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 with traverse of Group I (drawn to a compound/pharmaceutical composition), and the species recited in claim 7, in the reply filed on 05/23/2024 is acknowledged.
Claims 1, 3-7, 11, 14-23 are pending of which (claims 14-17, 20-23) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected INVENTION, there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1, 3-7, 11, 18-19 have been examined on the merits.
Please note, for clarity of the record, Applicant’s election of the species of compound recited in claim 7, having the following structure:
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corresponding claim 1’s genus when R5, R6, R8, R9 are hydrogen; R1, R2, R3, R4 are aryl; O=Y=O is a dioxolane ligand in the form of semiquinone,
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, wherein R31 is OR34 where R34 is an alkyl; m is +1; X- is PF6-, reading on claims 1, 3-7, 11 and 18-19.
Withdrawn Rejections
The rejection of claims 1, 3-7, 11, 18-19 under 35 U.S.C. 103 as being unpatentable over CN107417736B in view of Ghosh et al. (J Biol. Inorg. Chem. 2005 Aug; 10(5):496-508), Wada et al. (Inorg. Chem. 2006 Oct 30; 45(22):8887-94) and Pyle et al. (J. of the Amer Chem Soc, 111(8), 3051–3058). As evidence by Notaro A. et al. (J Med. Chem. 2020 May 28; 63(10):5568-5584. All references are being made to the English translation (machine generated). The Chinese version can be found at the end of the English translated version is withdrawn in view of the claim amendment.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/26/2025 has been entered.
New Grounds of Rejection due to the Applicant’s Claim Amendments
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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
Non-obviousness.
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.
Claims 1, 3-7, 11, 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over CN107417736B in view of Ghosh et al. (J Biol. Inorg. Chem. 2005 Aug; 10(5):496-508), Wada et al. (Inorg. Chem. 2006 Oct 30; 45(22):8887-94) and Pyle et al. (J. of the Amer Chem Soc, 111(8), 3051–3058). As evidence by Notaro A. et al. (J Med. Chem. 2020 May 28; 63(10):5568-5584. Gransbury et al., Inorg Chem, vol. 58, no. 7, Apr. 2019, pp. 4230–43. All references are being made to the English translation (machine generated). The Chinese version can be found at the end of the English translated version.
Regarding claims 1, 3-7, 18-19, CN ‘736 in ([0018]) teaches a compound Ru(DIP)2(SA) wherein R1 to R4 are phenyl; R5, R6, R8 and R9 are each hydrogen, comparable to the
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instant claim. CN ‘736 (abstract) teaches that ruthenium complex exhibits anticancer or antitumor activity in vitro. CN ‘736 ([0007]) discloses that one of the major mechanisms of ruthenium complex is targeting DNA, comparable to instant claim (specification page 37). CN ‘736 does not teach a dioxolene ligand or a semiquinone.
However, Ghosh (page 496-497, Figure 1) teaches multiple structural analogs of ruthenium (II) complexes bearing different polypyridyl ligands, including dioxolane or semiquinone ligand; for example, Ru(phen)2(bsq)+. Ghosh (page 500-501) teaches the salt
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form of multiple structural analogs of ruthenium (II) complexes bearing PF6- counterion, wherein m+ is +, (X-)m is PF6- ; for example Ru(phen)2(bsq)](PF6). Ghosh (page 500-504) also teaches PF6- counterion is used to stabilize cationic ruthenium complexes, regardless of the particular ligand environment. Therefore, it would have been obvious for a person of ordinary skill in the art (POSITA) to modify CN ‘736’ teachings with the disclosure of Gosh by incorporating PF6- counterion to improve the stability, solubility and characterization of ruthenium (II) complexes.
Regarding dioxolane, Ghosh (page 502 and 504-505) teaches incorporating dioxolane (semiquinone-type) in ruthenium complexes plays critical role by enabling reversible redox activity through their coordination with ruthenium. This is supported by Wade (8887-8888; Scheme 1) which teaches that “ruthenium-dioxolane complexes are particularly interesting because of their close energy levels between the d-orbital and the π-orbital of the metal and the dioxolane ligand, respectively. As a result, there are formally six possible electronic structures for RuII/III-dioxolane complexes.” This teaching indicates that the close energy matching allows for strong interaction between metal center and the ligand, and the electronic flexibility and the ability to access multiple oxidation states represent some of the key advantages to replace salicylic acid with dioxolane ligand,
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wherein R30 and R31 are hydrogen.
However, the combined teachings of CN ‘736 and Ghosh do not teach R30 and R31 to be other than hydrogen.
Gransbury (abstract; page 4231) discloses metal complex containing bidentate dioxolane
(catecholate/semiquinone) ligand, which is analogous to the instant claim. Gransbury (abstract; page 4231) discloses that dioxolane ligand is optionally substituted with X = Br4, Cl4, H4, 3,5-Me2, and 3,5-tBu2, which corresponds to the R30 and R31 as disclosed in the instant claim.
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Gransbury (page 4230-4231) also teaches that such substituents on the dioxolane ring enables valence tautomerism, which in turn stabilizes the ruthenium complex. Given that Ghosh teaches the importance of electronic properties and flexibility of the RuII/III-dioxolane complexes, and Gransbury further discloses that variation in the ring substituents influence valence tautomerism and stability, thus, a person of ordinary skill in the art (POSITA) would view these teachings as practical guidance in pharmaceutical medicine. Furthermore, a POSITA would also predict that modifying dioxolane ligand substituent is an effective and predictable method to control the redox and electronic properties of ruthenium complex. Therefore, it would have been obvious that a POSITA would modify the combined teachings of CN ‘736 and Ghosh in view of Gransbury to arrive at the claim invention, due to the relative improvement in stability and valence tautomerism that the substituents offer. As evidence by Heike’s disclosure (page 29888-29892) of halogens substituents withdraw electron density from the catecholate ligand, make it
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more electron-poor and harder to oxidize. Thus, this electronic effect stabilizes lower-energy ligand states and shifts redox processes to more positive potential, which strongly influencing valence and thus stabilizing the metal complex. (Hieke et al., ACS Omega, vol. 10, no. 27, July 2025, pp. 29888–98.)
This redox flexibility allows the ruthenium complex not only to bind to DNA but also to participate in chemical electron transfer through their unique electron delocalization which enables reversible redox activity. This is supported by the specification (page 37, line 29-32)
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This suggests the inherent property of ruthenium complex to bind with DNA. Thus, incorporating a dioxolane ligand can further enhance this interaction, as the redox versatility of dioxolane enable not only binding but also dynamic electron transfer processes, potentially enhancing their impact on DNA interaction. Therefore, it would have been obvious to a POSITA to modify the CN ’736’ teachings in view of Gosh and Wade by replacing salicylic acid ligand with dioxolane to arrive at the claimed invention, because of the unique electrochemical properties and dynamic DNA interactions, enhancing the complex activity such as catalysis or targeted biological intervention.
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The other possibility, is modifying Gosh’s teaching in view of CN’ 736, this is because Pyle (page 3057, right col.; page 3052, Figure 3) teaches ruthenium complex containing DIP core structure which has a higher binding affinity to DNA because of larger surface area and non-planarity compared to phen core structure. In fact, Pyle (page 3057, right col.; page 3052, Figure 3) teaches ruthenium complex containing DIP core structure is better than phen, thus it would have been reasonable to a POSITA to consider modifying Gosh’s teachings in view of Pyle and CN ‘736 by considering to replace phen core structure with DIP to come to [Ru(DIP)2(bsq)] (PF6) and arrive at the claimed invention. Therefore, it would have been prima facie obvious to a POSITA to combine the teachings of Gosh and CN in view of Pyle and Wade, on the use of ruthenium complex compound as anticancer drugs, to arrive at the claimed invention. A POSITA would have been motivated to do so because CN ‘763 teaches Ru (DIP)2 with a more favorable IC50 against certain cancer cell lines in vitro, Pyle teaches a ruthenium complex with DIP core structure exhibits a stronger binding affinity to DNA compared to phen core structure, and Wade discloses a wide range capability of dioxolane ligand binding to ruthenium (II).
Regarding claim 11, CN ‘736 does not explicitly teach a pharmaceutical composition. However, Gosh (page 498-501) teaches various ruthenium analogs are in a water solution during both the synthesis and purification steps, indicating water as a pharmaceutical excipient. As evidence by Notaro describes administering ruthenium complexes in water-containing buffers before animal injections. Therefore, a POSITA would have strong motivation to use water as an excipient when formulating ruthenium analogs for therapeutic applications.
Response To Argument
Applicant argues that the instant claim has been amended to exclude hydrogen, and the cited prior art does not teach the specific structural changes necessary to yield anticancer properties. Applicant’s argument is not persuasive because the newly cited Gransbury reference explicitly discloses dioxolane bearing non-hydrogen substituents, such as X = Br4, Cl4, 3,5-Me2, 3,5-tBu2, which corresponds to the R30 and R31 as disclosed in the instant claim. Furthermore, Gransbury teaches that halogens and alkyl substituents on bidentate dioxolane provides electronic stabilization and control over valance tautomerism in the metal complex. This indicates that such substitution provides desirable stability to the coordination environment; thus, a POSITA would recognize such benefits, and would implement such approach. This is because valence tautomerism can stabilize the ruthenium complex, thereby enhancing its ability to intercalate within the DNA groove, which in turn can improve the compound effectiveness.
Applicant argues that ancillary and intercalative ligands, particularly the salicylic ligand, are essential for achieving anticancer activity through DNA interaction, which contradict Examiner’s assertion regarding ruthenium analogs exhibit inherent anticancer activity. This argument is not persuasive because, while salicylic ligand may influence the compound’s therapeutic benefit, it does not negate the primary activity associated with Ru(II) analogs. Ru analogs are well established to exhibit intrinsic cytotoxic, because of their binding association with the DNA. Not to mention, Ru(II) coordination environment providing predictable stability and DNA association across divers ligands; which can’t be said regarding salicylic ligand. Furthermore, in the Ru-salicylic analogs, as an example, DNA interaction is driven primarily by the Ru(phen)2 core, whose planar aromatic ligands mediate groove binding and π-stacking and salicylic ligand does not participate in this mechanism, as mentioned previously. This is why CN ‘736 (Table 1) discloses varying levels of anticancer activity across different Ru analogs, even though the salicylic ligand remains constant. Therefore, Applicant’s argument that none of Gosh, Pyle, Wada, or Notaro cures the deficiencies of CN ‘736, is not persuasive; as it appears that Applicant overlooks CN ‘736’s teachings reading Ru analogs in relation to the salicylic ligand.
Applicant argues that there is no motivation to replace the phen ligands in Ghosh's
complexes with the DIP ligand, because such a changed would not enhance anticancer activity. Applicant’s argument is not persuasive because Pyle (3057, right col.) discloses binding data from absorption titration demonstrates that DIP actually shows increased binding affinity compared to phen. Moreover, both emission enhancement and absorption red shifts are greater for DIP complexes, than phen. These findings suggests that DIP and phen have distinct binding characteristic and that DIP may be favored over phen. This is supported by CN ‘736 that clearly demonstrates that Ru-complexes containing DIP exhibit superior and consistent anticancer potency, based on the IC50 values, compared to those containing phen, as an example.
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Table 1 further supports that DIP would be the preferred ligand over either phen or phi.
Furthermore, 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). Therefore, Applicant should consider the combined teachings of the prior art as a collective disclosure for the obviousness rejection, rather on differences found in any single prior art.
Applicant further argues that the complexes of the present invention exhibit a
remarkable anticancer activity. Applicant’s argument is not persuasive and does not establish “remarkable anticancer activity.” Applicant’s data (specification page 34, Table 1) show that Ru(DIP)2Cl2 exhibits an IC50 of 15.03±0.4 in HeLa cells, while CN ‘736 (Table 1) Ru(DIP)2(SA) is 20±2.3 under comparable conditions. These values are closely aligned and do not represent a “remarkable anticancer activity.” Therefore, the specification does not support a claim of “remarkable anticancer activity” that is sufficient to overcome the 103 rejection, thus the rejection is maintained.
Conclusion
Therefore, claims 1,3-7, 11, and 18-19 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622