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 .
Election/Restrictions
Applicant’s election without traverse of Compound (2-1) depicted below
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in the reply filed on 08/27/2026 is acknowledged.
Claims 2-5, 10-12, and 16 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/27/2026.
Priority
This application is a 371 of PCT/JP2023/006307 filed on 02/21/2023, which claims priority to JAPAN 2022-030488 filed on 02/28/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/26/2024 and 10/16/2024 has been considered by the examiner.
Status of claims
Claims 1-17 are pending. Claims 2-5, 10-12, and 16 withdrawn. Claims 1, 6-9, 13-15, and 17 are examined to the extent they read on the elected species.
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 1, 6-9, 13-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Giuliani et al. (US2012/0171703 A1, cited herein as “Giuliani-1”) in view of Giuliani et al. (Tetrahedron Letters 53 (2012) 5114–5118, cited as “Giuliani-2”)
Findings regarding the Primary Reference
Giuliani-1 discloses naïve coelenterazine, a compound having an imidazopyrazinone nucleus substituted with a 4-hydroxybenzyl group at the 2-posiiton, a 4-hydroxyphenyl group at the 6-position, and a benzyl group at the 8-posiiton as depicted below
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as one of the compounds of Formula I having luminescent and/or bioluminescent reagents. See Abstract, Figure 1 and Table 3.
Giuliani-1 additionally discloses sulfur-containing coelenterazine derivatives in Table 6 and describes their preparation in Scheme 8 and paragraph [0142]. Giuliani-1 also teaches the compounds are endowed with an improved red-shifted photoemission in bioluminescence while maintaining lipophilicity and enzymatic binding properties of the original coelenterazine molecules. Yet, the efficiency and sensibility to Ca' depends on the interactions of the particular compound in the enzymatic binding pocket and the environment involved. Indeed, the bivalent sulfur and Selenium atoms are bioisosteres of the methylene group. The present invention relates to new photochemical entity obtained by modification of the methylene (—CH2—) in position C-8 of the imidazo 1.2-cpyrazin-3 (7H)-one nucleus, while the other substituents in position C-2, C-5 and C-6 are preserved. These teachings establish that sulfur-containing substituents at the 8-position were recognized structural alternatives within the coelenterazine class.
The naïve coelenterazine structure disclosed by Giuliani-1 corresponds to the compound represented by the elected structural Formula (2-1), except that the substituent at the 8-position contains a methylene linkage between the imidazopyrazinone nucleus and the phenyl group, whereas elected compound (2-1) contains a sulfur linkage between the same nucleus and phenyl group.
Naïve coelenterazine of Giuliani-1 Elected coelenterazine derivative (2-1)
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Giuliani-2 expressly teaches the replacement of the methylene linkage at the 8-position of the imidazopyrazinone nucleus with sulfur to obtain structurally modified coelenterazine derivatives. See p. 5115, left column, and p. 5115, right column. In particular, Giuliani-2 discloses compounds 3 and 4
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, wherein compound 3 contains a benzyl substituent at the 8-posiiton and compound 4 contains a phenylthiol at the corresponding position. The compounds otherwise possess the same substituent at the remaining positions of the imidazopyrazinone nucleus. See p. 5115, Figure 3, and p. 5116, Scheme 1.
Findings regarding the secondary Reference
Giuliani-2 demonstrates that replacing the C-8 methylene linkage with sulfur alters the photochemical properties of the coelenterazine derivative. Specifically, Table 1 on p. 5116 reports that compound 3 exhibits a relative bioluminescence quantum yield of 1.0, whereas the corresponding sulfur-containing compound 4 exhibits a relative bioluminescence quantum yield of 3.6.
Giuliani-2 further reports that the sulfur substitution produces a bathochromic shift in emission. See p. 5115, right column, and p. 5116, figures 4-5. Additionally, Giuliani-2 discloses compound 8, which contains both a 4-hydroxyphenyl substituent at the 6-position and a 4-chlorophenylthio substituent at the 8-position. See p. 5115, Figure 3, and p. 5116, Table 1. The abstract on p. 5114 identifies compound 8 as exhibiting emission at approximately 510 nm and an unusual slow kinetic decay in the presence of Renilla luciferase.
Accordingly, Giuliani-2 demonstrates that sulfur-containing coelenterazine derivatives retaining a para-hydroxyl substituent on the 6-posiion phenyl ring can exhibit useful luminescent properties.
Motivation to combine
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify naïve coelenterazine disclosed by Giuliani-1 by replacing the methylene linkage between the 8-posiiton of the imidazopyrazinone nucleus and its phenyl substituent with sulfur, as expressly taught by Giuliani-2.
One of ordinary skill in the art would have been motivated to make the proposed modification because Giuliani-1 suggests C-8 methylene linkage can be replaced with a sulfur linkage and also Giuliani-2 teaches that replacement of the C-8 methylene linkage with sulfur provides a means of modifying the photochemical properties of coelenterazine derivatives, including producing a bathochromic shift in emission and, for certain derivatives, increasing bioluminescence quantum yield. In particular, the approximately 3.6-fold increase in relative bioluminescence quantum yield demonstrated for compound 4 relative to compound 3 would have provided a specific experimental reason for investigating the corresponding sulfur substitution in other structurally related coelenterazine derivatives.
Moreover, Giuliani-1 independently discloses sulfur-containing coelenterazine derivatives, further establishing that proposed modification is consistent with the structural modifications contemplated for this class of compounds. The proposed modification would preserve the imidazopyrazinone nucleus and the 2-(4-hydroxybenzyl) and 6-(4-hydroxypheny) substituents already present in naïve coelenterazine while replacing the C-8 methylene linkage with the sulfur linkage taught by Giuliani-2.
The resulting compound possesses the structure represented by elected structural formula (2-1).
Reasonable expectation of success
One of ordinary skill would have had a reasonable expectation of successfully preparing the proposed sulfur-containing coelenterazine derivative because Giuliani-2 expressly demonstrates that replacement of the methylene linkage at the C-8 position of the imidazopyrazinone nucleus with a sulfur linkage is synthetically achievable and produces coelenterazine derivatives exhibiting bioluminescent activity. Specifically, Giuliani-2 disclosed the preparation of sulfur-containing coelenterazine derivatives compounds 4, 6, and 8, using the synthetic methodology illustrated in Scheme 1 (p. 5115, left column). The disclosed synthesis includes introduction of the phenylthiol substituent through reaction of the corresponding bromopyrazine intermediate with an appropriate thiophenol, including by condensation with a suitable carbonyl-containing reagent to form the imidazopyrazinone nucleus. See p. 5115, right column, continuing onto p. 5116, Scheme 1.
Furthermore, Giuliani-2 demonstrates that the resulting sulfur-containing coelenterazine derivatives retain bioluminescent activity. In particular, Table 1 (p. 5115) reports that compound 4 exhibits a relative bioluminescence quantum yield of 3.6 compared with 1.0 for compound 3, which contains the corresponding methylene linkage. Giuliani-2 also reports bathochromically shifted emission resulting from the sulfur substitution. See p. 5115, right column; p. 5116, Tble 1 and Figure 4. Thus, the prior art provides evidence that the proposed structural modification is synthetically feasible and can produce an operative bioluminescent coelenterazine derivative.
Although the precise magnitude of luminescence intensity or emission shift may vary depending on the particular substituents and luciferase system employed, one of ordinary skill in the art would have required certainty regarding the resulting photochemical properties. Rather, in view of the stablished synthesis of structurally related phenylthiol-substituted coelenterazine derivatives and their demonstrated bioluminescent activity, the skilled artisan would have had a reasonable expectation of successfully obtaining a corresponding sulfur-containing derivative of a naïve coelenterazine having useful photochemical properties.
Accordingly, the proposed modification of naïve coelenterazine disclosed by Giuliani-2, in view of the sulfur-containing substitution teachings of Giuliani-2, would have yielded a compound possessing the structure represented by elected structure formula (2-1), with a reasonable expectation of successfully preparing the compound and obtaining a bioluminescent coelenterazine derivative.
Dependent claims 6-9, 13-15, and 17
With respect to the dependent claims 6-9, 13-15, and 17, the limitation recited therein are likewise met by the compound resulting from the proposed modification of naïve coelenterazine disclosed by Giuliani-1 in view of Giuliani-2, as the claims read on elected compound (2-1). Accordingly, these additional limitations, as they read on the elected compound (2-1), do not patentably distinguish the claimed subject matter from the teachings of combined references.
Conclusion
Claims 1, 6-9, 13-15, and 17 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
