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 statement (IDS) submitted on May 25, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is 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Claims 23, 26 and 29 are withdrawn.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 Objections
Claim 1 objected to because of the following informalities: the conjunction between formula III and formula IV should be “and” not “or”. “Alternatives may be set forth as ‘a material selected from the group consisting of A, B, and C’”. (MPEP 2173.05(h)). Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
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:
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wherein R3 is a NOD2 agonist selected from the group consisting of
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.
A preferred compound of formula (I) is for example, compound 30:
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(named in claim 22, structure presented on p. 47 of the Specification).
Gutjahr teaches a chimeric TLR7/NOD2 agonist, CL325, having the following structure:
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(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:
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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:
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(Gobec, Compound 9, p. 2710)
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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.
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.
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/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).