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 371 of PCT/EP2021/079141, filed Oct. 20, 2021, and claims foreign priority to LU102145, filed Oct. 21, 2020 in the Grand Duchy of Luxembourg.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Nov. 5, 2025; Feb. 11, 2026; and Apr. 10, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Response to Restriction/ Election -- Claim Status
Claims 1-3, 5-6, 8-9, 11, 14-18, 20, 22, 23, and 26-29 are currently pending.
Applicant’s election without traverse of Group I in the reply filed on Sept. 30, 2025 is acknowledged.1
Claims 1-3, 5-6, 8-9, 11, 14-18, 20, 22 and 27-28 are active and subject to examination.
Claims 23, 26 and 29 are withdrawn.
Claim Rejections – 35 USC § 103 – Previously Presented
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.Response to Arguments
The Applicant argues that the Office’s conclusion of obviousness is based on an impermissible picking and choosing of disclosure from the references and that there is no motivation provided in the references to modify Gutjahr to arrive at the claimed invention (Remarks, p. 10). These arguments were fully considered but are not persuasive. First, “picking and choosing may be entirely proper in the making of a 103 obviousness rejection” In re Arkley, 455 F.2d 586, 587-88 (C.C.P.A. 1972). Second, as stated in MPEP § 2144.09:
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c).
MPEP 2144.09.
A prima facie case of obviousness for the modification of Gutjahr with Gential was made because Gential teaches similar bivalent TLR7 conjugates with a similar TLR7-linker structure to Gutjahr. One of ordinary skill in the art would have a reasonable expectation that replacing the TLR7-linker structure of Gutjahr with the TLR70-linker structure of Gential would produce a compound with similar properties to Gutjahr.
The Applicant argues that there would be no motivation to use the PEG linker of Gential because is overlooks the fundamental issue of the attachment point of the linker on the NOD2 agonist, particularly because Gential teaches that the position of attachment significantly affects immunogenicity (Remarks, p. 10). These arguments were fully considered but are not persuasive. As noted by the Applicant the NOD2 agonist of Gobec is a small molecule with multiple attachment points (id.). The NOD2 agonist of Gobec was made as an analog to the MDP agonist as in Gutjahr (Gobec, Abstract). Gutjahr teaches that the point of attachment of the MDP agonist to the linker is though the MurNAc moiety, so at least one of ordinary skill in the art would have a reasonable expectation of success to attach the NOD2 agonist of Gobec through the MurNAc surrogate, as in the present claims. Furthermore, Gential teaches that the point of attachment is only important because the compound needs to be cleaved by the proteasome for efficient T-cell epitope generation (Gential, p. 1344), whereas no such issue exists for the NOD2 agonists of the present claims/ of Gobec. As such, one of ordinary skill in the art would have a reasonable expectation of success to attach the linker to the MurNac surrogate, the N-terminal surrogate (L-ala) or the C-terminal surrogate (D-Glu diethyl ester) and they would know how to do so because Gential teaches an ordinary artisan how to attach a linker to multiple points on a peptide/ peptide analog and Gutjahr teaches how to attach to the MurNAc. As stated in the MPEP:
As a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure.
MPEP § 2143.I.B (example 11).
The Applicant argues that the claimed compounds represent a surprising synergistic effect of the claimed TLR7 agonist, linker and NOD2 agonist combination (Remarks, p. 10-11). These arguments were fully considered but are not persuasive. It is not persuasive that one of ordinary skill in the art would not have found synergy between a TLR7-NOD2 conjugate because Gutjahr teaches that there is synergy between the epitopes of such compounds, which outperforms the free compounds:
While the co-administration of TLR7 and NOD2 ligands induced the overexpression of multiple cytokines, the hybrid molecule enhanced synergistically this effect. In fact, TLR7/NOD2L induced significantly the secretion of Th1 (IFN-γ and IL-2, p<0.05), Th2 (IL-10 and IL-5, p<0.05), Th17 (IL-17, p<0.05) and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α, p<0.05). It also induces chemokines (IL-8, MCP-1 and MIP-1β, p < 0.05).
Gutjahr, p. 5-6.
Reiterated Rejection
Claim(s) 1-3, 5-6, 8-9, 11, 14-18, 20, 22 and 27-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gutjahr et al. (EBioMedicine, Vol. 58, 2020, 102922, p. 1-9, published July 30, 2020) (of record) om view of Gential et al. (Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 11, 1 June 2019, Pages 1340-1344) and Gobec et al. (J. Med. Chem 2018, 61, 2707-2724) (of record IDS p. 3).
Claim 1 is directed towards a chimeric TLR7/NOD2 agonist of formula I:
PNG
media_image1.png
165
178
media_image1.png
Greyscale
wherein R3 is a NOD2 agonist selected from the group consisting of
PNG
media_image2.png
126
293
media_image2.png
Greyscale
PNG
media_image3.png
255
266
media_image3.png
Greyscale
.
A preferred compound of formula (I) is for example, compound 30:
PNG
media_image4.png
145
595
media_image4.png
Greyscale
(named in claim 22, structure presented on p. 47 of the Specification).
Gutjahr teaches a chimeric TLR7/NOD2 agonist, CL325, having the following structure:
PNG
media_image5.png
287
340
media_image5.png
Greyscale
(Gutjahr, p. 3). This compound has the same activity as in the instant invention and functions as a vaccine adjuvant which outperforms the unconjugated compounds applied together:
Background
PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels.
Methods
Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors.
Finding
The combined TLR7/NOD2 agonist showed increase efficacy than TLR7L or NOD2L agonists alone or combined in different in vitro models. Dual TLR7/NOD2 agonist efficiently stimulates TLR7 and NOD2, and promotes the maturation and reprogramming of human dendritic cells, as well as the secretion of pro-inflammatory or adaptive cytokines. This molecule also strongly induces autophagy in human cells which is a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24.
Interpretation
Dual TLR7/NOD2L agonist is a very potent and versatile vaccine adjuvant and promote very efficiently both systemic and mucosal immunity.
Gutjahr, Abstract.
While Gutjahr does not teach the specific linker and TLR7 agonist as instantly claimed, one of ordinary skill in the art would have a reasonable expectation of success to use the PEG linker and the claimed TLR7 agonist because Gential teaches chimeric TLR7 ligands having the same TLR7 and linker structure as instantly claimed:
PNG
media_image6.png
411
698
media_image6.png
Greyscale
Gential, p. 1341.
Gential teaches that “Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines.” (Gential, Abstract). Gential teaches that it is a common practice to covalently link TLR7 ligands to macromolecules such as peptides in order to develop new compounds with improved immunological properties (Gential, p. 1340, col. 1-2). Gential also teaches that the PEG linker is preferred and the orientation of the peptide can be varied to improve the properties of the compound:
An ethylene glycol spacer, exhibiting minimal steric hindrance is selected for its favourable influence on the biological activity of the TLR7 ligand upon conjugation, as was shown in previous studies.16
Gential, col. 2, p. 1341;
The three conjugates all induced significantly enhanced T cell proliferation when compared to unconjugated peptide or a mix of TLR7 ligand and peptide(Fig. 3B). In comparison, the conjugates with the ligand at the N-terminal position (conjugates 3 and 4) performed better than the C-terminal conjugate (conjugate 5) as shown by the mean division index (Fig. 3B).
Gential, col. 2, p. 1343.
While CL325 uses the classic muramyl dipeptide (MDP) ligand to stimulate NOD2 instead of the fragment of formula II, III or IV, one of ordinary skill in the art would have a reasonable expectation of success to substitute the fragment of formula II, III or IV for MDP because Gobec teaches that compounds of formula II, III and IV are NOD2 agonists which have the same activity as MDP but improved properties as NOD2 agonists. For example, compound 9:
PNG
media_image7.png
124
340
media_image7.png
Greyscale
(Gobec, Compound 9, p. 2710)
PNG
media_image8.png
475
1037
media_image8.png
Greyscale
Gobec, Abstract.
Gobec also suggests that these compounds would be useful in combination with TLR ligands:
Activation of NOD2 itself is sufficient to shape adaptive immune responses,10,11 but more importantly, NOD2 agonist synergistically augments the adjuvant capacity of other PRR ligands such as Toll-like receptor (TLR) ligands. This NLRTLR crosstalk has been proved to be essential for adaptive immunity and underlines the importance of NLRs.12−15
Gobec, col.. 1, p. 2708.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claims 2-3, 5-6, 8, 11, 14-18, 20, and 22 read on compound 30 and were prima facie obvious at the time of filing for the reasons presented in claim 1.
Claim 27 is directed towards a pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients or carriers. Claim 28 is directed towards a vaccine comprising a compound according to claim 1.
One of ordinary skill in the art would have a reasonable expectation of success to include the compound of claim 1 in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients or carriers, specifically wherein the composition is a vaccine because it is known that chimeric TLR7/ NOD2 ligands are also used as vaccine adjuvants.
For example, Gutjahr teaches that the TLR7/NOD2 agonist was used as an adjuvant in a NP-p24 HIV intranasal vaccine to enhance systemic and mucosal immune humoral responses in mice:
In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24.
Gutjahr, Abstract.
Therefore, claims 27-28 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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 extension fee 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 HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 86-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Prosecution Insights