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 .
Claim Status
Claims 67-71 and 75-76 are pending. Claims 72-74 were canceled; claim 67 was amended; and no claims were added in the Reply filed 12/18/2025. Claims 67-71 and 75-76 are presently considered.
Election/Restrictions
Applicant’s election without traverse of the species of Example 28 administered via single dosing subcutaneous injection at 0.01 µmol/kg in the reply filed on 5/23/2025 is acknowledged.
The originally elected species is understood to be the species of Example 28 administered via single dosing subcutaneous injection at 0.01 µmol/kg1, wherein the GLP1 peptide of SEQ ID NO: 22 is the “GLP1 receptor ligand conjugate moiety”, a malemimide acid linker corresponding to claim 67(B) is used for the conjugate linker, MALAT1 ASO (SEQ ID NO: 58) is the oligonucleotide, X is directly connected to SEQ ID NO: 22 and Y is indirectly attached to the oligonucleotide of SEQ ID NO: 58 via a hexylamino group and a phosphate group. Accordingly, the claimed species is understood to have the following general structure:
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(see, e.g., Spec. filed 2/23/2024 at Example 28 at 117-118). Notably, ION#1123118 is described as “GLP-1 conjugated MALAT-1 ASO conjugated via a maleimide acid linker” (see, e.g., Spec. filed 5/7/2020 at Example 29 on 118 at lines 21-23, page 119 at lines 5-10, Example 30 at 119 at lines 10-15). This description is reasonable, because the linker is understood to be a ring-opened maleimide.
Following an extensive search and examination, the elected species was previously deemed obvious for reasons of record. The amended claims are understood to continue reading upon the originally elected species, which has been again searched, examined, and deemed obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, the claims have been rejected in view of the originally elected species and claims directed to non-elected species have been withdrawn.
Examination has not progressed beyond the originally elected species.
Accordingly, claims 67-71 and 75-76 have been examined.
Priority
The earliest priority claim to US Provisional Application 62/583,398 filed 11/08/2017 is acknowledged.
Information Disclosure Statement
No IDS was filed in the Reply submitted 12/18/2025.
Claim Interpretation and Examiner Notes
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111.
Amended claim 67 is understood to be representative of the pending claim scope, and the applicable claim interpretation is set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
The preamble of claim 67 recites an intended and expected result (i.e., “modulating the expression of a nucleic acid target in a pancreatic beta-islet cell comprising ….”), which is understood to express the intended result of the positively recited steps and structures set forth in the body of claim 67 (see, e.g., MPEP §§ 2111.02(II), 2111.04(I)). Accordingly, the preamble of claim 67 is deemed fully satisfied by prior art teaching or rendering obvious the steps of “contacting a [beta-islet cell] . . . with a compound comprising a modified oligonucleotide linked to a GLP-1 receptor ligand . . .” having the structure as set forth in the body of instant claim 67.
“Modified oligonucleotide” is interpreted in view of the broadest definition provided in the Specification (see, e.g., Spec. filed 2/23/2024 at 8 at lines 5-10). Accordingly, “oligonucleotide” includes any “polymer of linked nucleosides each of which can be modified or unmodified, independent one from another” and is understood to be an oligonucleotide comprising at least one modified sugar, nucleobase, or internucleoside linkage (see id.).
Amended claim 67 requires the modified oligonucleotide to be complementary to an RNA transcript in the cell. The term “complementary” is understood to read upon and encompass mismatched sequences (see, e.g., Spec. filed 2/23/2024 at 5 at lines 14-25).
“Conjugate linker” is interpreted in view of the definition provided in the Specification (see, e.g., Spec. filed 2/23/2024 at 5 at lines 25-30) and at claim 67(A)-(C) as filed 5/07/2024.
The phrase “GLP-1 receptor ligand conjugate moiety” is not explicitly defined on record, and is therefore interpreted in view of the defined term “conjugate moiety” (see, e.g., Spec. filed 2/23/2024 at 5 at lines 24-30, at 45 at line 20 to page 71 at line 17), which is understood to mean a group of atoms that is attached to an oligonucleotide via a conjugate linker (see id).
Examiner notes that one of ordinary skill in the art would readily appreciate that bioconjugates comprising oligonucleotides conjugated to targeting ligands were well-known in the therapeutic oligonucleotide arts years prior to filing (see, e.g., Ming2 at title, abs, 83 at § 2 at col I). For example, WO2009/089186 (Henke et al.; July 16, 2009; cited in previous action) claims peptide-conjugated oligonucleotides of form [targeting peptide]-[heterobifunctional linker]-[antisense oligonucleotide] (see, e.g., WO’186 at title, abs, claim 1).
Additional claim interpretations are set forth in the rejections below.
Withdrawn Claim Rejections
The rejection of claims 67-74 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn in view of the cancellation of claims 72-74 and the amendments to claim 67 as submitted in the Reply filed 12/18/2025.
Claim Rejections
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 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.
[Prior Art Rejection 01]
Claims 67-71 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/089186 A23 in view of Korner4, WO 2012/177443 A25 and Fontaine6.
Claim Interpretation: The applicable claim interpretation has been set forth in a separate section above, and in preceding rejections, and those discussions are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Forming cell-targeted antisense oligonucleotides by conjugating oligonucleotides to “homing peptides” was routine in the prior art circa 2009 and addressed an art-recognized problem: WO 2009/089186 A2 identifies that antisense oligonucleotides are capable of targeting “mRNA having a complementary sequence to interfere with expression of the protein encoded by the mRNA” (see, e.g., WO’186 at 1 at 3rd ¶; compare id. with instant claim 71), but have an art-recognized problem, namely that antisense oligonucleotides lack the ability to “reliably deliver effective amounts of the oligonucleotide into the cells containing the target mRNA in vivo” (see, e.g., WO’186 at 1 at 3rd ¶; compare id. with instant claim 71). WO’186 discloses an art-recognized solution, namely WO’186 informs artisans to address the known problem by conjugating antisense oligonucleotides to “homing peptides” (see, e.g., WO’186 at p. 4-5 at bridging ¶, claim 1). Regarding instant claim 67 and the usage of peptide conjugated antisense agents to treat diseases in patients, WO’186 identifies that the disclosed conjugates may have a general structure summarized by the formula
[targeting peptide]-[heterobifunctional linker]-[antisense oligonucleotide]
(see, e.g., WO’186 at title, abs, claim 1),
and informs artisans that such structures could be used “to treat diseases associated with over expression of a target protein” by directing antisense agents to “cells relevant to the disease”, including diseases such as cancers (see, e.g., WO’186 at 3 at 3rd full ¶, 4 at 3rd to 5th full ¶¶, claims 1-3, 6, 10, 16, 19-20, 26, 32). Accordingly, the general structure and utility of such conjugates in methods of treating diseases was taught by WO’186. Regarding the structural limitations of the oligonucleotides at instant claims 67-71, WO’186 informs artisans that antisense oligonucleotides are explicitly intended to target “mRNA having a complementary sequence to interfere with expression of the protein encoded by the mRNA” within a targeted cell (see, e.g., WO’186 at 1 at 3rd ¶; compare id. with instant claim 71). WO’186 also identifies that “antisense oligonucleotides” may include oligonucleotide chemistries involving “modifications” at the nucleobase, sugar, nucleoside, or linkages by directing artisans that oligonucleotides may be “DNA, RNA, morpholino oligonucleotides, peptide nucleic acids, LNA or chemically modified derivatives thereof”, and single- or double-stranded oligonucleotides (see, e.g., WO’186 at 4 at 3rd full ¶ to 4th full ¶; compare id. with instant claim 69). WO’186 reasonably directs artisans to utilize “gapmer” designs by exemplifying an antisense 5-13-5 gapmers wherein “the first and last 5 bases in the sequence being 2’-O-methyl RNA bases, and the intervening 13 bases being phosphorothioate linked DNA bases” (see, e.g., WO’186 at 6 at final ¶, 15 at 1st ¶; compare id. with instant claims 68-71). Accordingly, the usage of a “modified oligonucleotide” such as a 23-mer, single-stranded “gapmer” antisense agent within the general structure of
[targeting peptide]-[heterobifunctional linker]-[antisense oligonucleotide]
(see, e.g., WO’186 at title, abs, claim 1),
in methods “to treat diseases associated with over expression of a target protein” by directing antisense agents to “cells relevant to the disease”, including diseases such as cancers (see, e.g., WO’186 at 3 at 3rd full ¶, 4 at 3rd to 5th full ¶¶, claims 1-3, 6, 10, 16, 19-20, 26, 32), would have been known in view of WO’186.
The teachings of WO’186 differ from the instant claims as follows: Although WO’186 does not explicitly (i) disclose the use of GLP-1 receptor ligand as a “homing” or “targeting” peptide for use in conjugates, or (ii) otherwise disclose the usage of the specific linker structure as set forth at claim 67(A) or 67(B).
GLP-1 receptor ligand peptides were already known and already recognized in the prior art for use a “targeting” or “homing” peptides suitable for use in conjugates with nucleic acid therapeutics, wherein the resulting therapeutics were disclosed as usable for the in vivo treatment of diseases: Korner discloses that the GLP-1 receptor was an art-recognized target having art-recognized potential for targeting therapeutics to tumors in vivo circa 2007 (see, e.g., Korner at title, abs, 742 at col II at § Conclusions, noting that “GLP-1 receptors are promising candidates for in vivo targeting for diagnostic and therapeutic purposes”). Therefore, “GLP-1 Receptor” targeting peptides would be readily understood by artisans to be useful as “homing peptides” or “targeting peptides” as discussed in WO’186 (see, e.g., WO’186 at title, abs, 2-3 at bridging ¶, 3 at 3rd full ¶, 4 at 3rd ¶ to 5th ¶, claims 1-3 and 26). In addition, WO2012177443 explicitly discloses and claims methods of using conjugates comprising peptide-based GLP-1 receptor ligands (e.g., peptides exhibiting sensitivity for the human GLP-1 receptor versus the GIP receptor), conjugated to a “nucleic acid molecule” (see, e.g., WO’443 at title, abs, ¶¶[0007]-[0008], [0038], [0057], [00185], [00213], claims 18-19 and 24-26), wherein such conjugates are taught for use in the treatment of diseases and conditions in patients (see, e.g., id.; see esp. id. at claims 18-19 and 24-26), and wherein the nucleic acid molecule is structurally unlimited and is conjugated to a GLP-1 receptor ligand peptide7 “via a linker” (see, e.g., WO’443 at ¶¶[0196]-[0197]; see also id. at ¶¶[0007]-[0008], [0057], [00185], claims 18-19).
Regarding the preamble of claim 67, and methods of administering to a patient [GLP-1 ligand peptide]-[linker]-[oligonucleotide] conjugates at a concentration of 0.01 µmol/kg via subcutaneous administration, the preamble of claim 67 is understood to express an intended and expected result fully satisfied by the performance of the positively recited steps and structures as set forth in the body of claim 67 (see, e.g., MPEP §§ 2111.02(II), 2111.04(I)). Accordingly, the preamble of claim 67 is deemed fully satisfied by prior art teaching or rendering obvious the steps of “contacting a [beta-islet cell] . . . with a compound comprising a modified oligonucleotide linked to a GLP-1 receptor ligand . . .” having the structure as set forth in the body of instant claim 67. Notably, such “contacting” would be understood to necessarily occur via systemic administration routes, which would “contact” all cells available within a system, which would include the route of “subcutaneous administration” of “0.01 µmol/kg” of a conjugate as present in the originally elected species. Notably, the prior art teaches that [GLP-1 ligand peptide]-[linker]-[oligonucleotide] and [targeting peptide]-[linker]-[oligonucleotide] conjugates may be delivered via subcutaneous administration routes (see WO’186 at 9 at 1st full ¶; see, e.g., WO’443 at ¶¶[0019]-[0021], [00239], [00303], at claims 18-19 and 24-26; see esp. id. at ¶[0303]), and explicitly exemplify the usage of administering via subcutaneous injection “between 1 and 10 nmol/kg” of similar embodiments (see, e.g., WO’443 at ¶¶[0019]-[0021], [00239], [00303], at claims 18-19 and 24-26; see esp. id. at ¶[0303]), which would reasonably guide and direct artisans to utilize and test similar administration routes and dosages with a reasonable expectation of success.
The linkage structures shown at instant claim 67(A)-(C) correspond to an art-recognized ring-opened maleimide-thiol conjugate having known benefits of enhanced stability: WO’186 provides examples of multiple heterobifunctional linkers having reactivity with amino and sulfhydryl groups suitable for use in producing peptide-conjugated oligonucleotides (see, e.g., WO’186 at 7, whole page, page, Fig. 1, claims 1-3). Specifically, WO’186 exemplifies the process of conjugation utilizing GMBS (4-maleimidobutyric acid N-hydroxysuccinimide ester) with an amine-modified oligonucleotide, modified with a C6-amino linker attached to the 5’ end of the oligonucleotide (WO’186 at 8-9 at bridging ¶, page 15 at Example 1, Fig. 1; Fig. 1 is reproduced in part below):
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Accordingly, the embodiments of claims 1-2 of WO’186 in view of the reaction exemplified at Figure 1 of WO’186 would be reasonably understood by artisans as including at least peptide-conjugated antisense oligonucleotides having the general structure of maleimide-thiol conjugates shown below:
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Fontaine informs artisans that although “coupling of a maleimide with a protein Cys is one of the most commonly used methods for bioconjugation” such Maleimide-thiol conjugates may undesirably undergo ring-opening (see, e.g., Fontaine at title, abs, 145 at col I, scheme 1 on 145, Fig. 1 on 146). The general ring-opening process is shown at the abstract image, scheme 1 on page 145, and at Figure 1 on page 146 (see, e.g., Fontaine at abs, scheme 1 on 145, Fig. 1 on 146, abs image reproduced in part below):
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Fontaine discusses an art-recognized problem with Maleimide-thiol conjugates, namely the ring opening reaction in the presence of water leading to potentially unwanted thiol exchange if it occurs unchecked (see, e.g., Fontaine at Scheme 1 on 145, 145 at col I-II at § Introduction, discussing retro-Michael reactions). Fontaine identifies that the ring-opened adduct is stable (see id.; see also id. at abs, noting the half-life of ring-opened products is “over two years”), and therefore Fontaine notes that such ring-opening adducts may be desirably formed on purpose prior to exposing the maleimide-thiol conjugates to other exogenous thiols to avoid unwanted thiol exchange (see, e.g. id. at 146 at col I at 1st full ¶). Accordingly, in view of Fontaine an artisan would readily appreciate that maleimide-thiol conjugated peptide-antisense conjugates as taught in view of WO’186, Korner, and WO’443 would also necessarily form ring-opened adducts leading to unwanted thiol exchange if allowed to occur unchecked. Accordingly, in view of WO’186, Korner, WO’443, and Fontaine, an artisan would be reasonably motivated to intentionally hydrolyze such conjugates under controlled conditions to avoid unwanted thiol exchange, and to desirably obtain a stabilized, ring-opened maleimide-thiol conjugate (see, e.g. Fontaine at 146 at col I at 1st full ¶). in view of WO’186, Korner, WO’443, and Fontaine, an artisan would readily conclude and understand that the structures recited at instant claim 67(A)-(C) merely correspond to a ring-opened maleimide-thiol as taught by WO’186; specifically, the structures at claim 67(A)-(C) correspond to maleimide rings that have been hydrolyzed to form a ring-opened, stabilized form as suggested by Fontaine, wherein “X” is a Cys-terminal polypeptide8, “Y” is an oligonucleotide, and the exact structure of “R” varies depending upon the exact heterobifunctional linker (HBL) used in the conjugation (i.e., GMBS as shown at Fig. 1 of WO’186 would result in an “R” having the structure of (CH2)n, wherein n is 3), as summarized in the following figure:
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Accordingly, the linkage structures shown at claim 67(A)-(C) were readily apparent in the prior art, would have expected benefits (enhanced stability), and would desirably avoid and address a known problem in the prior art identified by Fontaine (i.e., unwanted thiol exchange). Specifically, the simple substitution or combination of a homing peptide corresponding to a GLP-1 Receptor peptide ligand as taught by WO’433 and Korner, in place of another homing peptide in a peptide-oligonucleotide conjugate structure as disclosed by WO’186 using a thiol-maleimide linker such as GMBS (4-maleimidobutyric acid N-hydroxysuccinimide ester) and per the method shown at Figure 1 of WO’186, which would predictably and expectedly produce a peptide-oligonucleotide having the structure
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,
which would necessarily hydrolyze or otherwise intentionally be hydrolyzed as taught by Fontaine as shown below, to predictably yield a ring-opened and stabilized product of form:
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Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The invention is an obvious method of treating diseases by administering variants of [GLP-1R targeting peptide]-[heterobifunctional linker]-[antisense oligonucleotide], wherein such variants are constructed by combining or substituting known prior art elements in the known arrangements and methods taught by WO’186 and WO’443, wherein the linker is a ring-opened maleimide linker that would necessarily or intentionally occur and would have known benefits and advantages as taught by Fontaine, and wherein such methods would predictably and desirably treat diseases in patients following subcutaneous administration exactly as taught and suggested by WO’186, Korner, and WO’443, but advantageously exhibit the added stability disclosed by Fontaine (see, e.g., MPEP §§ 2143(I)(A), (B), (C), (D), (G)). Furthermore, each component merely performs its art-recognized function as it does separately. Accordingly, the claimed invention is obvious in view of the prior art9.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to perform methods taught and disclosed in the prior art, using prior art compounds in known arrangements and for their intended purposes, conjugated via a ring-opened maleimide linker, because such components merely perform their art-recognized and expected tasks.
Accordingly, claims 67-71 are rejected as obvious in view of the prior art.
[Prior Art Rejection 02]
Claims 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/089186 A210 in view of Korner11, WO 2012/177443 A212 and Fontaine13 as applied to claims 67-71 above, and further in view of US 2015/0320871 A114.
Claim Interpretation: The applicable claim interpretation has been set forth in a separate section above and in the preceding rejection, and those discussions are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of WO’186 in view of Korner, WO’443 and Fontaine as applied to claims 67-71 have been set forth above in a preceding rejection, and that discussion is incorporated into the instant rejection.
WO’186 in view of Korner, WO’443 and Fontaine differ from instant claims 75-76 and the originally elected species as follows: These references do not teach nor disclose the specific GLP-1 receptor ligand corresponding to instant SEQ ID NO: 22 (“HXEGTFTSDVSSYLEEQAAKEFIAWLVKGGPSSGAPPPSC”, where “X” is Aib).
As explained above in view of the rejection of instant claims 67-71, WO’186 in view of Korner, WO’443 and Fontaine direct artisans to perform methods of treating diseases by administering to patients compounds having the general structure of
[GLP-1R targeting peptide]-[ring-opened Maleimide linker]-[antisense oligonucleotide]
(see rejection, above). Accordingly, the relevant issue is whether or not it would have been obvious to simply substitute the GLP-1R targeting peptides of WO’443 for another GLP-1R targeting peptide.
An artisan would be directed to utilize a GLP-1R ligand peptide having a C-terminal cysteine: The prior art reasonably directs artisans to select a GLP-1 Receptor ligand peptide that may be conjugated to another substance through “a C-terminal Cys” (see, e.g., WO’443 at ¶¶[0062], [0095]; see also id. at ¶¶[00157]-[00158], [00174], [00187], [00197]-[00198], [00206], [00214], [00216], claim 10). Accordingly, an artisan would reasonably be directed to GLP-1 receptor ligand sequences having a C-terminal cysteine suitable for conjugation to a compound via a maleimide linker and also suitable for use as a “homing peptide” or “targeting peptide” of a therapeutic.
Instant SEQ ID NO: 22 is a prior art GLP-1 receptor ligand ending with a C-terminal Cystine and also taught and disclosed in the prior art for use in conjugates to therapeutics: US’871 pertains to GLP-1 receptor ligand sequences ending in a C-terminal cysteine and identified as suitable for conjugating to a drug and acting as a targeting moiety to direct the drug to GLP-1 expressing tissues (see, e.g., US’871 at ¶¶[1134], [1137], [1139], [1167], [1130], [1131]). Specifically, US’871 discloses and exemplifies SEQ ID NO: 1662, which consists of the sequence “HXEGTFTSDVSSYLEEQAAKEFIAWLVKGGPSSGAPPPSC”, wherein “X” is Aib, and wherein the terminal Cys is conjugated to a drug moiety via a maleimide linker:
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(image modified from US’871 at ¶[1130]; see also id. at SEQ ID NO: 1662). Accordingly, instant SEQ ID NO: 22 is a prior art element corresponding to SEQ ID NO: 1662 of US’871, has a C-terminal Cys, and is also taught and disclosed as capable of being linked to a therapeutic via a sulfur-maleimide linkage (compare instant SEQ ID NO:22, instant claims 75-76 with US’871 at ¶[1130] and SEQ ID NO: 1662, showing identity 100% identity).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The courts have stated that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle" (see, e.g., Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), 325 U.S. at 335, 65 USPQ at 301). Similarly, following the guidance of WO’186 in view of Korner, WO’443, and Fontaine would direct artisans to perform methods of predictably treating diseases by administering to patients compounds having the general structure of
[GLP-1R targeting peptide]-[ring-opened Maleimide linker]-[antisense oligonucleotide]
Such methods would yield predictable results, namely the treatment of a patient’s disease following subcutaneous administration exactly as taught and suggested in view of the prior art. Accordingly, the simple substitution of the GLP-1R targeting peptide of SEQ ID NO: 1662 of US’871 in place of the generic GLP-1R targeting peptides would continue to yield the same predicted and expected results, because SEQ ID NO: 1662 of US’871 is an art-recognized GLP-1R targeting peptide usable in conjugation with therapeutics (see, e.g., MPEP §§ 2143(I)(B), (G)). Accordingly, the selection of a known GLP-1R targeting peptide for use as a GLP-1R targeting peptide based on its suitability for its intended use as a GLP-1R ligand is prima facie obvious per MPEP § 2144.07.
No unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to perform a known method using a known peptide-oligonucleotide conjugate by combining only known sequences and components, in order to predictably obtain the exact results taught and suggested by the prior art.
Accordingly, claims 75-76 are rejected as obvious.
[Prior Art Rejection 03]
Claims 67-71 and 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/089186 A215 in view of Korner16, WO 2012/177443 A217, Fontaine18, and US 2015/0320871 A119 as applied to claims 67-71 and 75-76 above, and further in view of Handbook20.
Claim Interpretation: The applicable claim interpretation has been set forth in a separate section above and in the preceding rejection, and those discussions are incorporated into the instant rejection. The instant rejection more specifically addresses the heterobifunctional crosslinker utilized to arrive at the originally elected species (i.e., BMPS). Additional claim interpretations are set forth below.
The teachings of WO’186 in view of Korner, WO’443, Fontaine, and US’871 as applied to claims 67-71 and 75-76 have been set forth above in preceding rejections, and those discussions are incorporated into the instant rejection.
The previously cited prior art differs from the originally elected species as follows: WO’186 in view of Korner, WO’443, Fontaine, and US’871 as applied to claims 67-71 and 75-76 do not explicitly teach nor disclose the specific linker moiety corresponding to the originally elected species (i.e., N-succinimidyl 3-maleimidopropionate; a.k.a., BMPS).
The linker utilized in the originally elected species (BMPS) is a prior art element that was commercially available in the prior art: Handbook establishes that BMPS, having the structure
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was known in the prior art and commercially available as a heterobifunctional linker circa 2015 (see, e.g., Handbook at Product # 22298 on internally numbered pages 26 and 37).
BMPS is functionally equivalent to GMBS: An artisan would readily appreciate that BMPS (see id) was a functional equivalent to GMBS as taught by WO’186 (see, e.g., Handbook at Product # 22309 on internally numbered pages 28 and 41) because such structures (i) share identical functional moieties, (ii) differ only by the successive addition or removal of the same chemical group, namely -CH2- groups (see, e.g., MPEP § 2144.09(II), discussing presumed expectation of compounds possessing similar properties), and (iii) are both identified and commercially available for use as heterobifunctional linkers (see, e.g., Handbook at Products # 22309 and 22298 at internally numbered pages 26-29, 37-28, and 41; see also id. at internally numbered pages 5 at col I at § Maleimides, 53). Furthermore, WO’443 explicitly teaches that the disclosed conjugates may be made using maleimido groups (see, e.g., WO’443 at ¶[00197], [00214]), and WO’186 identifies that such conjugates may be made using SMCC, GMBS, and EMCS (see, e.g., WO’186 at 3 at 1st partial ¶). Accordingly, an artisan would readily appreciate that BMPS and GMBS “have the same reactive groups, the maleimido group and the hydroxysuccinimide group, but differ in the intervening structure of spacer”.
The simple substitution of BMPS in place of GMBS would yield predictable results: The resulting structure obtained by substituting BMPS in place of GMBS would differ only with respect to the intervening structure of the spacer between the two reactive groups (see, e.g., WO’186 at 8-9 at bridging ¶). As noted in a preceding rejection, WO’186 discloses peptide-conjugated oligonucleotide methods wherein a heterobifunctional linker (“HBL”) with reactivity towards amino and sulfhydryl groups is used to conjugate an antisense agent to a “homing peptide”, wherein the “homing peptide” is used to target the conjugate to cells relevant to a disease of interest (see, e.g., WO’186 at title, abs, 2-3 at bridging ¶, 3 at 3rd full ¶, 4 at 3rd ¶ to 5th ¶, claims 1-3 and 26). WO’186 exemplifies the process of conjugation utilizing GMBS (4-maleimidobutyric acid N-hydroxysuccinimide ester) with an amine-modified oligonucleotide, modified with a C6-amino linker attached to the 5’ end of the oligonucleotide (WO’186 at 8-9 at bridging ¶, page 15 at Example 1, Fig. 1; Fig. 1 is reproduced in part below):
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Accordingly, the use of BMPS in place of GMBS followed by ring-opening as taught by Fontaine would predictably yield a conjugate having the general structure of
[GLP-1R targeting peptide]-[ring-opened maleimide linker]-[antisense oligonucleotide]
Wherein the ring-opened maleimide linker using BMPS would be a single methyl group shorter than one using GMBS.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The courts have stated that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle" (see, e.g., Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), 325 U.S. at 335, 65 USPQ at 301). Similarly, following the guidance of WO’186 in view of Korner, WO’443, Fontaine, and US’871 would direct artisans to perform methods of predictably treating diseases by administering to patients compounds having the general structure of
[GLP-1R targeting peptide]-[ring-opened Maleimide linker]-[antisense oligonucleotide]
Such methods would yield predictable results, namely the treatment of a patient’s disease following subcutaneous administration exactly as taught and suggested in view of the prior art. Accordingly, the simple substitution of one commercially available bifunctional linker (i.e., BMPS) for another (e.g., GMBS) would continue to yield the same predicted and expected results, because BMPS is an art-recognized functional equivalent of GMBS as taught by WO’186 (see, e.g., MPEP §§ 2143(I)(B), (G)). Accordingly, the selection of a known bifunctional linker based on its suitability for its intended use as a linker is prima facie obvious per MPEP § 2144.07.
No unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to perform a known method using a known peptide-oligonucleotide conjugate by combining only known sequences and components, in order to predictably obtain the exact results taught and suggested by the prior art.
Accordingly, claims 67-71 and 75-76 are rejected as obvious.
[Prior Art Rejection 04]
Claims 67-71 and 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/089186 A221 in view of Korner22, WO 2012/177443 A223, Fontaine24, US 2015/0320871 A125 and Handbook26 as applied to claims 67-76 above, and further in view of WO 2017/053995 A127.
Claim Interpretation: The applicable claim interpretation has been set forth in a separate section above and in the preceding rejection, and those discussions are incorporated into the instant rejection. The instant rejection more specifically addresses the antisense oligonucleotide utilized in the originally elected species (i.e., MALAT1 ASO, a.k.a. instant SEQ ID NO: 58). Additional claim interpretations are set forth below.
The teachings of WO’186 in view of Korner, WO’443, Fontaine, US’871 and Handbook as applied to claims 67-71 and 75-76 have been set forth above in preceding rejections, and those discussions are incorporated into the instant rejection.
The previously cited prior art differs from the originally elected species as follows: WO’186 in view of Korner, WO’443, Fontaine, US’871, and Handbook as applied to claims 67-71 and 75-76 do not explicitly teach nor disclose the specific antisense oligonucleotide of MALAT1 ASO (i.e., instant SEQ ID NO: 58; a.k.a. ISIS 786434, nucleobase sequence TCAGCATTCTAATAGCAGC) utilized in the originally elected species.
MALAT1 ASO (i.e., instant SEQ ID NO: 58) is a prior art element: WO’995 pertains to antisense oligonucleotides, including antisense oligonucleotides having a C6-hexylamino linker at the 5’ end, namely the C6-Hexylamino modified oligonucleotide of Isis No. 812133, Isis No. 827935, and Isis No. 812134, which each share the nucleobase sequence TCAGCATTCTAATAGCAGC and a Hexylamino modification (see, e.g., WO’995 at Table 3 on 62, Table 4 on 63, Table 5 on 6, Table 6 on 64, Table 14 at 70-71), and which were reduced to practice and exemplified as Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALA T-1) targeting antisense oligonucleotides (see id). Accordingly, the prior art sequences share 100% identity with the nucleobase sequence of instant SEQ ID NO: 58 (compare instant SEQ ID NO: 58 with SEQ ID NO: 4, and Isis No. 812133, Isis No. 827935, and Isis No. 812134 of WO’995 at Table 3 on 62, Table 4 on 63, Table 5 on 6, Table 6 on 64, Table 14 at 70-71, showing 100% sequence identity).
MALAT1 ASO (i.e., instant SEQ ID NO: 58) had predicted and expected applications in vivo treatments of diseases, could be delivered via subcutaneous administration routes, and had a known target mRNA sequence: WO’995 discloses that the sequence at issue targets Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALA T-1) (compare instant SEQ ID NO: 58 with SEQ ID NO: 4, and Isis No. 812133, Isis No. 827935, and Isis No. 812134 of WO’995 at Table 3 on 62, Table 4 on 63, Table 5 on 6, Table 6 on 64, Table 14 at 70-71, showing 100% sequence identity), and is capable of reducing MALAT-1 expression in vivo following administration (see, e.g., WO’995 at Example 3 and Table 3 on 62). WO’995 reasonably informs artisans that conjugates comprising the MALAT-1 antisense oligonucleotide could be administered to individuals and utilized to treat diseases in individuals (see, e.g., WO’995 at claims 217, 224, 231), including by targeting cancer and tumor cells (see, e.g., WO’995 at claim 234), and could be administered via subcutaneous administration (see, e.g., WO’995 at claim 235).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The courts have stated that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle" (see, e.g., Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), 325 U.S. at 335, 65 USPQ at 301). Similarly, following the guidance of WO’186 in view of Korner, WO’443, Fontaine, US’871, and Handbook would direct artisans to perform methods of predictably treating diseases by administering to patients compounds having the general structure of
[GLP-1R targeting peptide]-[ring-opened Maleimide linker]-[antisense oligonucleotide]
Such methods would yield predictable results, namely the treatment of a patient’s disease following subcutaneous administration exactly as taught and suggested in view of the prior art. Accordingly, the simple substitution of the prior art antisense oligonucleotide of MALAT-1 of WO’995 in place of another antisense oligonucleotide would continue to yield the same predicted and expected results, because the prior art of WO’186 in view of Korner, WO’443, Fontaine, US’871, and Handbook reasonably inform artisans that any antisense oligonucleotide could be utilized in the disclosed constructs, and forming a conjugate with the antisense oligonucleotide of WO’995 would predictably and expectedly yield a conjugate capable of treating diseases in cells expressing GLP-1R by reducing levels of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALA T-1) in vivo following subcutaneous injection (see, e.g., MPEP §§ 2143(I)(A), (B), (G)). Accordingly, the selection of a known antisense oligonucleotide based on its suitability for use in known methods of targeting known transcripts in targeted cell populations using conjugates as disclosed by WO’186 and WO’443 is prima facie obvious per MPEP § 2144.07.
No unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to perform a known method using a known peptide-oligonucleotide conjugate by combining only known sequences and components, in order to predictably obtain the exact results taught and suggested by the prior art.
Accordingly, claims 67-71 and 75-76 are rejected as obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
[NSDP Rejection 01]
Claims 67-71 and 75-76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12115225 in view of Fontaine28.
Claim Interpretation: The applicable claim interpretation has been set forth in a separate section above and in the preceding rejection, and those discussions are incorporated into the instant rejection.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an obviousness analysis.
Regarding instant claims 67-71 and 75-76, both pending claims sets are directed to methods of modulating the expression of a nucleic acid target in a pancreatic beta-islet cell comprising contacting the cell with a conjugate comprising a GLP-1R ligand peptide of SEQ ID NO: 22 conjugated to an antisense oligonucleotide targeting a mRNA (compare instant claims 67, 72 with US’225 at claims 1-3), having a length between 15-30 bases (compare instant claim 68 with US’225 at claim 4), modifications (compare instant claims 68-70 with US’225 at claims 5-6), that may be single-stranded (compare instant claim 71 with US’225 at claim 7). Furthermore, both documents teach the same subgenus of GLP-1R ligand peptides (compare instant claims 67, 73-76 with US’225 at claims 1, 8-12).
The scope of the issued claims differ from the pending claims as follows: The issued claims broadly encompass any linkers between the GLP-1 peptide and the antisense oligonucleotide (see, e.g., US’225 at claim 1) or more specifically maleimide-based linkers (see, e.g., US’225 at claims 9-10), whereas the instant claims require linkers having a ring-opened maleimide structure.
Accordingly, the scope of the issued claims differs because US’225 encompasses
A linker such as
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Rather than a ring-opened maleimide structure as recited and required at instant claim 67(A)-(C).
This difference would have been obvious in view of the knowledge of the prior art. Fontaine informs artisans that although “coupling of a maleimide with a protein Cys is one of the most commonly used methods for bioconjugation” such Maleimide-thiol conjugates may undesirably undergo ring-opening (see, e.g., Fontaine at title, abs, 145 at col I, scheme 1 on 145, Fig. 1 on 146). The general ring-opening process is shown at the abstract image, scheme 1 on page 145, and at Figure 1 on page 146 (see, e.g., Fontaine at abs, scheme 1 on 145, Fig. 1 on 146, abs image reproduced in part below):
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Fontaine discusses an art-recognized problem with Maleimide-thiol conjugates, namely the ring opening reaction in the presence of water leading to potentially unwanted thiol exchange if it occurs unchecked (see, e.g., Fontaine at Scheme 1 on 145, 145 at col I-II at § Introduction, discussing retro-Michael reactions). Fontaine identifies that the ring-opened adduct is stable (see id.; see also id. at abs, noting the half-life of ring-opened products is “over two years”), and therefore Fontaine notes that such ring-opening adducts may be desirably formed on purpose prior to exposing the maleimide-thiol conjugates to other exogenous thiols to avoid unwanted thiol exchange (see, e.g. id. at 146 at col I at 1st full ¶). Accordingly, in view of Fontaine an artisan would readily appreciate that maleimide-thiol conjugated peptide-antisense conjugates as claimed by US’225 will necessarily form ring-opened adducts over time leading to unwanted thiol exchange if allowed to occur unchecked. Accordingly, an artisan would readily appreciate that such structures as recited by US’225 could be improved by intentionally hydrolyzing such conjugates under controlled conditions to avoid unwanted thiol exchange, and to desirably obtain a stabilized, ring-opened maleimide-thiol conjugate (see, e.g. Fontaine at 146 at col I at 1st full ¶). Such reaction would yield linker structures as recited at instant claim 67(A)-(C), and would desirably have a ring-opened, stabilized form as suggested by Fontaine, wherein “X” is a Cys-terminal polypeptide “Y” is an oligonucleotide, and the exact structure of “R” varies depending upon the exact heterobifunctional linker (HBL) used in the conjugation (i.e., GMBS as shown at Fig. 1 of WO’186 would result in an “R” having the structure of (CH2)n, wherein n is 3), as summarized in the following figure:
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Accordingly, the linkage structures shown at claim 67(A)-(C) would be obvious in view of the issued claims and the disclosure of Fontaine.
In sum, the differences between the reference claims and instant claims appear to be minor because both claim sets recite the same general method using the same compounds differing only with regard to the linker utilized29, and therefore the answer to the question “Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent”30 is clearly “yes” in view of the secondary reference.
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping method, wherein the issued claims are generic to the instant claims, and only differ with respect to the specific linker utilized; however, the same linker would necessarily or advantageously be formed as explained above in view of Fontaine (see, e.g., MPEP § 804(II)(B)(3)(B)). Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to improve a known structure using a known reaction that yields known benefits (e.g., a ring-opened maleimide linker would be advantageously more stable, and would necessarily result from the claimed subgenera set forth in the claim scope of US’225) (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(I)(A), (B), (C), (D), and (G)).
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
As noted at MPEP § 804(II)(B)(4), the reference patent and the instant Application are understood to require only a one-way test for distinctiveness.
Accordingly, instant claims 67-71 and 75-76 are rejected
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive. Arguments pertaining to withdrawn claims are moot. Remaining applicable arguments are addressed below.
It is the Examiner’s understanding that Applicant summarizes the first rejection under 35 USC 103 (see, e.g., Reply filed 12/18/2025 at 6 at 1st full ¶). Examiner notes that the summary does not reflect the nuances of the rejection, and directs artisan to the rejection above.
It is the Examiner’s understanding that Applicant recites legal standards and case law (see, e.g., Reply filed 12/18/2025 at 6 at 2nd full ¶). The holdings of the cases and the cited standards are neither disputed nor dispositive of obviousness. Applicant does not provide analysis of any such case to the merits of the instant case. Examiner notes that although Applicant mentions consideration of “the totality of the prior art”, Applicant does not acknowledge or address any prior art listed in the “Pertinent Prior Art” section, which establishes that ring-opening methodologies and practices were well-known in the prior art at the time of filing.
Applicant addresses the teachings of Fontaine alone: Applicant addresses less than the total combination of art relied upon by the Examiner (see, e.g., Reply filed 12/18/2025 at 6-7 at bridging ¶, addressing Fontaine alone). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Fontaine is analogous art: It is the Examiner’s understanding that Applicant is alleging that Fontaine is non-analogous art (see, e.g., Reply filed 12/18/2025 at 6-7 at bridging ¶, alleging that Fontain is “inappropriate for comparison” and is “too distinct” relative to the invention claimed). In response to applicant's argument that Fontaine is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Fontaine directly pertains to ring-opened maleimide linkers as present in the claimed invention, and is therefore clearly analogous art.
Suggestions of inoperability, skepticism of experts, or lack of efficacy regarding ring-opening rates are not persuasive: It is the Examiner’s understanding that Applicant is either alleging the existence of skepticism of experts, alleging that Fontaine is inoperable, or otherwise arguing a lack of efficacy (see, e.g., Reply filed 12/18/2025 at 6-7 at bridging ¶, alleging that “the benefits the Examiner describes in Fontaine … would be detrimental to its use in a GLP1-oligonucleotide conjugate because…GLP-1, by itself, is short-lived signaling peptide”). First, if Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. Second, if Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 because evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. Third, if Applicant is suggesting that efficacy is required to establish obviousness, this is incorrect (see, e.g., MPEP § 2143.02(I)-(II), explaining that obviousness does not require “Conclusive proof of efficacy”, and that “obviousness does not require absolute predictability” but instead only “at least some degree of predictability”). Fourth, the stated concern regarding the slow rate of ring-opening relative to the half-life of GLP-1 is acknowledged (see, e.g., Reply filed 12/18/2025 at 6-7 at bridging ¶), but does not appear relevant because unmodified “GLP-1, by itself” is not at issue, and Applicant fails address the half-life of SEQ ID NO: 22 and conjugates prior to ring-opening (see id). In addition, Fontaine explicitly addresses accelerating the ring-opening reaction (see, e.g., Fontaine at abs, explaining how “ring-opening rates are greatly accelerated”), and Applicant fails to identify why the rate of ring-opening would continue to be a problem in view of the guidance of the prior art. In sum, arguments suggesting skepticism of experts, inoperability, lack of efficacy, etc. are not persuasive for the reasons set forth above, including the lack of objective supporting evidence, explanation of relevance of “GLP-1, by itself” to the claimed invention, and failure to address “greatly accelerated” ring-opening rates as discussed by Fontaine.
Suggestions of inoperability, skepticism of experts, or lack of efficacy regarding “potential liabilities toward hydrolytic and other conditions” using oligonucleotides are not persuasive: It is the Examiner’s understanding that Applicant is alleging either the existence of skepticism of experts or otherwise alleging that Fontaine is inoperable or non-enabling for use with oligonucleotide containing compounds (see, e.g., Reply filed 12/18/2025 at 7-8 at bridging ¶). First, if Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. Second, if Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 because evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be conjecture of counsel unsupported by relevant, objective evidence. Third, none of the conditions identified appear germane to the invention as actually claimed, or otherwise identify, with specificity, what reactions are allegedly inoperable or non-enabling (see, e.g., Reply filed 12/18/2025 at 7-8 at bridging ¶).
Examiner has not relied upon improper hindsight: It is the Examiner’s understanding that Applicant is suggesting that the Examiner relied upon improper hindsight because the instant invention could allegedly only be arrived at “in view of the instant application” (see, e.g., Reply filed 12/18/2025 at 8-9 at bridging ¶). In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, Applicant fails to identify any portion of the rejection that relies upon the instant disclosure.
Applicant’s reliance upon post-filed, non-patent literature is misplaced: It is the Examiner’s understanding that Applicant is attempting to rebut prima facie obviousness by relying upon Knerr et al., published in 2021 (see, e.g., Reply filed 12/18/2025 at 8-9 at bridging ¶). This is not persuasive because, per MPEP 2143.02(III), predictability is determined before the effective filing date of the claimed invention. Accordingly, because Knerr et al. was published years after filing, it does not establish a lack of prima facie obviousness because it does not reflect predictability in the art before the effective filing date of the invention.
Applicant addresses the teachings of US’871 alone: Applicant addresses less than the total combination of art relied upon by the Examiner (see, e.g., Reply filed 12/18/2025 at 9 at 1st full ¶, alleging that “the ’871 publication fails to teach or suggest open-ring maleimide conjugate”). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant addresses the teachings of Handbook alone: Applicant addresses less than the total combination of art relied upon by the Examiner (see, e.g., Reply filed 12/18/2025 at 9 at 2nd full ¶, alleging that “the Handbook fails to teach or suggest open-ring maleimide conjugate”). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant addresses the teachings of US’995 alone: Applicant addresses less than the total combination of art relied upon by the Examiner (see, e.g., Reply filed 12/18/2025 at 10 at 1st full ¶, alleging that “the ’995 publication fails to teach or suggest open-ring maleimide conjugate”). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
No e-filed Terminal Disclaimer over US 12,115,225 has been filed: It is the Examiner’s understanding that Applicant does not dispute the NSDP rejection over US’225, but instead alleges that “Applicant e-filed a Terminal Disclaimer over US Patent No. 12,115,225”. However, upon review of the record, Examiner is unable to find evidence that a Terminal Disclaimer was filed or approved.
Examiner notes that prior responses in the Parent Application remain applicable (see, e.g., Application 16/762,391 in Final mailed 6/26/2023 at pages 16-22).
Applicant did not dispute the rationales supporting a determination of obviousness as relied upon by the Examiner with specificity (e.g., MPEP §§ 2143(I)(A), (B), (C), (D), (G)). Examiner notes that the expected and predicted results have been explicitly set forth in the rejection.
Zero evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record to date.
Zero evidence of skepticism of experts commensurate in scope with the requirements of MPEP § 716.05 have been placed on record to date.
Zero evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record to date.
Accordingly, all arguments raised in the Reply filed 12/18/2025 have been fully considered but not found persuasive. Accordingly, the rejections are maintained as revised above, wherein all revisions were necessitated by Applicant’s amendments.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20190134214 A131 pertains to GLP-1 Receptor ligand moieties conjugated to oligonucleotides.
Juliano32 reviews the chemistry of oligonucleotide conjugates in therapeutics circa 2012, including modified oligonucleotide chemistries (see, e.g., Juliano at Fig. 2 on 1069), and typical conjugation methods for use in conjugating oligonucleotides to peptides (see, e.g., Juliano at 1071 at col I-II at § 2 at §§ “Peptides”, Table 1 at 1073). Juliano discloses the basic structure of such conjugates (see id at image at abstract).
Henke33 discloses, discusses, and reduces to practice peptide-conjugated antisense oligonucleotides (see, e.g., Henke et al. at title, abs, Fig. 1).
Tumey34 discloses that ring-opening reactions improve stability of ADC compounds:
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And that such reactions yield “significantly improved efficacy” (see, e.g., Tumey at abs, 1872 at col I).
Whitehead35 discusses advances in siRNA delivery (see, e.g., id. at title, abs), including modifications to the oligonucleotide (see, e.g., id. at 131 at § Modified siRNA, 133 at Fig. 3).
Juliano200936 discloses barriers to therapy for siRNA and antisense approaches (see, e.g., id. at title, abs), including modifications to the oligonucleotide (see, e.g., id. at 687 at Fig. 1), and the use of “targeting ligands” or “cell penetrating peptide” conjugates (see, e.g., id. at 692 at col II to 694 at col II).
Bennett37 discloses therapeutic platforms for using siRNA and antisense therapy approaches (see, e.g., id. at title, abs), including modifications to the oligonucleotide (see, e.g., id. at 272 at Fig. 3), and the use of conjugation strategies involving targeting ligand conjugates (see, e.g., id. at 272 at 1st para to 279 at 1st para).
Winkler38 discusses oligonucleotide conjugates for therapeutic applications (see, e.g., id. at title, abs), including conjugation of oligonucleotides to peptide and protein ligands (see id, see passim).
Ikeda39 discusses ligand-targeted delivery of therapeutic siRNA (see, e.g., id. at title, abs), including antibodies (see id., passim).
Conclusion
No claims are 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.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 0.01 µmol/kg is understood to be equivalent to 10 nmol/kg.
2 Ming et al., Bioconjugates for targeted delivery of therapeutic oligonucleotides. Adv Drug Deliv Rev. 2015 Jun 29;87:81-9. doi: 10.1016/j.addr.2015.02.002. Epub 2015 Feb 15. PMID: 25689735; PMCID: PMC4504788; cited in previous action.
3 WO 2009/089186 A2, Henke et al.; July 16, 2009; cited in IDS filed 2/23/2024 as Cite No: 4)
4 Korner et al., GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting, The Journal of Nuclear Medicine, vol. 48(5) (May 2007); hereafter “Korner”; cited in IDS filed 2/23/2024 as cite No. 13.
5 WO 2012/177443 A2, Dec. 27, 2012; cited in IDS filed 2/23/2024 as Cite No: 6.
6 Fontaine et al., Long-Term Stabilization of Maleimide-Thiol Conjugates, Bioconjugate Chem., vol 26:145-152 (2015); hereafter Fontaine; cited in IDS filed 2/23/2024 as cite No. 4.
7 WO’443 explicitly directs artisans to GLP-1 receptor peptide ligands (see, e.g., WO’443 at title, abs, ¶¶[0007]-[0008], [0038], [0057], [00185], [00213], claims 18-19 and 24-26). Notably, WO’443 discloses a GLP-1 receptor ligands, including SEQ ID NO: 13, which comprises the 9-mer sequence “HAibQGTFTSD”, which shares at least 80% sequence identity relative to the equal length portion of instant SEQ ID NO: 22 (e.g., “HAibEGTFTSD”) (compare instant SEQ ID NO: 22 with WO’443 at claims 1 and 18-19).
8 WO’443 repeatedly informs artisans that conjugation could occur “through adding a C-terminal Cys” to the GLP-1 Receptor peptide ligand (see, e.g., WO’443 at ¶¶[0062], [0095]; see also id. at ¶¶[00157]-[00158], [00174], [00187], [00197]-[00198], [00206], [00214], [00216], claim 10). And as noted in the rejection, the linkages disclosed by WO’186 include, presume, or require the presence of such residues. Therefore, an artisan would readily appreciate that the disclosed [GLP-1 receptor peptide ligand]-[nucleic acid molecule] conjugates could be prepared through a C-terminal Cysteine already present, or otherwise added to the peptide ligand, and reacting the modified peptide with a maleimide-modified nucleic acid. As noted by Fontaine, such reactions are routine in the art (see, e.g., Fontaine at title, abs, 145 at col I, scheme 1 on 145, Fig. 1 on 146).
9 In KSR, the Supreme Court reaffirmed principles based on its precedent that "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results" (see, e.g., MPEP 2141(I); see also KSR Int'l Co. v. Teleflex Inc., 550 U.S. 538, 417, 82 USPQ2d 1385, 1396 (2007); stating that "If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. Here, all components were known, the conjugate structure combining the separate components were known, the methods of treating diseases by systemic administration were known, and the method and benefits of ring-opening a maleimide was already known. To date, no evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record, and all components merely appear to perform the expected and predicted functions taught by the prior art.
10 WO 2009/089186 A2, Henke et al.; July 16, 2009; cited in IDS filed 2/23/2024 as Cite No: 4)
11 Korner et al., GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting, The Journal of Nuclear Medicine, vol. 48(5) (May 2007); hereafter “Korner”; cited in IDS filed 2/23/2024 as cite No. 13.
12 WO 2012/177443 A2, Dec. 27, 2012; cited in IDS filed 2/23/2024 as Cite No: 6.
13 Fontaine et al., Long-Term Stabilization of Maleimide-Thiol Conjugates, Bioconjugate Chem., vol 26:145-152 (2015); hereafter Fontaine; cited in IDS filed 2/23/2024 as cite No. 4.
14 US 2015/0320871 A1; DiMarchi et al; Nov. 12, 2015; cited in IDS filed 2/23/2024 as cite No. 7.
15 WO 2009/089186 A2, Henke et al.; July 16, 2009; cited in IDS filed 2/23/2024 as Cite No: 4)
16 Korner et al., GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting, The Journal of Nuclear Medicine, vol. 48(5) (May 2007); hereafter “Korner”; cited in IDS filed 2/23/2024 as cite No. 13.
17 WO 2012/177443 A2, Dec. 27, 2012; cited in IDS filed 2/23/2024 as Cite No: 6.
18 Fontaine et al., Long-Term Stabilization of Maleimide-Thiol Conjugates, Bioconjugate Chem., vol 26:145-152 (2015); hereafter Fontaine; cited in IDS filed 2/23/2024 as cite No. 4.
19 US 2015/0320871 A1; DiMarchi et al; Nov. 12, 2015; cited in IDS filed 2/23/2024 as cite No. 7.
20 Crosslinking Technical Handbook, Crosslinking Technical Handbook, Thermo Scientific, 56 pages with 1 page citation information (Aug. 20, 2015); hereafter “Handbook”; cited in IDS filed 2/23/2024 as cite No. 1.
21 WO 2009/089186 A2, Henke et al.; July 16, 2009; cited in IDS filed 2/23/2024 as Cite No: 4.
22 Korner et al., GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting, The Journal of Nuclear Medicine, vol. 48(5) (May 2007); hereafter “Korner”; cited in IDS filed 2/23/2024 as cite No. 13.
23 WO 2012/177443 A2, Dec. 27, 2012; cited in IDS filed 2/23/2024 as Cite No: 6.
24 Fontaine et al., Long-Term Stabilization of Maleimide-Thiol Conjugates, Bioconjugate Chem., vol 26:145-152 (2015); hereafter Fontaine; cited in IDS filed 2/23/2024 as cite No. 4.
25 US 2015/0320871 A1; DiMarchi et al; Nov. 12, 2015; cited in IDS filed 2/23/2024 as cite No. 7.
26 Crosslinking Technical Handbook, Crosslinking Technical Handbook, Thermo Scientific, 56 pages with 1 page citation information (Aug. 20, 2015); hereafter “Handbook”; cited in IDS filed 2/23/2024 as cite No. 1.
27 WO 2017/053995 A1; Swayze et al.; March 2017; cited in IDS filed 2/23/2024 as cite No. 12.
28 Fontaine et al., Long-Term Stabilization of Maleimide-Thiol Conjugates, Bioconjugate Chem., vol 26:145-152 (2015); hereafter Fontaine; cited in IDS filed 2/23/2024 as cite No. 4.
29 See, e.g., MPEP § 804(II)(B), “To decide the question above, the examiner should first construe the claim(s) in the application under examination and the claim(s) in the reference application or patent to determine what are the differences
30 See, e.g., MPEP § 804(II)(B), noting that “In determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
31 US 20190134214 A1 (May 9,2019; filed 5/6/2016; cited in IDS filed 2/23/2024 as Cite No. 13)
32 Juliano et al. (The Chemistry and Biology of Oligonucleotide Conjugates, Acc. Chem. Res. 2012, 45, 7, 1067–1076 (February 21, 2012); hereafter “Juliano”; cited in IDS filed 2/23/2024 as Cite No. 10).
33 Henke et al. (Peptide-Conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo, Nature Biotechnology, Vol. 26(1):91-100 (Jan. 2008); cited in IDS filed 2/23/2024 as Cite No. 6)
34 Tumey et. al., (Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy, Bioconjugate Chemistry, vol. 25(10):1871-1880 (Oct. 6, 2014), PMID: 25216346; hereafter “Tumey”; cited in IDS filed 2/23/2024 as Cite No. 21)
35 Whitehead et al., Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009 Feb;8(2):129-38. doi: 10.1038/nrd2742. Erratum in: Nat Rev Drug Discov. 2009 Jun;8(6):516. PMID: 19180106; PMCID: PMC7097568; cited in previous action.
36 Juliano et al., Biological barriers to therapy with antisense and siRNA oligonucleotides. Mol Pharm. 2009 May-Jun;6(3):686-95. doi: 10.1021/mp900093r. PMID: 19397332; PMCID: PMC2758224; cited in previous action.
37 Bennett et al., RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259-93. doi: 10.1146/annurev.pharmtox.010909.105654. PMID: 20055705; cited in previous action.
38 Winkler, Oligonucleotide conjugates for therapeutic applications. Ther Deliv. 2013 Jul;4(7):791-809. doi: 10.4155/tde.13.47. PMID: 23883124; PMCID: PMC3787477; cited in previous action.
39 Ikeda et al., Taira K. Ligand-targeted delivery of therapeutic siRNA. Pharm Res. 2006 Aug;23(8):1631-40. doi: 10.1007/s11095-006-9001-x. PMID: 16850274; cited in previous action.