CONJUGATES COMPRISING REVERSIBLE LINKERS AND USES THEREOF

DETAILED ACTION This office action is in response to the applicant’s filing dated July 1st, 2026. 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 . Priority This application is a CON of PCT/EP2021/071775 filed on August 4th, 2021; and claims benefit of foreign priority of EP20216058.6 filed on December 21st, 2020 and EP20189583.6 filed on August 5th, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Status of Claims Claims 1-3, 5, 10, 12, 15-17, 19-23 and 25-28 are pending in the instant application. Acknowledgement is made of Applicant’s remarks and amendments filed on July 1st, 2026. Acknowledgment is made of Applicant’s amendment of claims 1 and 16-17; and the cancelation of claims 4, 6-9, 11, 13-14, 18 and 24. Claims 2, 19-22 and 27-28 remain withdrawn. Objections and/or Rejections and Response to Arguments Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application. New Objections and/or Rejections Necessitated by Claim Amendment Claim Rejections - 35 USC § 112(b) 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. Claims 1, 3, 5, 10, 12, 15-17, 23 and 25-26 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. Regarding claims 1, 3, 5, 10, 12, 15-17, 23 and 25-26, in the instantly claimed Formulas (I’a and I’d) the variable PNG media_image1.png 33 31 media_image1.png Greyscale is present, but there is no definition for variable PNG media_image1.png 33 31 media_image1.png Greyscale present in the claims. Maintained Objections and/or Rejections Claim Rejections - 35 USC § 112 Claims 1, 3, 5, 10, 12, 15-17, 23 and 25-26 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 § 2117. The Markush grouping of compounds of Formulas (I’a and I’d) are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The Markush grouping is directed to a conjugate, or pharmaceutically acceptable salt thereof, comprising at least one moiety -D conjugated via at least one moiety -L1-L2- conjugated to at least one moiety Z; wherein L1 is conjugated to -D and L2 is conjugated to Z; wherein L1 is represented by Formula (I’a or I’d) shown below: PNG media_image2.png 135 249 media_image2.png Greyscale PNG media_image3.png 139 252 media_image3.png Greyscale The * marked dashed line indicates the attachment point to L2. The unmarked dashed line indicates the attachment point of to -D. E is a cleavable moiety of Formula (a’) shown below: PNG media_image4.png 62 147 media_image4.png Greyscale wherein the dashed line indicates the attachment to -W-; wherein -Nu is selected from the group consisting of primary, secondary or tertiary amine and amide; wherein E’ is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -Rx which are the same or different; wherein -Y- is selected from the group consisting of -O-, C(R6)(R6a)-, N(R4)-, and -S-; and wherein =Y is selected from the group consisting of =O, =S and =N(R4). The -D variable encompasses all known peptides and proteins, which include structural and functionally diverse members. Exemplary members are type I collagen, IgG antibody, oxytocin and insulin. Although peptides and proteins may broadly constitute recognized biochemical classes, the encompassed members are not functionally equivalent and do not share a common use in the claimed conjugate merely by virtue of comprising amino-acid residues joined by peptide bonds. For example, these members differ substantially in size, sequence, higher order structure, biological activity and intended function. Thus, the -D alternatives do not possess a common property that is mainly responsible for their function in the claimed combination and are not interchangeable with the expectation of achieving the same result. The Z variable is a polymeric moiety that may comprise structurally diverse heterocyclic and polycyclic moieties shown below as illustrated in the specification (pages 76-77). PNG media_image5.png 54 73 media_image5.png Greyscale PNG media_image6.png 96 97 media_image6.png Greyscale PNG media_image7.png 133 117 media_image7.png Greyscale PNG media_image8.png 126 146 media_image8.png Greyscale These alternatives differ in size, electronic properties, rigidity and functional group composition; thereby introducing substantial structural variability into the encompassed polymeric Z moieties and consequently affecting reactivity, binding interactions and physicochemical behavior. Accordingly, the disclosed Z alternatives are not shown to be functionally equivalent or substitutable for one another in the claimed conjugate with the expectation that the same intended result would be achieved. The E variable does not define a single recognized class of compounds, but instead spans simple hydrophobic aromatic esters, rigid fused polycyclic aromatic systems, bicyclic scaffolds, and ionizable amino carbamate containing aromatic systems illustrated by the example groups shown below from the specification (pages 47-49): PNG media_image9.png 127 93 media_image9.png Greyscale PNG media_image10.png 99 105 media_image10.png Greyscale PNG media_image11.png 120 160 media_image11.png Greyscale PNG media_image12.png 117 159 media_image12.png Greyscale PNG media_image13.png 65 173 media_image13.png Greyscale These structures differ significantly in polarity and ionization, conformational rigidity, hydrogen bonding capacity, and expected physiochemical and biological behavior. Accordingly, the disclosed E alternatives are not shown to be functionally equivalent or substitutable for one another in the claimed conjugate with the expectation that the same intended result would be achieved. The L2 variable can be as simple as a single bond, or any spacer moiety. The breadth of this is illustrated in the elected Compound 3b, wherein L2 is PNG media_image14.png 214 609 media_image14.png Greyscale . Moreover, the entirety of Formulas (I’a and I’d) are completely variable, except for the two C-C atoms making up the core structure, circled in the image shown below, which is too small to form a proper Markush grouping: PNG media_image15.png 135 543 media_image15.png Greyscale As such, the compounds of claims 1, 3, 5, 10, 12, 15-17, 23 and 25-26 include compounds with no common core structure and are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper. Furthermore, the Markush grouping is improper because the claimed alternatives do not share a common use that stems from a substantial structural feature essential to that utility, but instead encompass compounds whose utilities arise from distinct and unrelated structural characteristics as illustrated by the structurally and functionally diverse embodiments discussed above; see In re Harnisch, 631 F.2d 716, 206 USPQ 300(CCPA 1980); and Ex parte Hozumi, 3 USPQ2d 1059 (Bd. Pat. App. & Int. 1984). 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. Response to Arguments Applicant argues: Applicant requests clarification of the Improper Markush rejection, as no provision, subsection or statutory basis was included after the 35 USC § 112 heading. Examiner's response: The Markush Claim guidelines, specifically the Improper Markush rejection information, can be seen in MPEP § 2117(II) and MPEP § 2173.05(h)(I). Applicant argues: Applicant contends that the variables -D, Z, -E, -L1- and -L2- represent recognized classes of substituents that are interchangeable alternatives for the respective positions of the claimed compounds. Examiner's response: The above argument has been carefully considered and has not been found persuasive. The Examiner acknowledges the amendments narrowing several variables and has revised the rejection to reflect those changes in their amended form. Regarding variable Z, Applicant correctly notes that amended claim 1 limits Z to a polymeric moiety. The polymeric Z moiety may comprise the structurally diverse moieties identified in the above maintained rejection. Those moieties do not share a substantial common structural feature, nor has the Applicant established that the resulting Z alternatives are functionally equivalent or interchangeable in the claimed conjugate. Moreover, the amendment of Z does not resolve the improper Markush grouping presented by the claims as a whole. Variable -D remains defined broadly as any peptide or protein drug moiety. This limitation encompasses structurally and functionally different members as discussed in the above rejection. Although such species may broadly be classified as peptides or proteins, they differ profoundly in their size, sequence, higher order structure, biological activity, intended function, pharmacologic activity and physicochemical properties. Their shared possession of amino acid residues and characterization as drug moieties does not establish that they are functionally equivalent or interchangeable in the claimed conjugate with an expectation of achieving the same result. Regarding variables -E and -L1-, the Examiner acknowledges that the amendments impose additional structural limitations and that the Applicant identifies a common cleavage mechanism. However, the claims continue to permit extensive structural variability through numerous substituent definitions including substantial variation in ring systems, heteroatoms, substitution patterns, linker composition and appended moieties. The fact that members may participate in the same general cleavage pathway does not by itself demonstrate that all the claimed alternatives are members of a single recognized class that are interchangeable in the claimed conjugates. Regarding variable -L2-, the Applicant contends that the alternatives are interchangeable because -L2- functions as a spacer. However, the claimed spacer encompasses diverse species such as a single bond or the structure shown in the above rejection. Merely assigning a functional label to otherwise unrestricted alternatives does not establish that the alternatives constitute an art recognized class having the recognized structural relationship and functional equivalence. The relevant inquiry is not merely whether each claimed species can be incorporated into a conjugate intended to exhibit biological activity, but whether the alternatives possess the required structural relationship and are functionally equivalent in the claimed context. The broad -D genus and the extensive variability permitted throughout the claimed conjugate encompass alternatives whose relevant biological and physicochemical properties arise from materially different structural characteristics. The claims lack a defined common structural element persistent across all variants sufficient to permit a complete and meaningful search of the full scope of the claims. Accordingly, the Improper Markush grouping materially impedes examination because the claimed alternatives cannot be searched as a single structurally coherent invention. Conclusion Claims 1, 3, 5, 10, 12, 15-17, 23 and 25-26 are rejected. No claim is allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTOPHER L JOHNSON whose telephone number is (571)272-1672. The examiner can normally be reached Monday - Friday 08:00AM - 5:00PM EST with Flex on Fridays. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /C.L.J./Examiner, Art Unit 1691 /RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691