-102,104-105,110-112 , and 1 2 1 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch , 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi , 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y). In re Harnish , 206 USPQ 300, 305, says, “ …we think it should be clear from our actions in Weber and Haas II that we there recognized the possibility of such a thing as an "improper Markush grouping." The court went on to reverse the rejection, (which had been made by the Board under Rule 196(b)) but not on the lack of a specific statutory basis but rather, “Clearly, they are all coumarin compounds which the board admitted to be "a single structural similarity." We hold, therefore, that the claimed compounds all belong to a subgenus, as defined by appellant, which is not repugnant to scientific classification (see claim 1 below for pictorial example): . Under these circumstances we consider the claimed compounds to be part of a single invention so that there is unity of invention…” Thus, the rejection was overturned because of the specific facts in the case. The Markush group was held proper in that case, as was the case also in Ex parte Price 150 USPQ 467, Ex parte Beck and Taylor, 119 USPQ 100, and Ex parte Della Bella and Chiarino 7 USPQ2d 1669. Cases where the Markush group was held improper include Ex Parte Palmer , 7 USPQ 11, In re Winnek , 73 USPQ 225, In re Ruzicka , 66 USPQ 226, Ex parte Hentrich , 57 USPQ 419, Ex parte Barnard , 135 USPQ 109, Ex parte Reid , 105 USPQ 251, Ex parte Sun and Huggins , 85 USPQ 516, In re Thompson and Tanner , 69 USPQ 148, In re Swenson , 56 USPQ 180, and In re Kingston , 65 USPQ 371. Indeed, as was stated in Ex parte Haas , 188 USPQ 374, “The rejection of a claim as containing an improper Markush grouping has a relatively long history in Office practice. The Court of Customs and Patent Appeals, at least as far back as 1942, has recognized that a rejection may be based upon the Examiner's holding that the claim has an improper Markush group. See In re Swenson, 30 CCPA 764, 132 F.2d 336, 56 USPQ 180 , citing Ex parte Palmer , 398 OG 707, 1930 CD 3.” It should be noted that in Harnish , there was a substantial structural feature from which the common use flowed and that the claimed compounds all belong to a subgenus . That is exactly what is lacking in this case, as there is no substantial structural feature when viewing the compound as a whole (in particular the open ended language regarding the TYK2 ligand). The Markush grouping is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. The examiner recommends that the claims should be amended to include only species that share a single structural similarity and a common use (e.g. drawn to compounds of the formula I wherein the TYK2 ligand consists of FORMULA 1-1E and L = -NH ) to overcome the rejection. Claim Rejections - 35 USC § 112 The following is a quotation 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 35 U.S.C. 112 (pre-AIA), first paragraph: 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 89-95,98-102,104-105,110-112 , and 1 2 1 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 compounds of the formula I wherein L = -NH and the Degradation tag is of the formulas 6A, 6B, 6C, or FORMULA 5 wherein the structure of said FORMULA 5 is of the following structure: does not reasonably provide enablement for other compounds . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Pursuant to In re Wands , 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck , 20 USPQ2d 1438, 1444. Analysis is described below: (A) Breadth of claims: The formula I is drawn to a myriad of substituents that vary independently and lead to compounds of a wide variety of structures. These compounds encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamic parameters, not to mention the ability to productively bind to claimed biological target molecules. T he claims cover compounds easily in the millions given the number of possible rings, ring systems covered by the claims' scope along with varying choices for remaining variables; thus the claims are very broad. (B) The nature of the invention: (C) ,(F),(G) State of the Prior Art /Direction/Guidance : Chemistry is unpredictable. See In Re Marzocchi and Horton 169 USPQ at 367 paragraph 3: "Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why. Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work ......Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious)" Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface . Little guidance or direction is provided by A pplicant in reference to making compounds other than those stated to be enabled therein . The presence of various bulky heterocyclic or carbocyclic rings attached to the compound’s core may be chemically incompatible with the method of use embraced in the instant claims. Specification offers no teachings or suggestion as to how to make and use these compounds. Also, note MPEP 2164.08(b) which states that claims that read on "... significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative."; The specification also gives some in vitro test results on TYK2 inhibitory effects of a limited number of preferable compounds, however it is too homogeneous to provide a clear evaluation of which moieties attached to the compound’s core out of the many claimed might affect potency to a large or small degree. The pharmaceutical art is unpredictable and target compounds need to be individually assessed for viability. Extremely broad generalizations as found in the instant claims are in contradiction with the basis of quantitative structure-activity-relationship (QSAR). Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p). (D) Skill of those in the art: The level of skill in the art is high. (E) Level of predictability in the art: It is well established that "the scope of enablement varies 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, 166 USPQ 18, 24 (CCPA 1970). (H) The quantity of experimentation needed: Since there are very limited working examples as described above, the amount of experimentation is expected to be high and burdensome. Applicant fails to provide guidance and supporting information for how to make and/or use the thousands of other compounds which are encompassed by the claims, therefore undue experimentation would be expected. Due to the level of unpredictability in the art, the very limited guidance provided, and the lack of working examples, the applicant has shown lack of enablement. MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here. Conclusion Claims 89-95,98-102,104-105,110-112 , and 1 2 1 are rejected . Claim 120 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT BRIAN E MCDOWELL whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-5755 . The examiner can normally be reached on FILLIN "Work schedule?" \* MERGEFORMAT 8:30-6 MF . If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at 571-272- 9023 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /BRIAN E MCDOWELL/ Primary Examiner, Art Unit 1624