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 .
Current Status
This action is responsive to the claims of 04/20/2023. Claims 1-19 are pending. Claims 2-6, 8, 11-12, 14-15, and 19 are withdrawn. Claims 1, 7, 9-10, 13, and 16-18 have been examined on the merits.
Election/Restrictions
Applicant's election with traverse of the compound
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wherein X is hexafluorophosphate and the cancer osteosarcoma in the reply filed on 10/20/2025 is acknowledged. The traversal is on the grounds that 1) no statement is made regarding the patentable distinctness of the species and 2) there is no search burden. This is not found persuasive. First, a statement regarding the patentable distinctness of the species was made in the restriction/election of 08/20/2025 at Pg. 3 paragraph 4. In short, the species are found to be mutually exclusive because of differences in chemical structure (for species of Formula (I) or differences in etiology (for species of cancer). Second, a statement regarding the search burden was made in the restriction/election of 08/20/2025 at Pg. 4 paragraph 4. In short, since the species are patentably distinct they require different fields of search and a search for one species would not retrieve a reference disclosing the other species.
The requirement is still deemed proper and is therefore made FINAL.
A search for the elected species, above, did not return any prior art (see SEARCH 6 of the attached search notes). Thus, the Markush search was extended to the following species:
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wherein X is Cl; the extended species of cancer are leukemia and colon cancer. Therefore, the Markush search will not be unnecessarily extend to other species in this action, in accordance with Markush search practice.
The extended species read on claims 1, 7, 9-10, 13, and 16-18.
Claims 2-6, 8, 11-12, 14-15, and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of Formula (I) or cancer (i.e., not the extended species above), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/20/2025.
Priority
The effective filing date is 04/20/2023.
Note, no claims of Foreign Priority or Domestic Benefit have been made.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/20/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 13 is objected to because of the following informalities: line 1 of the claim recites “wherein following the administering an amount of”. While the claim is clearly referencing administration of the complex of Formula (I), please amend the claim to explicitly state this. For example: “wherein, following administration of the complex, an amount of”. Appropriate correction is required.
Note: Withdrawn claims 14-15 and 19 have this same issue and would be similarly objected to if not withdrawn.
Claim 16 is objected to because of the following informalities. While the claim language is clear, claim form could be improved by amending as follows: “The method of claim 1, wherein is administered.” Appropriate correction is required.
Claim 17 is objected to because of the following informalities. While the claim language is clear, claim form could be improved by amending as follows: “The method of claim 1, wherein the complex administered orally, parenterally, topically, transdermally, or nasally.” Appropriate correction is required.
Note: withdrawn claims 2-3 and 5-6 would be objected to, if not withdrawn, for the following reasons.
Claims 2-3 and 5-6: please insert “the complex” before the phrase “has the structure of formula” so that the claims read “the complex has the structure of formula”.
Claim 6: line 2 recites an aliphatic chain comprising 2 carbon atoms; however, the structure of formula (V) shows a 1 carbon atom aliphatic chain. This would rise to the level of a 112b indefiniteness rejection if the claim was not withdrawn.
Claim Interpretation
Claim 1 recites “wherein R1 is a substituted or unsubstituted cyclic amine, wherein a ring of the cyclic amine has 5-7 atoms”. Examiner interprets this limitation as follows: the cyclic amine may be a mono-, bi-, tri-cyclic etc. ring of any size as long as at least one ring of the cyclic amine has 5-7 atoms. Further, a cyclic amine is understood to be any heterocycle, saturated or unsaturated, containing at least one N atom. Other heteroatoms may be present in the cycle, such as O or S.
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.
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, 7, 9-10, 13, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over MIRABELLI (Mirabelli, C.K. et al. J. Med. Chem., 1986, 29, 218-223), CHAVES (Chaves, J.D.S. et al. Inorganica Chimica Acta, 2014, 414, 85-90, Abstract provided in IDS of 04/20/2023 – Examiner has attached a full copy with all relevant pages), and ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
MIRABELLI teaches a series of gold(I) coordination complexes including analogs of auranofin were evaluated for in vivo antitumor activity against leukemia in mice (Pg. 218 Abstract). Auranofin analogs including compound 21
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Et3-P-Au-S-Pyridine and compound 28 i-Pr3-P-Au-S-Glu(Ac)4 are taught to have similar IC50 values of 2 and 4 uM, respectively, and the same maximum tolerated dose (MTD) of 14 umol/kg in an in vivo mouse model of leukemia (Pg. 222 Table II). Compound 21 reads on the instant compound of Formula (I) wherein R1 is pyridine (i.e., cyclic amine with 6 atoms); however, R2 differs in that the carbon chain is a C2 chain not a C3 chain. Note, the bond between the pyridine and S is drawn as a single bond; however, due to resonance, the structure is understood to read on the R1=S of the instant Formula (I). Compound 28 differs in that R1 is not a cyclic amine, although the equivalent cycle is still a heterocycle; however, R2 does read on the instant Formula (I) wherein R2 is a branched C3 chain. MIRABELLI teaches the gold(I) complexes (i.e., including compounds 21 and 28) were dissolved in a solution comprising saline. Thus, the gold(I) complexes are understood to have a counter ion that is chloride, i.e., instant X is Cl.
MIRABELLI teaches the resulting gold(I) complex solutions were administered intraperitoneally (i.e., parenterally) to a mouse model of leukemia (Pg. 219 Left Col. last para – Right Col. first para). Since MIRABELLI teaches the MTD of compounds 21 & 28 is 14 umol/kg weight of subject (Pg. 222 Table II), Examiner understands this to be equivalent to a dose of ~6 mg/kg and ~10 mg/kg, respectively. MIRABELLI further teaches cisplatin was used as a positive control (Pg. 219 Right Col. para 1); however, MIRABELLI is silent as to the IC50 of cisplatin in the in vivo model. Thus, Examiner understands MIRABELLI as silent as to the efficacy of cisplatin vs. the gold(I) complexes in reducing a number of cancer cells.
CHAVES teaches the antineoplastic activity of auranofin has been evaluated in vivo to show potent cytotoxic activity (Pg. 85 Right Col. para 3) and similar or greater in vitro activity than cisplatin (Pg. 86 para 3). CHAVES teaches preparation and characterization of new gold(I) complexes with tertiary-phosphine ligands (Pg. 86 last para), including complex 2:
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. Complex 2 reads on instant Formula (I) wherein R1 is a substituted thiazole (i.e., a substituted cyclic amine wherein 1 ring has 5 atoms) and X is Cl. Complex 2 differs from the instant Formula (I) at R2, wherein the carbon chains are only C2 not C3. CHAVES teaches the in vitro IC50 against colon cancer cells for complex 2 is 0.20 uM and for cisplatin is 0.70 uM (a 3.5x difference) (Pg. 90 Table 3). For melanoma cells, the IC50 of complex 2 is 0.13 uM and cisplatin is 6.40 uM (a ~49x difference) (Pg. 90 Table 3). CHAVES teaches all gold(I) complexes were more active than cisplatin (Pg. 90 Conclusion).
ANSEL teaches the safe and effective dose of a drug depends on a number of
factors including characteristics of the drug, the dosage form, and a variety of patient
factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different
patients (Pg. 48 Left Col. para 4). ANSEL further teaches the schedule of dosage or the
dosage regimen is determined based on a drug’s duration of action, pharmacokinetics,
and characteristics of the dosage form (Pg. 40 Right Col. para 2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
MIRABELLI teaches an analogous gold(I) complex administered to a subject for treatment of a cancer; however, the analogous R2 is a C2 chain not a C3 chain.
CHAVES does not teach wherein R2 is a C3 chain nor a method of treatment administering the gold(I) complex to a subject (only in vitro).
ANSEL does not teach the instant compound or method of use thereof.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of gold(I) auranofin analog complexes useful for treatment of cancer and possesses the technical knowledge necessary to make adjustments to the gold(I) complex and dosing thereof to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding gold(I) auranofin analogs and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references MIRABELLI, CHAVES, and ANSEL.
Regarding claim 1 and 7, the artisan would find it obvious to replace the ethyl C2 chains of MIRABELLI’s compound 21 with the isopropyl C3 chains of MIRABELLI’s compound 28 and would arrive at a compound of the instant Formula (I): i.e.,
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wherein X is Cl. The motivation for this replacement arises based on the close structural similarity providing a reasonable expectation that compounds similar in structure will have similar properties (see MPEP 2144.09(I)). Compound 21 and the instant compound (above) only differ by the addition of a CH3 group to the R2 groups. Furthermore, the compound 28 of MIRABELLI, wherein R2 is isopropyl, has very similar anti-tumor activity (IC50) and the same MTD as compound 21 (Pg. 222 Table II). Moreover, compound 28 and 21 are both taught as analogs of auranofin (Pg. 222 Table II) which CHAVES teaches auranofin as a known potent anticancer compound (Pg. 85 Right Col. para 3). Thus, the artisan would have a reasonable expectation of success in arriving at an auranofin analog gold(I) complex with similar or improved anti-tumor activity by making the suggested replacement of ethyl with isopropyl.
Regarding claim 16-17, since the compound of instant claim 1 Formula (I) is obvious by the logic above and since MIRABELLI teaches the limitations of instant claims 16 and 17: a dose of ~6-10 mg/kg of the subject (Pg. 222 Table II) and parenteral administration (Pg. 219 Left Col. last para – Right Col. first para), the instant claims 16-17 are obvious.
Regarding claim 18, while MIRABELLI is silent as to the efficacy of cancer cell reduction of cisplatin in comparison to the compounds 21 and 28, CHAVES teaches auranofin has similar or greater in vitro activity than cisplatin (Pg. 86 para 3) and an analogous gold(I) complex (complex 2) is ~3.5-49x more effective than cisplatin by the measure of IC50 in two cancer cell lines (Pg. 90 Table 3). The artisan would have been motivated to optimize the activity/efficacy of the auranofin gold(I) complex in view of these teachings.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
In the instant case, CHAVES teaches an analogous gold(I) complex (complex 2) is ~3.5-49 times more effective than cisplatin (Pg. 90 Table 3); the instant range of 5-30 times more effective lies within the range of CHAVES. CHAVES (Pg. 90 Table 3) and MIRABELLI (Pg. 222 Table 2) both teach dosages of their respective auranofin gold(I) complex analogs. Since ANSEL teaches the safe and effective dose of a drug depends on many factors (Pg. 48 Left Col. para 2), dosing may be different for different patients (Pg. 48 Left Col. para 4), and the dosage regimen is determined based on a drug’s pharmacokinetics and other characteristics (Pg. 40 Right Col. para 2), the artisan would recognize the relationship between a drug’s dosage and the drug’s effect on the target disease. Thus, the artisan would recognize the efficacy of a drug as an outcome of the dosage/dosing regimen and would recognize the dosage/dosing regimen as a results-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage/dosing regimen is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. The optimization of the drug’s efficacy at reducing cancer cells would naturally follow. Therefore, the determination of the optimum or workable dosage of the instant compound and the accompanying efficacy would have been well within the practice of the artisan. Furthermore, absent any evidence of unexpected results or secondary consideration, the determination of the optimum or workable dosing regimen and the accompanying efficacy, given the guidance of the prior art, would have been generally prima facie obvious to the artisan.
Regarding claim 9, the artisan would be motivated to administer the instant compound, made obvious in analysis of claim 1 above, to a subject having colon cancer in view of the combined references. Since CHAVES teaches an auranofin gold(I) complex analog (complex 2) is effective against colon cancer cells (Pg. 90 Table 3), and since MIRABELLI teaches administration of a structurally similar auranofin gold(I) complex analog to a mouse model of cancer (Pg. 218 Abstract & Pg. 222 Table II), the artisan would be motivated, with an expectation of success, to administer the instant compound to a subject having colon cancer, such as a mouse model thereof. The fact that the compounds of MIRABELLI, the compound of CHAVES, and the instant obvious compound are all auranofin gold(I) complexes with close structural similarity provides a reasonable expectation that the compounds will have similar properties, and thus, the instant compound would be expected to be applicable for treatment of colon cancer.
Regarding claims 10 and 13, administration of the instant compound to a subject with colon cancer is obvious by the logic laid out for claim 9, above. The artisan would have been motivated to optimize the IC50 and the percent reduction of colon cancer cells in view of the combined references.
See the quotations from MPEP 2144.05(II)(A) for guidance about the routine optimization of prior art conditions. Further, MPEP 2144.05(I) provides guidance about similar ranges: “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
In the instant case, CHAVES teaches the in vitro IC50 against colon cancer cells for complex 2 is 0.20 uM (Pg. 90 Table 3) and MIRABELLI teaches an MTD of ~6-10 mg/kg of the subject for in vivo administration (Pg. 222 Table II). Both references are silent as to the percent reduction of cancer cells in the subject. Since ANSEL teaches the safe and effective dose of a drug depends on many factors (Pg. 48 Left Col. para 2), may be different for different patients (Pg. 48 Left Col. para 4), and the dosage regimen is determined based on a drug’s pharmacokinetics and other characteristics (Pg. 40 Right Col. para 2), the artisan would recognize the relationship between a drug’s dosage and the drug’s effect on the target disease (e.g., % reduction in cancer cells). Thus, the artisan would recognize the efficacy of a drug as an outcome of the dosage/dosing regimen and would recognize the dosage/dosing regimen as a results-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage/dosing regimen is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. The optimization of the drug’s efficacy at reducing cancer cells would naturally follow. Therefore, the determination of the optimum or workable dosage of the instant compound and the accompanying efficacy would have been well within the practice of the artisan. Furthermore, absent any evidence of unexpected results or secondary consideration, the determination of the optimum or workable dosing regimen and the accompanying efficacy, given the guidance of the prior art, would have been generally prima facie obvious to the artisan.
Moreover, based on the logic in the analysis of claim 1, the instant compound’s structure would be obvious. The IC50 against a cancer cell is understood as a property of the claimed compound. MPEP 2112.01.II states: “‘Products of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Since the combined references teach the compound of instant Formula (I), it would be expected that the compound would have the same chemical properties as the compounds in the instant application, namely that the compound exhibits an IC50 of 1-15 uM against colon cancer cells.
Therefore, the combined references teach the instant claims 1, 7, 9-10, 13, and 16-18.
Conclusion
Claims 1, 7, 9-10, 13, and 16-18 are rejected.
To expedite time to allowance: Applicant is encouraged to provide evidence of surprising/unexpected results (see MPEP 716.02(a)) and/or any other evidence of secondary considerations (see MPEP 716.01) for the full scope of the independent claim 1. This would help to overcome the 103 rejection, above, and preclude Examiner from making further 103 rejections.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. It is noted that, while not applied here as prior art based on the current Markush search extension, the document WO 95/14703 (provided in IDS of 04/20/2023) teaches auranofin analogs similar to those taught by MIRABELLI and CHAVES above. The compounds of WO ‘703 read on instant Formula (I) at R1-S-Au-P, but differ in that R2 is a C2 carbon chain not a C3-10 carbon chain (e.g., see Pg. 10 Example 1a).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625