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 .
Status of the Claims
Claims 1,3-8,13-14 and 16-26 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/14/2024 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 1 is objected to because the claim contains very faint chemical structure image that is difficult to interpret.
Claim 8 is objected to because of the following informalities: the word “flurbiprofen” is misspelled as “flubrbiprofen”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 3-4, 6, 8, 14, 16, 18-20, 22-26 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.
Claim 1 is drawn to an antifungal compound, an (R) enantiomer thereof, an (S) enantiomer thereof, a diastereomer thereof, a racemate thereof, or a salt thereof, comprising an azole pharmacophore coupled to a “Ru” moiety via a link, wherein “Ru” is a COX inhibitor coupled to the azole pharmacophore via an amide bond between the primary amine of the azole pharmacophore and a carboxylic acid of the COX inhibitor, and wherein the antifungal compound is according to Formula (I):
PNG
media_image1.png
196
236
media_image1.png
Greyscale
Claim 1 is indefinite because a person of ordinary skill in the art would not understand the metes and bounds of Formula (I) as presented in claim 1, given that the claim does not clearly define the structure of the “Ru” moiety:
Claim 1 does not define what structure qualifies as a “COX inhibitor”, thus the claim provides a functional rather than structural description:
The claim does not define what constitutes “inhibition” in the context of “COX inhibitor”, for example:
agent(s) that inhibit the protein expression of a COX enzyme (e.g., small interfering RNA (siRNA));
small molecules that interfere with COX enzyme activity via competitive/non-competitive/uncompetitive binding (including with what maximum IC50); a great many compounds may serve as COX inhibitors given sufficient concentration;
macromolecules that interfere with COX enzyme activity (e.g., antibodies)
agent(s) that promote the degradation of COX enzyme (e.g. proteolysis-targeting chimera)
The claim does not define whether the structure of moiety “Ru” should qualify as a “COX inhibitor” only before being coupled to the remainder of the structure of the compound (i.e., the “azole pharmacophore”), or only after being coupled to the remainder of the structure (i.e., as a compound of Formula (I)), or must qualify as a “COX inhibitor” both before and after coupling to the remainder of the structure;
The instant Specification provides further information on the structure of “COX inhibitor” that does not narrow the scope of the genus (page 5), for example that the COX inhibitor may be chiral or achiral, and may linked to the “azole pharmacophore” by a direct bond, a linker moiety or molecule (another undefined structural element, and one that challenges the definition of “molecule”), or a chemically bound linker moiety or molecule, which is as undefined as “linker moiety or molecule” in the same manner and also ambiguous in how a “linker moiety or molecule” is distinct from a “chemically bound linker moiety or molecule”. Thus the instant Specification does not inform a person of ordinary skill in the art with regard to what structures would or would not qualify as a “COX inhibitor” in the context of informing the structure of the “Ru” moiety of instant Formula (I) as claimed in claim 1. Exemplary structures of “Ru” are provided, including wherein “Ru” corresponds to the structures of known small molecule COX inhibitors including ibuprofen, flurbiprofen, ketoprofen, and others, wherein the structure of the small molecule COX inhibitor is joined to the “azole pharmacophore” portion of the molecule of Formula (I) via the carboxylic acid functional group of each of these known compounds, as illustrated in the structures of disclosed compounds 1-17 in instant Figure 1. However, the provision of exemplary structures that do fall within the scope of instant Formula (I) does not define the limits of the genus, particularly regarding what structures do not fall within scope of the genus.
The closest comparison with the field of art is found in Liu (Liu, et al. Journal of Medicinal Chemistry, v65, pp12219-12239; 2022). Liu teaches a study in the design, synthesis and biological evaluation of dual-target COX-2/CYP51 inhibitors for the treatment of fungal infections diseases (Abstract, page 12219). Liu teaches that structural modeling studies comparing the theoretical binding of the known COX-2 inhibitor flurbiprofen and the known antifungal CYP51 inhibitor VT-1161 in the binding pockets of both COX-2 and CYP51, to show how part of VT-1161 shares space where flurbiprofen would bind, and therefore how to form a hybrid structure with moieties from each compound, as shown in Liu’s Figure 2, below (page 12220):
PNG
media_image2.png
202
780
media_image2.png
Greyscale
Liu proceeds to prepare compounds bearing moieties corresponding to the structures of flurbiprofen, ketoprofen and naproxen bound to an azole-containing moiety, as variants of structures “6”, “10” and “16”, as shown in the images below taken from Liu’s Schemes 1, 2 and 3, respectively:
PNG
media_image3.png
234
782
media_image3.png
Greyscale
PNG
media_image3.png
234
782
media_image3.png
Greyscale
PNG
media_image4.png
150
788
media_image4.png
Greyscale
Liu shows that compounds of families “6”, “10” and “16” exhibit antifungal activity (Table 1, page 12223) and shows the enzyme inhibition of COX-1 and COX-2 as well as CYP51 enzymes by the most potent of the antifungal compounds disclosed therein (Table 4, page 12224). Finally, Liu provides binding site analysis of prepared compounds in the active site of COX-2, as shown in Liu’s Figure 6, below (page 12225):
PNG
media_image5.png
458
794
media_image5.png
Greyscale
A person of ordinary skill in the art would readily understand how Liu describes and demonstrates a “dual-target” inhibitor based on azole antifungal and non-steroidal anti-inflammatory drug (NSAID) model compounds. In contrast, the instant Specification does not define whether the term “COX inhibitor” as the functional description of the structural limits of the “Ru” moiety is intended to require that the instant compounds are dual-target inhibitors, or that the “Ru” moiety must correspond to a known compound with established inhibitory property over COX-1 and/or COX-2, and at what IC50 efficacy, or even to a molecule that inhibits a COX enzyme by other means (e.g., inhibition of protein expression, directed protein degradation, or immunoglobulin-antibodies). Thus, a person of ordinary skill in the art could not discern the metes and bounds of the genus of compounds of Formula (I) of claim 1.
Claims 3-4, 6, 8, 14, 16, 18-20, 22-26 depend directly or indirectly from claim 1 and do not resolve the indefiniteness of claim 1 with regard to the lack of structural definition to the functional description of the “Ru” moiety of a compound of instant Formula (I) as being a “COX inhibitor”. Specifically regarding claim 8, the terms “ibuprofen-based” and “flubrbiprofen-based” do not define in what matter the “Ru” moiety is similar to the structures of the known compounds ibuprofen and flurbiprofen, and these terms are not further defined in the instant Specification. Regarding claims 18-20 and 22, while these claims require that the synthesis of a compound of instant Formula (I) include specific steps that involve discrete structures, these claims do not limit the synthesis to these step(s) and therefore any number of subsequent synthetic operations can be performed that could transform a compound to an indefinite genus of final product(s).
For the purpose of examination herein, the structure of the “Ru” moiety is understood to permit a single atom or collection of atoms of any element(s), for example a hydrogen atom, phenyl ring, or any other arrangement of atoms.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 14 are anticipated by Bartroli.
Claims 1 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bartroli (Bartroli, et al.; Journal of Medicinal Chemistry, v41, pp1869-1882; 1998).
The limitations of claim 1 are discussed in the rejection above, and hereby incorporated into the instant rejection.
Bartroli teaches a study in the synthesis and antifungal activity of 3-substituted-4(3H)-quinazolines (Abstract, page 1869), including multiple compounds that anticipate the genus of instant claim 1, for example Voriconazole1, and an un-numbered anthranylamide compound2 shown in the table below (page 1870, Figure 1 and Scheme 1, respectively):
Claim Number(s) of Instant Application
Instant Application
Bartroli
1
PNG
media_image1.png
196
236
media_image1.png
Greyscale
wherein:
“Ru” is (5-fluoropyrimidin-4-yl)ethyl
PNG
media_image6.png
146
130
media_image6.png
Greyscale
1
PNG
media_image1.png
196
236
media_image1.png
Greyscale
wherein:
“Ru” is [2-aminophenyl(formamido)]ethyl
PNG
media_image7.png
168
248
media_image7.png
Greyscale
wherein:
X1 = X2 = F
Y = N
Thus, claim 1 is anticipated by the teaching of Bartroli.
Claim 14 further limits claim 1 to a method of making the compound comprising coupling a COX inhibitor (i.e., the “Ru” moiety) to an azole pharmacophore. Bartroli teaches that the anthranylamide compound shown in the table above is prepared by coupling anthranilic acid to the remainder of the structure (i.e., the “azole pharmacophore”), as described by Bartroli on pages 1875-1876 (bridging paragraph) and shown in Scheme 1:
PNG
media_image8.png
203
594
media_image8.png
Greyscale
Thus, claim 14 is anticipated by the teaching of Bartroli.
Allowable Subject Matter
Claims 5, 7, 13, 17 and 21 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
2 2-amino-N-[(3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-
2-yl]benzamide
Prosecution Insights