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 05/15/2023, is a 371 filing of PCT/US2021/059910, filed 11/18/2021, which claims domestic priority to U.S. provisional app no. 63/115,288, filed 11/18/2020.
Amendments and Claim Status
The amendment filed on 04/10/2026 is acknowledged and entered.
Claims 102 and 103 are amended;
Claims 1-101 are cancelled;
Claims 107-119 are added.
Claims 102-119 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/15/2025 and 05/15/2023 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statements are considered.
Restriction/Election
Applicant’s election without traverse of Group II in the reply filed on 04/10/2026 is acknowledged. Applicants further election of a specific species of a compound of Formula (I) in the reply filed on 07/15/2025 is also acknowledged.
In accordance with the MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
As per MPEP 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species (Figure 1) does not make contribution over the prior art of record.
Figure 1. Elected Species
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Figure 1. 4-chloro-2-((2-chloro-4-nitrophenyl)-carbamoyl)phenylpiperazine-1-carboxylate
Status of Claims
Claims 102-119 are pending in the instant application. Claims 103-111, 113-115, and 119 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 102, 112, and 116-118 read on an elected invention and species and are therefore under consideration in the instant application.
Drawings
The drawings filed on 05/15/2023 are objected to under 37 CFR § 1.83(a) for the following reasons:
The different data types are indistinguishable in Figures 1-3 (all individual panels included in the objection, i.e. A, B, etc.). The original figures rely on color-coding of the data, a feature not available in the black and white drawings. The figures must be remade with shapes or line-types used to describe the different data points.
Figures 9 A-D and 16 A/B are of low-resolution and difficult to read Figure Y. The figures must be remade higher resolution to better reflect the data as well as the axes in the case of Figure 16.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR § 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR § 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Improper Markush Rejection
Claims 102, 112, and 116-118 are rejected on the basis of containing an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
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The Markush grouping of the claims is improper because the alternatives defined by the Markush grouping do not share a single structural similarity. The cited claims of the instant application claim a compound represented by the following general formulas recited in claim 1 as Formula (I) (right) comprising a wide range of substituents which substantially affect the core structure of the compound.
Considering Formula (I), the possibility of R3 and R4 joining to form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl fundamentally changes the core structure of the compounds claimed. As a result, the definition of R3 and R4 is determined to be an improper Markush grouping.
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Considering Y, Some limited examples of possible ring moieties encompassed by the claims are included herein (left), which vary both in their structural composition, as well as in their chemical properties. Furthermore, regarding R11 and R13, the joining of these substituents to form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl further affects the mark whose grouping, and distinguishes the compounds further from one another. As a result, the definition of ring Y is determined to be an improper Markush grouping.
Further considering substituent X, the definition comprises —PO(R1A)(R2A), —C(O)R1B ,or —C(O)NR1CR2C; which groups the highly polar phosphate moiety with the less polar carbonyl and amide moieties. These substituents differ substantially in their electronic configurations, structures, as well as their size. Thus, the definition of X is determined to be an improper Markush grouping.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted for the other, with the expectation that the same intended result would be achieved. Such is not the case in the instant claims because none of the rings in each of the core structures of each of the general formulas are obvious variants nor could they be substituted for one another with a reasonable expectation of similar results.
Thus, the claims are rejected since the Markush claim contains an improper Markush grouping because the members of the Markush group do not share a single structural similarity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 102, 112, and 116-118 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 102, 112, and 116-118 of the instant application are drawn to methods administering the compounds having following substituents:
X is —PO(R1A)(R2A), —C(O)R1B ,or —C(O)NR1CR2C;
R1B is C1-C12 alkyl, C1-C12 haloalkyl, hydroxy(C1-C8 alkyl), alkoxy(C1-C8 alkyl), or amino(C1-C8 alkyl), cycloalkyl optionally substituted with one or more R14, aryl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14;
R1C is C1-C6 alkyl, C1-C6 haloalkyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl), or R1C and R2C, together with the atoms to which they are attached, form a 5- to 8-membered monocyclic heterocyclyl optionally substituted with one or more R15 selected from C1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl; or R1C and R2C, together with the atoms to which they are attached, form a bicyclic heterocyclyl selected from a 5- to 8-membered monocyclic heterocyclyl bridged with 1-3 additional carbon atoms, and a 5- to 8-membered monocyclic heterocyclyl fused to a monocyclic cycloalkyl, monocyclic aryl, a monocyclic heterocycloalkyl, or a monocyclic heteroaryl;
R2C is C1-C6 alkyl, C1-C6 haloalkyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl), or R1C and R2C, together with the atoms to which they are attached, form a 5- to 8-membered monocyclic heterocyclyl optionally substituted with one or more R15 selected from C1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl; or R1C and R2C, together with the atoms to which they are attached, form a bicyclic heterocyclyl selected from a 5- to 8-membered monocyclic heterocyclyl bridged with 1-3 additional carbon atoms, and a 5- to 8-membered monocyclic heterocyclyl fused to a monocyclic cycloalkyl, monocyclic aryl, a monocyclic heterocycloalkyl, or a monocyclic heteroaryl;
R3 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), or —S(O)0-2(C1-C6 alkyl), or R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
R4 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), or —S(O)0-2(C1-C6 alkyl), or R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
Q is N or CR5;
R5 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), cycloalkyl optionally substituted with one or more R14, aryl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14;
R6 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), cycloalkyl optionally substituted with one or more R14, aryl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14, or R5 and R6, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
Y is
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or
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;
Z is O or S;
R7 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R8 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R9 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R10 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R11 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2;
R12 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2;
R13 is hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2;
R11 and R13, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14; R11 and R13 as together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
R14 is halogen, —NO2, —CN, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy;
35 U.S.C. § 112(a) and the first paragraph of pre-AIA 35 U.S.C. § 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the lack of a representative number of species that characterizes the entire claimed genus and accounts for variations between species of the genus.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
X as —C(O)NR1CR2C;
R1B as C1-C12 haloalkyl, hydroxy(C1-C8 alkyl), or amino(C1-C8 alkyl), cycloalkyl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14;
R1C as C1-C6 alkyl, C1-C6 haloalkyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl), or R1C and R2C, together with the atoms to which they are attached, form a 5- to 8-membered monocyclic heterocyclyl optionally substituted with one or more R15 selected from C1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl; or R1C and R2C, together with the atoms to which they are attached, form a bicyclic heterocyclyl selected from a 5- to 8-membered monocyclic heterocyclyl bridged with 1-3 additional carbon atoms, and a 5- to 8-membered monocyclic heterocyclyl fused to a monocyclic cycloalkyl, monocyclic aryl, a monocyclic heterocycloalkyl, or a monocyclic heteroaryl;
R2C as C1-C6 alkyl, C1-C6 haloalkyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl), or R1C and R2C, together with the atoms to which they are attached, form a 5- to 8-membered monocyclic heterocyclyl optionally substituted with one or more R15 selected from C1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, cycloalkyl, or heterocycloalkyl; or R1C and R2C, together with the atoms to which they are attached, form a bicyclic heterocyclyl selected from a 5- to 8-membered monocyclic heterocyclyl bridged with 1-3 additional carbon atoms, and a 5- to 8-membered monocyclic heterocyclyl fused to a monocyclic cycloalkyl, monocyclic aryl, a monocyclic heterocycloalkyl, or a monocyclic heteroaryl;
R3 as halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), or —S(O)0-2(C1-C6 alkyl), or R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
R4 as halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), or —S(O)0-2(C1-C6 alkyl), or R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
Q as N;
R5 as hydrogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), cycloalkyl optionally substituted with one or more R14, aryl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14;
R6 as halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), cycloalkyl optionally substituted with one or more R14, aryl optionally substituted with one or more R14, heteroaryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14, or R5 and R6, together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
Y as
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Z as O or S;
R7 as hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R8 as hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R9 as hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R10 as hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, or C1-C6 haloalkyl;
R11 as —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2,
R12 as —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2,
R13 as —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHCO(C1-C6 alkyl), —N(C1-C6 alkyl)CO(C1-C6 alkyl), —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CO2H, —CO2(C1-C6 alkyl), —CHO, —CO(C1-C6 alkyl), —S(O)0-2(C1-C6 alkyl), —S(O)0-2NH2, —S(O)0-2NH(C1-C6 alkyl), or —S(O)0-2N(C1-C6 alkyl)2,
R11 and R13 as together with the atoms to which they are attached, form a 5- or 6-membered aryl, heteroaryl, or heterocyclyl optionally substituted with one or more R14;
R14 as halogen, —NO2, —CN, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —OH, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy;
The instant specification (pages in 27 and 28) teaches compounds which are characterized as having only the following substituents:
X is —PO(R1A)(R2A), and —C(O)R1B
R1B is C1-C12 alkyl, alkoxy(C1-C8 alkyl), aryl optionally substituted with one or more R14, or heterocycloalkyl optionally substituted with one or more R14;
R1C is not exemplified.
R2C is not exemplified.
R3 is hydrogen,
R4 is hydrogen
Q is CR5;
R5 is halogen,
R6 is hydrogen
Y is
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Z is not exemplified
R7 is not exemplified
R8 is not exemplified
R9 is not exemplified
R10 is not exemplified
R11 is hydrogen, halogen, and —NO2,
R12 is hydrogen, halogen, and —NO2,
R13 is hydrogen, halogen, and —NO2,
R14 is C1-C4 haloalkyl,
Therefore, the methods and compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-20, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 41-59, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 21-40, above). Thus, the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 102, 112, and 116-118 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claim Rejections - 35 U.S.C. § 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.
Claim 102 is rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Nitulescu et al. (I J Mol Med, Volume 48, Issue 2, pages 467-488, published May 18, 2020, cited on applicant IDS filed 05/15/2023), hereinafter Nitulescu.
The instant claim is drawn to a method of treating a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) comprising the administration of a compound of Formula (I).
Nitulescu teaches Nitazoxanide, also known as RN 55981-09-4. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 55981-09-4. Entered STN: 16 Nov 1984] used in a method of treating SARS-CoV-2. Specifically, Nitulescu teaches that a placebo-controlled study (NCT04343248) evaluated nitazoxanide (300 mg x 2/day) as post-exposure prophylaxis for COVID-19 elderly patients, and a related study (NCT04359680) focused on healthcare workers (page 477).
Nitazoxanide anticipates the method of administering a compound according to Formula (I) wherein (see Figure 2),
Figure 2. Comparison of instantly claimed Formula (I) and prior art compound
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710
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Figure 2. a) Instantly claimed Formula (I); b) CAS Registry Number: RN 55981-09-4
X is -C(O)R1B, wherein R1B is C1 alkyl
Q is CR5 and R5 is H
R3, R4, and R6 are H
Y is
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139
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where Z is S, R7 is H, and R8 is NO2
Both the method and compound of the claim is anticipated by the teachings of Nitulescu, and the claim stands rejected.
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 102, 112, and 116-118 are rejected under 35 U.S.C. § 103 as being unpatentable over Wood et al. (WO 2010101648 A1, published September 10, 2010), hereinafter Wood, in view of Westmark et al. (Front Cell Dev Biol, Volume 8, Issue 856, published August 26, 2020) hereinafter Westmark, and further in view of Shaquiquzzaman et al. (J Med Chem, Volume 57, pages 10257−10274, published September 25, 2014), hereinafter Shaquiquzzaman.
The instant claims are drawn to a method of treating disease caused by SARS-CoV-2 comprising the administration of the elected species to a subject in need thereof.
Wood teaches benzamide compounds that modulate the activity of Group I glutamate receptor modulators (mGluR1 and mGluR5). U Wood teaches that these compounds are useful in treating disorders of the lungs (Abstract). Specifically, Wood teaches CAS Registry Number: RN 1243092-28-5. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1243092-28-5, Entered STN: 27 Sep 2010] claim 7 (page 15, line 3), which differs from the elected species by a single methyl group, according to Figure 3 below.
Figure 3. Structural comparison of elected species and prior art compound
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1017
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Figure 3. a) Instantly claimed elected species; b) Wood prior art compound CAS RN 1243092-28-5
The compound renders obvious the elected species according to Formula (I) wherein,
X is -C(O)R1B, wherein R1B is heterocycloalkyl
Q is CR5 and R5 is Cl
R3, R4, and R6 are H
Y is
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156
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where R11 is H, R12 is Cl, and R13 is NO2
Wood fails to teach using the compound disclosed to treat disease caused by SARS-CoV-2. Would further fails to teach wherein the piperazine nitrogen is unsubstituted.
The deficiencies of Wood are remedied by Westmark, who teaches that mGluR5 negative allosteric modulators can be repurposed to inhibit SARS-CoV-2 viral replication (Abstract, page 6). Westmark teaches that mGluR5 is ubiquitously expressed in the body, including the lungs, which is the primary site of SARS-CoV-2 infection (page 6).
A person having ordinary skill in the art would have been motivated to combine the teachings of Wood with the teachings of Westmark because Wood teaches that benzamide compounds modulate mGluR5, and are contemplated for treating diseases of the lungs. Westmark teaches that mGluR5 modulators are effective against SARS-CoV-2, which primarily affects lung tissue. A person having ordinary skill in the art would have recognized the mGluR5-modulating benzamide compounds disclosed by Wood would predictably serve as candidates for treating SARS-CoV-2. A reasonable expectation of success exists, as Westmark demonstrates that structurally diverse mGluR5 inhibitors reduce SARS-CoV-2 viral load, and the compounds disclosed by Wood are established mGluR5 modulators.
The deficiencies of Wood are further remedied by Shaquiquzzaman, who teaches that piperazine is one of the most common heterocyclic scaffolds for the development of new drug candidates (Abstract, page 488). Within the disclosure, Shaquiquzzaman catalogs over 30 FDA-approved drugs containing piperazine (Table 1)—the overwhelming majority of which exhibit an unsubstituted piperazine ring. This establishes that the free NH piperazine is one of the most common forms of the scaffold across diverse therapeutic areas. Shaquiquzzaman further teaches piperazine-containing antiviral agents, specifically demonstrating that the piperazine scaffold is an established motif in antiviral drug design (pages 518 and 519).
A person having ordinary skill in the art seeking to develop novel therapeutics against SARS-CoV-2 would have been motivated to combine the teachings of Wood and Westmark with teachings of Shaquiquzzaman because removal of the N-methyl group from the compounds disclosed by Wood to yield the unsubstituted piperazine would result in one of the most routine and predictable scaffolds already successfully used in medicinal chemistry. Shaquiquzzaman’s extensive survey of approved piperazine drugs demonstrates that the art overwhelmingly favors the free NH piperazine over the N-methylated form. Recognizing that demethylation provides an additional protein datable hydrogen, which serves as a solubility handle in hydrogen bond donor, a person having ordinary skill in the art would have had a reasonable expectation of success in a resulting compound of increase solubility. The methyl-to-hydrogen change is among the smallest structural privations available. The disclosure by Shaquiquzzaman demonstrates that the unsubstituted piperazine scaffold exhibits biological activity across pharmacological classes.
Correspondence
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
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