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 .
Priority
The instant application, filed 09/26/2023 does not claim any foreign or domestic priority.
Information Disclosure Statement
The Information Disclosure Statement filed on 09/26/2023 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statement is considered.
Restriction/Election
Applicant’s election without traverse of Group II in the reply filed on 03/04/2026 is acknowledged. However, applicant has not elected a single compound of formula 2, as required by the restriction requirement, filed 12/10/2025. In an effort to advance prosecution, the Examiner will begin examination for preparing a compound of formula 2 wherein R is
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i.e. compound 24, also known as CAS Registry Number: RN 3025716-40-6[ Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 3025716-40-6, Entered STN: 25 Jan 2024].
Status of the Claims
Claims 1-9 are pending in the instant application. Claims 1-3 and 6-9 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention. Therefore, claims 4 and 5 read on an elected invention and are therefore under consideration in the instant application.
Drawings
The drawings filed 09/26/2023 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Objections
The instant claims are objected to for the following informalities:
Claim 4 depends on a withdrawn claim (claim 1). In order to overcome the rejection, the claim must be rewritten in independent form to include the compound of formula 2 and the sidechains intended to be claimed.
Claim 4 refers to intermediates I, II, III, and IV , corresponding to compounds having structural formulas 3 to 6. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
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In order to overcome the objection, Applicant is required to rewrite claim 4 to include the structural formulas directly within the claim language.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 5 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Specifically, it is unclear how the claimed intermediates of claim 4 are made to react with one another. The claim does not provide sufficient detail to define the metes and bounds of the claimed method, and the claim is thus, rendered indefinite.
Claim 5 depends on a claim rejected as being indefinite (claim 4), and does not remedy the indefiniteness of the claim on which it depends, and is therefore dually rejected as indefinite.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 4 and 5 are rejected under 35 U.S.C. § 103 as being unpatentable over Ling et al. (Arch Pharm Chem Life Sci, Volume 345, pages 638–646, published April 25, 2012), hereinafter Ling in view of Zhang et al. (Chem Eur J, Volume 26, Issue 72, pages 17289-17317, published May 29, 2020), hereinafter Zhang, and Kikelj and Urleb (Science of Synthesis, Eds.; Thieme: Stuttgart, Germany, 2002; Volume 11: Category 2, Product Class 17, pages 627-833, published 2002).
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The instant claims are drawn to a preparation method for a pleuromutilin derivative with a thiazole side chain. The derivatives examined is that of formula 2, wherein R is disclosed in the instant application as compound 24.
Ling teaches the design, synthesis, and antibacterial activity of pleuromutilin derivatives bearing an amino thiazolyl ring. Within reaction scheme 1, Ling teaches the synthesis of compound 11, also known as CAS Registry Number: RN 1345825-91-3. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1345825-91-3. Entered STN: 18 Nov 2011]. The prior art compound differs from the compound of the instant claims only by two CH2 groups, highlighted in Figure 1, below.
Figure 1. Structural comparison of instantly claimed compound and prior art compound
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Fig 1. a) Instantly claimed CAS Registry Number 3025716-40-6; b) Ling CAS Registry Number: RN 1345825-91-3
The method of synthesis of the prior art compounds is very similar to that instantly claimed.
Figure 2. Reaction scheme to synthesize prior art compound taught by Ling
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Fig 2. Reaction scheme reproduced from Ling: (a) TsCl, triethylamine, CH2 Cl 2 , rt,17 h, 50%; (b) KI, acetone, reflux, 3 h, 87%;(c) (2-aminothiazol-4-yl)methanethiol, 30%NaOH, THF, 08C rt, 2 h, 72%; (d) 2-chloro-acetyl chloride, K2 CO 3 , CH 2 Cl 2 , 08C rt, 1 h,92%;
Similar to the instant claims, the first two steps described by the instant claims as shown below
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(see page 9 of the instant specification) are identical, showing that the general synthesis route is well understood within the art.
The only difference between the prior art and the preparation method described by the instant claims is the use of KI in the prior art, versus NaI in step (2) of the instant claims.
However, both KI and NaI are used interchangeably within the context of sulfide bond formation as demonstrated by Zhang (see Scheme 18, page 17298, Scheme 38, page 17305). Thus, KI and NaI are considered substitutable equivalents used for the same purpose. According to MPEP § 2144.06 (II), art-recognized equivalents substituted for the same purpose are rendered obvious. The courts have stated:
In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958)
Therefore, person of ordinary skill in the art would have found it obvious to substitute NaI for KI, as both are known to be used for a common purpose, i.e., nucleophilic substitution in the process of sulfide bond formation.
According to Figure 1, the compounds of the prior art are undeniably similar to that of the instant claims. The courts have previously stated that compounds which differ only in the addition of CH2 groups are considered homologous compounds, and there is a presumption that the homologous structure would possess similar properties. The courts have stated,
[c]ompounds 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). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious) (see MPEP § 2144.09).
With respect to compounds which are close in structure, the courts have stated,
similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close' structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP § 2144.08(d)).
The difference between the prior art compound and that of the instant claims are extended linker groups of additional methylene units, resulting in compounds with similar properties. As such, the only feature which distinguishes the preparation method of the instant claims is the use of reagents which differ from that of the prior art by the successive addition of CH2 groups to create homologous structures.
With regard to step (3), use of intermediate III is reflected in the prior art in step c (see Figure 1) as (2-aminothiazol-4-yl)methanethiol, differing only by a single CH2 group from that which is instantly claimed. Intermediate III, or formula 5, a thiazole compound is well-known in the art to be synthesized using carbon disulfide (CS2) and aminonitriles, according to Kikelj and Urleb (Scheme 64, page 670, reproduced below)
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The instant limitation is simply drawn to using a well-known method to synthesize a reagent as opposed to including the reagent out right within the synthesis scheme. According to MPEP § 2144.07, the selection of a known material based on its suitability for its intended purpose supports a prima facie obviousness determination,
See also In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960) (selection of a known plastic to make a container of a type made of plastics prior to the invention was held to be obvious); Ryco, Inc. v. Ag-Bag Corp., 857 F.2d 1418, 8 USPQ2d 1323 (Fed. Cir. 1988) (Claimed agricultural bagging machine, which differed from a prior art machine only in that the brake means were hydraulically operated rather than mechanically operated, was held to be obvious over the prior art machine in view of references which disclosed hydraulic brakes for performing the same function, albeit in a different environment.).
Therefore, a person of ordinary skill in the art would have found it obvious to synthesize a reagent according to methods well-known to person of ordinary skill in the art, instead of buying the reagent, upon considering commercial unavailability and costs associated with purchasing a reagent. Synthesizing the reagent is considered an obvious choice, in view of the well-known methods for synthesis to person of ordinary skill in the art for the common intended purpose, i.e., addition of a thiazole group as defined in the prior art by Ling.
Finally, the homolog of compound 10 is reacted with an acyl chloride to produce compound 11 of the prior art (see step d, Figure 1), which again differs from the instantly claimed compound only by an additional methylene unit.
As such, it would have been obvious to a person of ordinary skill in the art to modify the prior art compound by adding CH2 units, because homologation is a well-recognized and routine structure-activity relationship strategy in medicinal chemistry. According to MPEP § 2144.09, “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.” Adjusting linker length between a known pharmacophore and a scaffold is a standard technique to fine-tune spatial orientation of binding elements, yielding nothing more than predictable results. Furthermore, because the core pleuromutilin scaffold and the general synthesis route is preserved in the claimed compound, a person of ordinary skill in the art would have had a reasonable expectation that resulting methylene homologs would retain or improve antibacterial activity, as taught in the prior art. Therefore the preparation method as claimed is rendered obvious over the prior art cited, as the instantly claimed preparation steps are explicitly outlined in the disclosure by Ling, and the addition of methylene groups to the prior art compound, represents nothing more than an obvious modification to the disclosed compounds with antibacterial properties.
Correspondence
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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