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 . 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.
Priority
The instant application claims foreign priority to application no. CN202211172829.0 filed on 09/26/2022. The certified copy of the foreign priority application filed on 10/10/2023 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/30/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 08/30/2023 is acknowledged. Claims 1, 3, and 7-10 are amended. Claims 11-15 are newly added.
Accordingly, claims 1-15 are pending and being examined on the merits herein.
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.
Claim(s) 1-2, 8, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over CN111704635 (in IDS filed 08/30/2023, an English translation is provided in PTO-892 and used as the basis for this rejection) in view of Lee et al. (Bioorganic and Medicinal Chemistry Letters, 2009 in PTO-892), Carvalho et al. (ACS Omega, 2020 in PTO-892), and Sartor et al. (EurJIC, 2017 in PTO-892).
CN’635 discloses an alkyl chain modified ruthenium complex that has applications in preparing high-efficiency and low-toxicity medicines for treating and/or preventing cancers (see Abstract).
CN’635 discloses that among metal complexes with antitumor activity, ruthenium complexes have attracted widespread attention and are generally considered to be low in toxicity, easily absorbed, and rapidly excreted from the body (paragraph 0005). CN’635 discloses that ruthenium complexes have entered clinical trials for cancer treatment (paragraph 0005). CN’635 discloses that there is a need to continue research on the mechanism of these complexes as well as structural modifications to enhance targeting while having low toxicity (paragraph 0006).
CN’635 teaches their ruthenium complexes are modified with an alkyl chain that have good lipophilicity and is beneficial to improve the drug absorption capacity (paragraph 0008). CN’635 shows several of their ruthenium complexes on pages 2-4 of the original document, which includes the complex shown below:
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Here, the compound above in CN’635 shows the same ruthenium complex and the 4 carbon alkyl chain as the compound recited in the instant claims. However, CN’635 does not further disclose the triazole and uridine moieties further attached to the alkyl chain on the ruthenium complex.
Lee discloses the synthesis of C5-modified nucleosides exhibiting anticancer activity using click chemistry reaction (see Abstract). Lee discloses that several nucleoside drugs have been developed as cancer treatment agents and that recently C5-ethynyl-modified nucleosides have been discovered as having anticancer activity (see left column page 4688). Therefore, Lee sought to synthesize nucleosides at the C5 position, and further disclose the use of a click reaction to generate their nucleosides (see left column page 4688). Lee discloses that click reactions are widely use for the synthesis of modified nucleosides and DNA strands and is a very simple and useful transformation that does not generate any side products or byproducts, unlike other 3+2 cycloadditions (see right column page 4688).
Lee demonstrates the synthesis of their nucleosides utilizing copper sulfate and sodium ascorbate as catalysts in a Sharpless click reaction between the azide and the dipolarphile (compound 5) in a mixed solvent of n-butanol and water shown below:
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Here, the click chemistry involves converting the bromine end to an azide (step 7) and then reacting this azide to the alkyne end of the nucleoside (step 5) to form the final product (compound 11, also see Figure 3 on page 4690) that contains the same uridine and triazole moieties as the recited Formula I of the instant claims.
Lee demonstrates in Table 1 (page 4690) that their synthesized nucleosides inhibited cancer growth of various human tumor cell lines, and further disclose that the triazole nucleosides (compound 10 and 11) exhibit no cytotoxicity at 300 um concentration and may have the better chance as drug candidates over the isoxazole derivatives (see second paragraph right column page 4689).
Carvalho discloses ruthenium-based complexes containing uracil derivatives that exhibit high cytotoxicity against cancer cells (see Abstract). Carvalho discloses that uracil is a well-known pyrimidine nucleobase in RNA building blocks. Carvalho discloses that several modified uracil-based drugs such as 5-fluorouracil (5-FU) have been developed as anticancer drugs and further discloses that these compounds have received further attention for the coordination to transition metals (see first paragraph left column page 122). Carvalho discloses that compounds containing these classes of molecules have been obtained to exhibit different physicochemical properties, and thus able to alter the effectiveness of the drug (see first paragraph left column page 122). Carvalho discloses that several strategies in preparative inorganic chemistry have been widely investigated to coordinate a bioligand with a metal center to increase their biological potential (see first paragraph left column page 122). Carvalho discloses previous studies of Ru(II)-thymine and Ru(II)-5-FU complexes and other uracil-metal based complexes, which show promise as metallodrug candidates against cancer (see left column last paragraph through right column first paragraph page 122).
Carvalho demonstrates in Scheme 1 the synthesis of new Ru(II)-based complexes containing 2-thiouracil derivatives shown below:
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Carvalho demonstrates in Table 1 (page 125) that their ruthenium complexes had lower IC50 values against cancer cells than against noncancer cells and were comparable with other cancer drugs such as oxaliplatin and doxorubicin (last paragraph right column page 124 through first paragraph left column page 125). Carvalho discloses that both ruthenium complexes had a weak interaction with DNA and further caused DNA fragmentation, leading to cell death by apoptosis (see section “Conclusions” right column page 125).
Sartor discloses multivalent azide-functionalized polypyridyl ruthenium complexes and their DNA conjugates through copper-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry reactions (see Abstract). Sartor demonstrates in Scheme 1 and Figure 5 the copper-catalyzed azide–alkyne cycloaddition (CuAAC), also known as click chemistry, forms ruthenium-DNA conjugates shown below:
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It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the alkyl chain group on the ruthenium complex disclosed in CN’635 by further conjugating a uridine moiety as disclosed in Lee and suggested in Carvalho using the click linking chemistry disclosed in Lee and Sartor to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to conjugate a uridine moiety to the ruthenium complex because Lee demonstrates that C5-modified uridine nucleosides were effective in inhibiting cancer cells with no cytotoxicity at 300 um concentration, and Carvalho suggests the conjugation of uracil derivatives to ruthenium complexes to increase its therapeutic effectiveness in cancer treatment. One of ordinary skill in the art would have a reasonable expectation of success because both CN’635 and Lee disclose their respective compounds (ruthenium complex and uridine nucleoside) are effective for treating cancers, and Carvalho further demonstrates the effectiveness of ruthenium-uracil derivative complexes against cancer. Furthermore, one of ordinary skill in the art would have been motivated to use the click linking chemistry to form the ruthenium-uridine complex because Lee discloses that click chemistry is a very simple and useful transformation that does not generate any side products or byproducts, unlike other 3+2 cycloadditions. One of ordinary skill in the art would have a reasonable expectation of success because Lee discloses click chemistry is widely used to synthesize modified nucleosides and demonstrates the click linking chemistry using uridine nucleosides, and Sartor further demonstrates the click linking chemistry using ruthenium complexes to DNA oligonucleotides.
In regards to instant claims 8 and 13, it would have also been prima facie obvious before the effective filing date of the claimed invention to have prepared the ruthenium complex from the combined teachings CN’635, Lee, Carvalho, and Sartor described above as an antitumor drug with a reasonable expectation of success because Carvalho provides guidance of ruthenium-uracil derivative complexes that show promise as anticancer agents, and CN’635 and Lee disclose that ruthenium complexes and uridine nucleoside derivatives, respectively, are effective for cancer treatment.
Claim(s) 3-6 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over CN111704635 (in IDS filed 08/30/2023, an English translation is provided in PTO-892 and used as the basis for this rejection) in view of Lee et al. (Bioorganic and Medicinal Chemistry Letters, 2009 in PTO-892), Carvalho et al. (ACS Omega, 2020 in PTO-892), and Sartor et al. (EurJIC, 2017 in PTO-892), as applied to claim 1 above, and further in view of Barge et al. (Current Organic Chemistry, 2011 in PTO-892).
The combined teachings of CN’635, Lee, Carvalho, and Sartor are as described above and teach the ruthenium complex recited in the instant claims.
Furthermore, CN’635 discloses that the molar ratio between the ligand (alkyl chain) and the ruthenium complex is preferably 2:1 (paragraph 0080). CN’635 discloses that after the reaction to form their ruthenium complex is complete, the resulting product was diluted with water, filtered, and salted out using sodium persulfate (paragraph 0097). CN’635 discloses that the solid was further filtered to obtain a crude product, which was further dissolved in acetonitrile, filtered using a neutral alumina column chromatography, and concentrated to obtain a red solid (paragraph 0097). The steps described here meet the limitation of instant claim 6.
Sartor discloses the synthesis of their azide-functionalized ruthenium complexes were carried out under nitrogen (see first paragraph under “Syntheses of Azide-Functionalized Ruthenium Complexes” left column page 2668), which meets the limitation of a “protective atmosphere” recited in instant claim 3.
The combined references, however, do not teach a method of preparing the recited ruthenium complex using microwave heating radiation.
Barge discloses the formation of various compounds using copper-catalyzed azide-alkyne cycloaddition (CuAAC), an example of click chemistry, under microwave or ultrasound irradiation (see Abstract).
Barge illustrates the CuAAC reaction in Scheme 1 shown below:
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Barge disclose that this click chemistry is appealing due to its application to label molecules of interest in complex biological samples without interference with any other chemical functionalities (see last paragraph page 3). Barge discloses this linking chemistry has broad application and discloses the synthesis of many modified nucleosides and oligonucleotides (second paragraph page 4). Barge discloses that the CuAAC reaction can be strongly accelerated by microwave (MW) irradiation and disclose several examples in which microwave irradiation resulted to excellent yields, high purity, and short reaction times (see first paragraph page 5).
Barge exemplifies nucleoside triazole derivatives formed by CuAAC reaction under microwave irradiation (see Section 3.1 pages 16-18). Barge discloses that MW irradiation promotes reaction times from 6 hours to 5 minutes, and increasing yield up to 95% (see last paragraph page 16). For example, Barge discloses that reaction yields higher than 85% was obtained under MW conditions (5-10 minutes at 90 degree C) for triazolyl linked nucleosides (see second paragraph page 17).
It would have been prima facie obvious before the effective filing date of the claimed invention to have prepared the ruthenium complex from the combined teachings CN’635, Lee, Carvalho, and Sartor described above by conjugating the uridine nucleoside using the copper sulfate and sodium ascorbate click chemistry under nitrogen atmosphere as disclosed in Lee and Sartor and further performing this reaction under microwave reaction for 5-10 minutes at 90 degree C as disclosed in Barge to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to use the click chemistry under nitrogen to form the ruthenium-uridine complex because Lee discloses that click chemistry is a very simple and useful transformation that does not generate any side products or byproducts, unlike other 3+2 cycloadditions. One of ordinary skill in the art would have a reasonable expectation of success because Lee discloses click chemistry is widely used in to synthesize modified nucleosides and demonstrates the click linking chemistry using uridine nucleosides, and Sartor further demonstrates the click linking chemistry reaction under nitrogen atmosphere using ruthenium complexes to DNA oligonucleotides. Furthermore, one of ordinary skill in the art would have been motivated to perform this reaction under microwave irradiation because Barge discloses that the copper-catalyzed click chemistry can be strongly accelerated by microwave (MW) irradiation and disclose several examples in which microwave irradiation resulted to excellent yields, high purity, and short reaction times (see first paragraph page 5). One of ordinary skill in the art would have a reasonable expectation of success Lee demonstrates the copper based click linking chemistry using nucleosides, Sartor further demonstrates this copper click linking chemistry using ruthenium complexes to DNA oligonucleotides, and Barge discloses that microwave irradiation at 5-10 minutes at 90C can produce greater than 85% for triazolyl linked nucleosides, which overlaps with the recited ranges in instant claim 5. See MPEP 2144.05 I.
In regards to instant claim 4, it would have also been prima facie obvious before the effective filing date of the claimed invention to have modified the ruthenium complex preparation described above by mixing the ruthenium complex and the uridine moiety at a molar ratio of 1:2 as disclosed in CN’635 to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because CN’635 provides guidance that mixing the ruthenium complex and the alkyl chain ligand at a molar ratio of 1:2 was effective in forming their ruthenium complexes. Therefore, an ordinary skilled artisan could have considered through routine experimentation of using this molar ratio when adding the uridine moiety at the alkyl chain position described above to the ruthenium complex. See MPEP 2144.05 II.
In regards to instant claim 6, it would have also been prima facie obvious before the effective filing date of the claimed invention to have modified the ruthenium complex preparation described above by further purifying and filtering the ruthenium compound using the steps as disclosed in CN’635 to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because CN’635 provides guidance of filtering and purifying the ruthenium complex after the reaction is complete by diluting in water, and salting out using sodium persulfate, filtering, re-dissolving in acetonitrile, filtering using a neutral alumina column chromatography, and then concentrating to obtain a red solid. Therefore, an ordinary skilled artisan could have considered through routine experimentation of performing these filtering and purifying steps after obtaining the modified ruthenium complex describe above. See MPEP 2144.05 II.
Claim(s) 1, 7, 10, 12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. (Molecules, published 02/24/22 in PTO-892) in view of CN111704635 (in IDS filed 08/30/2023, an English translation is provided in PTO-892 and used as the basis for this rejection), Lee et al. (Bioorganic and Medicinal Chemistry Letters, 2009 in PTO-892), Carvalho et al. (ACS Omega, 2020 in PTO-892), and Sartor et al. (EurJIC, 2017 in PTO-892).
Jiang teaches the use of ruthenium(II) polypyridyl complexes as probes and photoreactive agents for G-quadruplex (G4) labeling (see Abstract). Jiang discloses that these ruthenium complexes containing pi-deficient TAP ligands can create a covalently linked adduct with G4s after a photoinduced electron transfer from a guanine residue to the excited complex (see Abstract).
Jiang discloses that G4 are formed from guanine-rich sequences of DNA or RNA (see first paragraph page 1). Jiang discloses that these G4 have high potential to be used as therapeutic targets for cancer treatments, as they play a crucial role in the cellular clock by shortening with each cell division and ultimately leading cells to a state of senescence (second paragraph page 2). Jiang discloses that the stabilization of G4 structures by small molecules or metal complexes is of key important as this can inhibit telomerase activity and thus kill the cell through the induction of apoptosis (third paragraph page 2).
Jiang discloses that ruthenium(II) polypyridyl complexes are composed of one central ruthenium (II) cation and three chelating diimines (first paragraph under section 3, pages 13-14). Jiang discloses that these ruthenium complexes have luminescence due its metal-to-ligand charge transfer triplet excited state (MLCT), and that this property can be finely tuned by the structure of the chelating diimines which allow for their use in a plethora of applications involving light-induced processes (see first paragraph page 14). Jiang discloses the ruthenium complex shown in Figure 13 (page 14) is a powerful tool to study DNA, as this complex do not luminescent in water but emit brightly in DNA containing aqueous solutions (second paragraph page 14). Jiang discloses this light-switch ON effect can be explained by two different MLCT excited states as shown in Figure 13.
Jiang further exemplifies additional ruthenium complexes that interact with G4 in section 3.1 (pages 15-32). Of the ruthenium complexes exemplified, Jiang discloses ruthenium complexes bearing imidazo-phenanthroline ligands as shown in Figure 20 (page 24) and shown below:
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Here, this ligand is the same ligand shown in the ruthenium complexes of CN’635. Jiang discloses that these ruthenium complexes have binding affinity against G4 and potential use as anti-cancer drugs and/or inhibition of telomerase activity (first paragraph page 24). Jiang discloses that their binding affinity for G4 are linked to its efficiency as potential anti-cancer drugs (see first paragraph page 24). Jiang also discloses these ruthenium complexes show the same light-switch ON property as dppz-containing complexes, and are selective towards G4 structures over double or single stranded DNA (last paragraph page 23).
The difference between Jiang and the claimed invention is that Jiang does not disclose the ruthenium complex shown in the instant claims.
The independent teachings of CN’635, Lee, Carvalho, and Sartor are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have used the ruthenium complex from the combined teachings of CN’635, Lee, Carvalho, and Sartor described above as a fluorescent probe as well as for targeting, recognizing, and binding G4 RNA as disclosed in Jiang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to use this ruthenium complex for these purposes because Jiang discloses that ruthenium complexes can be finely tuned to selectively luminescence when binding to G4 structures found in DNA and RNA, and further disclose that ruthenium complexes have potential anticancer drug use based on its binding affinity to G4 structures. One of ordinary skill in the art would have a reasonable expectation of success because Jiang discloses that ruthenium complexes bearing imidazo-phenanthroline ligands can have these properties and for use as an anticancer drug, CN’635 shows that their ruthenium complexes also bear the same imidazo-phenanthroline ligands with anti-tumor properties, and Carvalho also provides guidance that ruthenium-uracil derivative complexes show promise as anticancer agents by inducing cell apoptosis.
Claim(s) 1, 9, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Munteanu et al. (Pharmaceutics, 2021 in PTO-892) in view of Jiang et al. (Molecules, published 02/24/22 in PTO-892), CN111704635 (in IDS filed 08/30/2023, an English translation is provided in PTO-892 and used as the basis for this rejection), Lee et al. (Bioorganic and Medicinal Chemistry Letters, 2009 in PTO-892), Carvalho et al. (ACS Omega, 2020 in PTO-892), and Sartor et al. (EurJIC, 2017 in PTO-892).
Munteanu discloses the use of ruthenium complexes against pathogenic microorganisms (Abstract). Munteanu discloses that the widespread use of antibiotics as resulted in the emergence of drug-resistant microorganisms, and therefore there is a need for new antimicrobial agents (Abstract). Munteanu discloses that ruthenium complexes, which have uses as anti-cancer drugs, may also have uses against antibiotic, antifungal, antiparasitic, or antiviral drugs (Abstract).
Munteanu discloses the antiviral activity of various ruthenium complexes in section 7 (pages 39-40). Munteanu discloses that despite extensive vaccination, there are a large number of mutations in SARS-CoV-2 with new variants being less susceptible to current treatment options and possibly to vaccines (first paragraph under section 7.2 page 39). Munteanu discloses a need to develop new drugs with a broader spectrum of activity, and exemplifies a ruthenium complex called BOLD-100 (shown in Figure 29 page 40). Munteanu discloses that BOLD-100 was developed as an anticancer agent, but has now shown to reduce viral loads in various COVID-19 variants (second paragraph under section 7.2 page 39). Munteanu discloses that BOLD-100 also has a tolerable safety profile (first paragraph page 40). Munteanu concludes that ruthenium-based antimicrobial agents have a complex mode of action involving multiple mechanisms acting in synergy and further discloses that these ruthenium complexes can act as antimicrobial agents with low levels of toxicity towards healthy cells (see Conclusions pages 40-41).
The difference between Munteanu and the claimed invention is that Munteanu does not disclose the use of the recited ruthenium complex in the instant claims.
The independent teachings of CN’635, Lee, Carvalho, and Sartor are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have prepared the ruthenium complex from the combined teachings of CN’635, Lee, Carvalho, and Sartor described above as a drug for treating SARS-CoV-2 as disclosed in Munteanu to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to use this ruthenium complex for treating SARS-CoV-2 because Munteanu discloses a need to develop new antiviral agents with a broader spectrum of activity to overcome new SARS-CoV-2 variants and suggests the use of ruthenium-based complexes. One of ordinary skill in the art would have a reasonable expectation of success because Munteanu suggests that ruthenium-based complexes may not only having uses as anticancer agents such as disclosed in CN’635 and Carvalho but may also be effective as antimicrobial agents and further discloses the use of a ruthenium complex that is effective against both cancer and SARS-CoV-2 with a tolerable safety profile.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693