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 .
Notice of Priority
This applications claims priority for European Patent Application: EP22181347 filed 27 June 2022.
DETAILED ACTION
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 18 December 2024, 18 March 2025, and 03 November 2025 have been considered by the Examiner.
Claim Status
Claim(s) 1-20 are examined on the merits herein.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
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 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.
Claim(s) 1-7, 9-11, 14-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bourotte et al (PCT Filing: 27 November 2019; WO 2020/109350; henceforth Bourotte) in view of Mitscher (Mitscher LA, Bacterial Topoisomerase Inhibitors: Quinolone and Pyridone Antibacterial Agents, Chem. Rev. 2005, 105, 559-592) and Peyton et al (Published: 24 March 2011; WO 2011034971; henceforth Peyton).
Bourotte teaches compounds according to formula (I), below:
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663
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and pharmaceutical compositions thereof, alongside their use in methods of reducing the virulence of bacteria via inhibition of quorum sensing mechanisms in species such as Staphylococcus aureus. In doing so, Bourotte meets several requirements of the Instant invention.
Claim 1 details a compound of Instant Formula (I), below:
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401
884
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In regards to Claim 1, limitations are drawn to the Instant R1, R3, m, n, R8A, R8B, R81, and R82 positions. These positions may be mapped onto the reference formula (I) R1, R3, and R8 positions. Bourotte meets the limitations of R1 and R3 in a specified manner, by teaching the R1 and R3 positions of formula (I) to be, at least, halogen or -C1-C6 alkyl [pg. 4; line 16-26]. In addition, the R2, R4, R5, R6, R7, and R9 positions taught by Bourotte may be hydrogen [pgs. 4-5; lines 12-28(4) and 01-14(5)], which overlaps with the structure of Instant Formula (I). In doing so, Bourotte also meets the limitations of Claim(s) 2-3. Bourotte addresses the various limitations of the substituted piperazine moiety by broadly teaching the R8 position to be an alkyl-substituted heterocycle [pg. 5; lines 14-15]. However, due to no specific teaching of their R17 to be an amide, as required by further limitation of their R8 position, Bourotte does not teach the alkyl-substituted heterocycle to be an alkylamido-substituted piperazinyl moiety at the R8 position. Therefore, and briefly, while Bourotte teaches a similarly structured compound at all positions other than R8, and details a panel of substitutions that R8 may potentially be (i.e. alkyl-substituted heterocycle), Bourotte does not specifically teach the piperazinyl moiety, nor alkylamido-substitutions of such.
Yet still, substitution with a piperazinyl compound as claimed could be contemplated with the teachings of further prior art. Mitscher teaches the quinolone family of compounds, their structural substitutions, reasons for performing those substitutions, and effects therefrom. For example, Mitscher teaches the 4-oxo-1,4-dihydro-quinolone scaffold [pg. 560; Figure 1], below:
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whose core structure bears significant similarity to the analogous core of Instant Formula (I). Mitscher goes on to teach that quinolones (to include fluoroquinolones) are anti-infective agents [pg. 559; Sect. 1; par. 1] that act on DNA-binding enzymes (i.e. DNA gyrase, topoisomerase) [pg. 561; par. 2], similarly to the action of the Instant Formula (I) upon the AgrA transcription regulator of the agr operon [Specification; pg. 2; lines 14-20] [Specification; pg. 3; lines 30-34]. Mitscher also teaches the most versatile position for substitution of quinolones to be C-7 and its analogous position in other ring systems [pg. 571; Sect. 5.9; par. 1] with the piperazinyl moiety or its N-methyl analogue becoming a standard feature among this class of molecules [pg. 572; par. 2], with piperazinyl analogs imbuing the compounds with enhanced potency [pg. 572; par. 2].
There exist other examples in the literature that teach that teach analogs of fluoroquinolones like ciprofloxacin as N-4’ (C-7) alkylamido- substitutions of the piperazinyl moiety. For example, Peyton teaches the compound DM1050 [pg. 57 of 73; Figure 1], below:
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383
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wherein the equivalent R8A and R8B are both -H, n is 0 and m is 1, and R81 and R82 moieties are C1-C6 alkyl, as required by Claim(s) 4-6; also the compound DM1051 [pg. 57 of 73; Figure 1], below:
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341
678
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wherein the equivalent R81 moiety is a C3 cycloalkyl, as required by Claim 7; also the compound DM1021 [pg. 57 of 73; Figure 1], below:
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245
427
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wherein the equivalent R81 moiety is a C6 aryl, as required by Claim 9; also the compound DM1094 [pg. 65 of 73; Figure 9], below:
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wherein the equivalent R81 moiety is a 6-membered heteroaryl and the equivalent R82 moiety is -H, as required by Claim(s) 10-11 and 16-17.
In regards to Claim(s) 14-15 and 20, both Bourotte [pg. 4; lines 12-15] and Peyton [pg. 29 of 73; [0223]] teach their compounds to be found and administered in the form of pharmaceutical compositions to treat a bacterial infection [Bourotte; pg. 9-10; lines 33-34, 01-04] [Peyton; pg. 29 of 73; [0222]] [Peyton; pgs. 9-13 of 73; [0026]-[0148]]. Bourette, specially, teaches treatment of bacterial infection or inflammatory skin disease caused or exacerbated by bacteria [pg. 10; lines 01-04].
A prima facie case of obviousness can be made for one of ordinary skill in the art to start from the R8-modifiable antibacterial compounds of Bourotte, and implement the piperazinyl moiety commonly found in other antibacterial compounds, given Bourotte’s teaching that N-heteroalkyl substituents are permitted at their R8 position. Mitscher provides rationale for N-4’ substitution of the piperazinyl moiety for quinolone (ciprofloxacin) analogs given the discovery that certain substitutions improved safety and efficacy of the parent compounds, and Peyton teaches a panel of amido-substituted-N-4’-piperazinyl-substituted ciprofloxacin analogs; many exemplary substitutions are also found in the Instantly claimed compounds. One of ordinary skill in the art would be motivated to implement the substituted piperazinyl moieties taught by Peyton into the compounds of Bourotte given the rationale provided by Mitscher that the piperazine is a medicinal chemical handle for safety and efficacy, and itself can be, at least, alkyl substituted in commonly available antibacterial compounds and pharmaceutical compositions thereof.
Furthermore, Claim(s) 12-13 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Bourotte (as applied above) in view of Mitscher (as applied above), Peyton (as applied above), and Wang et al (Published Online: 26 December 2013; Wang KM et al, Design, Synthesis and Antibacterial Evaluation of Novel Fluoroquinolone and its Derivatives, Asian Journal of Chemistry; Vol. 26, No. 1 (2014), 209-215; henceforth Wang).
Wang teaches the synthesis of novel fluoroquinolones as they apply to bactericidal activity [pg. 209; Introduction; par. 1]. Wang, specifically, explores N-4’ substitution of the piperazinyl moiety due to discovery that other 4-substituted piperazin-1-yl prodrugs of norfloxacin were prepared to improve the bioavailability of the parent compound [pg. 209; Introduction; par. 3], culminating in compounds such as Compound GI-12, below:
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In teaching Compound GI-12, Wang meets the limitations R81 and R82, together with the nitrogen atom to which they are attached, combine to form a 4- to 11-membered heterocycloalkyl (i.e. morpholinyl). In doing so, Wang meets the limitations presented by Claim(s) 12-13, and 18. In context to the close structural similarity between the methyl-substituted piperazine in GI-12 and the claimed Formula (I), MPEP 2144.09 (I) states:
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963). Furthermore, MPEP 2144.09 (II) states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
The methyl-substituted piperazine found in GI-12 is a homolog of the same core structure found for the piperazine of the mentioned claims, differing by the addition of a methyl group, and their structural similarity for the rest of R8 presumes, along with mutual teachings of antibacterial activity, the expectation that such compounds possess similar properties. Given this to be the case, the skilled artisan would be sufficiently motivated to extrapolate the teachings of Wang to use the non-methylated piperazinyl substituent.
A prima facie case of obviousness can be made similarly for implementing the morpholine substituent taught by Wang into the R8-equivalent positions of compounds taught by Bourotte, in similar fashion to Peyton. While Peyton does not teach the morpholine substituent, its knowledge in the art within similar antibacterial compounds to Peyton lends sufficient motivation to one of ordinary skill in the art to extend their palette of analogs to encompass morpholine substituents per the rationale of efficacy modulation provided by Mitscher and data provided by Wang.
Furthermore, Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Bourotte (as applied above) in view of Mitscher (as applied above), Peyton (as applied above), and Zimmermann et al (Published: 20 December 2007; US 20070293478 A1; henceforth Zimmermann).
Zimmermann teaches the fluoroquinolone Compound 77 [pg. 48; [0478]], below:
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bearing the pyrrolidine amide, in which the fluoroquinolone piperazinyl group is di-methyl-substituted (treated as a homolog, explanation above).
A prima facie case of obviousness can be made similarly for implementing the pyrrolidine substituent taught by Zimmerman into the R8-equivalent positions of compounds taught by Bourotte, in similar fashion to Peyton. While Peyton does not teach the pyrrolidine substituent, its knowledge in the art within similar antibacterial compounds to Peyton lends sufficient motivation to one of ordinary skill in the art to extend their palette of analogs to encompass pyrroldine substituents per the rationale of efficacy modulation provided by Mitscher and synthesis provided by Zimmerman.
Furthermore, Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Bourotte (as applied above) in view of Mitscher (as applied above), Peyton (as applied above), and Yang D et al (Published: 20 November 2013; CN103396396A; henceforth Yang; Original Document and Translation attached).
Yang teaches ciprofloxacin derivative compounds, specifically TM1-38 [Original Document; pg. 12 of 33], below:
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wherein the equivalent R81 moiety is a 5-membered heterocycloalkyl, as required by Claim 8.
A prima facie case of obviousness can be made similarly for implementing the heterocycloalkyl substituent taught by Zimmerman into the R8-equivalent positions of compounds taught by Bourotte, in similar fashion to Peyton. While Peyton does not teach the heterocycloakyl substituent, its knowledge in the art within similar antibacterial compounds to Peyton lends sufficient motivation to one of ordinary skill in the art to extend their palette of analogs to encompass the heterocycloalkyl substituents per the rationale of efficacy modulation provided by Mitscher and synthesis by Yang.
Therefore, Claim(s) 1-20 are rejected under 35 USC § 103.
Conclusion
No claims are allowed in this action.
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/STANLEY BRAM/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
