Detailed Action
The present office action is in response to the amendments filed on 03 Sep 2025.
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03 Sep 2025 has been entered.
Status
Claims 1-2, 4-6, 9-10, 12, 14, and 16 of the pending application have been examined on the merits. Acknowledgement is made of the amendments filed 03 Sep 2025. Acknowledgement is made of the cancelation of claims 2-3, 7-8, 11, 13, 15, and 17-20.
Priority
Applicants identify the instant application, Serial #: 17/494,110, filed 05 Oct 2021, as a Continuation of International Patent Application #: PCT/US2020/026837, filed 06 Apr 2020, which claims priority from U.S. Provisional Application #: 62/830,384, filed 06 Apr 2019.
Response to Applicant Elections
In the amendments filed 03 Sep 2025, applicant amended claims and limited the scope to compounds of Formula (I) that did not include ferroptocide, the compound species elected in the reply filed 25 Sep 2024. Because the instantly elected compound is no longer within the scope of the instant claims, examiner extended the Markush search to a compound P30b in claim 14 (below) which reads on claims 1, 4-6, 9-10, 12, 14, and 16. This search retrieved prior art.
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Response to Applicant Arguments
Examiner acknowledges applicant amendments filed 03 Sep 2025.
The rejection of claims 1-2, 4-6, 9-10, 12, 14, and 16 under 35 U.S.C. 102(a)(1) over Hicklin (University of Illinois Urbana-Champaign, 2015, Doctoral Dissertation; provided in the office action mailed 13 Nov 2024), hereinafter Hicklin, are rendered moot following applicant amendments. New grounds of rejection for claims 1, 4-6, 9-10, 12, and 14 necessitated by applicant amendments are found below.
The rejection of claims 1-2, 4-6, 9-10, 12, 14, and 16 under 35 U.S.C. 103 over Hicklin and further in view of US 2019/0352262, hereinafter ‘262, are rendered moot following applicant amendments. New grounds of rejection of claims 1, 4-6, 9-10, 12, 14, and 16 necessitated by applicant amendments are found below.
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 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 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, 4-6, 9-10, 12, 14, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hicklin, further in view of Boens et al. (Chem Soc Rev, 2012, 41:1130-1172), hereinafter Boens, Monsma et al. (J Neurochem, 1989, 52:1333-1663), hereinafter Monsma, and ‘262 and in light of Loudet et al. (Chem Rev, 2007, 107:4891-4932), hereinafter Loudet.
The instant application claims compounds of Formula (I) and compositions of compounds of Formula (I) and pharmaceutically acceptable buffers, carriers, diluents, and excipients. Examiner extended the Markush search to include compound P30b:
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Applicant previously elected “gelatin” as a pharmaceutically acceptable buffer, carrier, diluent, or excipient in applicant’s remarks filed 25 Sep 2024.
Hicklin teaches compound P2 as a pleuromutilin derivative with anticancer activity in ES-2 cells (IC50 of 1.6 ± 0.1 µM) and HCT 116 cells (IC50 of 3.5 ± 0.2 µM) (pg. 179; and pg. 199):
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Hicklin further teaches modifying the 1,2,4-triazolidine-3,5-dione ring of compound P2 to determine the anticancer activity of P2 derivatives including compound P34 with activity against ES-2 cells (IC50 of 2.5 ± 0.4 µM) and HCT 116 cells (IC50 6.4 ± 0.9 µM) (pg. 199):
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Further experimenting with the pleuromutilin derivatives, Hicklin teaches the synthesis and structure of compound P36, a fluorescent derivative of compound P34 with anticancer activity against ES-2 cells (IC50 of 5.3 ± 0.1 µM) and HCT 116 cells (IC50 of 10.5 ± 1.0 µM) (pgs. 199-200):
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Loudet, cited for evidence, teaches the fluorophore of P36 is a known asymmetrical BODIPY dye with a maximum absorption at 499 nm and a maximum emission at 509 nm (pg. 4892, column 2):
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However, Hicklin does not teach the compound P30b found in the instant claims or a pharmaceutical composition comprising compound P30b and gelatin.
Boens teaches about advances made using the BODIPY scaffold as a fluorophore in the design, synthesis, and application of fluorescent indicators of pH, metal ions, anions, biomolecules, reactive oxygen species, reactive nitrogen species, redox potential, chemical reactions, and various physical phenomena (Abstract). Boens further teaches that fluorescence spectroscopy, fluorescence imaging, and fluorescence indicators are nowadays indispensable tools in various fields of modern science and medicine and that fluorescence techniques applied to intracellular measurements have a great spatial and temporal sampling capacity and are generally minimally disruptive to cells (pg. 1130, columns 1-2). Boens teaches that among the numerous classes of highly fluorescent dyes, BODIPY dyes show the highest potential and the many excellent features of these dyes explain their success (pg. 1130, column 2). These features include robustness against light and chemicals, the high molar absorption coefficients and fluorescence quantum yields, negligible triplet-state formation, narrow emission bandwidths with high peak intensities, good solubility, resistance towards self-aggregation in solution, excitation/emission wavelengths in the visible spectral region, and the ability to finely tune spectroscopic/photophysical properties based on the moieties attached to the BODIPY core (pg. 1130, column 2).
Monsma teaches the synthesis and characterization of fluorescently labeled ligands with high affinity and specificity for the D1 and D2 dopamine receptors (Abstract). Monsma teaches that the cellular and subcellular localization of dopamine receptors is not possible using radiolabeled ligands, but it is desirable to have receptor probes that could be directly visualized with high resolution, especially via fluorescence microscopy (pg. 1641, column 2). For the D1 receptor, Monsma teaches modifying SCH-23390 with various fluorescent probes, and for the D2 receptor, Monsma teaches modifying NAPS with the same fluorescent probes (pg. 1642, column 1). Overall, Monsma concludes that SCH-23390-bodipy VI and SCH-23390-rhodamine I appear to be the best candidate probes for D1 receptors and NAPS-bodipy III and NAPS-rhodamine appear to be the best probes for D2 receptors (pg. 1644, column 1). SCH-23390-bodipy VI and NAPS-bodipy III have the same fluorophore as taught in Hicklin:
SCH-23390-bodipy VI
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Based on the teachings of Hicklin, Boens, and Monsma, a person of ordinary skill in the art would modify compound P2, taught in Hicklin, with the BODIPY fluorophore, also taught in Hicklin, to monitor the cellular and subcellular localization of the pleuromutilin derivative in ES-2 and HCT 116 cells via fluorescence spectroscopy, as taught by Monsma and Boens, and so arrive at the instant compound P30b. The artisan would be motivated to use fluorescence measurement instead of other methods due to the great spatial and temporal sampling capacity and generally minimal disruption to cells, as taught by Boens. Further, the artisan would find motivation to use BODIPY derivatives due to the excellent properties of these dyes, as found in Boens. The artisan would further use the specific BODIPY fluorophore taught in Hicklin and Monsma for the expectation of success derived in synthesizing the fluorophore found in Hicklin, and the ability of this fluorophore to maintain high activity against cellular targets, as found in Hicklin and Monsma. Taking all these elements together, the artisan would have the ability, motivation, and expectation of success in forming and testing the instant compound P30b from the teachings of Hicklin, Boens, and Monsma.
Regarding claim 16, ‘262 teaches a pharmaceutical composition of a pleuromutilin derivative (abstract) and gelatin as a pharmaceutically acceptable excipient for the purposes of therapeutic oral administration (paragraphs [0146]-[0147]).
By combining the compound of the instant claims taught by Hicklin, Boens, and Monsma and the composition of pleuromutilin derivative and gelatin taught by ‘262, one having ordinary skill in the art would arrive at the invention of a composition of instant compound P30b and gelatin. The artisan would be motivated to use gelatin in a pharmaceutical composition with the reference compound P30b to facilitate therapeutic oral administration of the composition.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625