DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, 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 1-26 and 32-43 are pending in the instant invention. According to the Amendments to the Claims, filed April 16, 2024, claims 3-16, 18, 19, 26, 32-35, 37, 39 and 41 were amended and claims 27-31 were cancelled.
Status of Priority
This invention is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/CA2022/050355, filed March 10, 2022, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application No. 63/159,325, filed March 10, 2021.
Although the inventor’s or joint inventor’s claim for the benefit of a prior-filed invention under 35 U.S.C. § 119(e) is acknowledged, the inventor or joint inventor has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. § 119(e) as follows:
The later-filed invention must be an invention for a patent, for an invention which is also disclosed in the prior-filed invention (the provisional invention). The disclosure of the invention in the prior-filed invention and in the later-filed invention must be sufficient to comply with the requirements of 35 U.S.C. § 112(a). {See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)}.
The specification of the prior-filed invention, US Provisional Application No. 63/159,325, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. § 112(a) for one or more claims of this invention for the following reason: the specification in the instant invention has been amended with respect to the scope of formula (I), which now discloses amended definitions for at least R9 and R11, respectively, and is no longer coextensive with that of US Provisional Application No. 63/159,325.
Consequently, since the specification of US Provisional Application No. 63/159,325 lacks adequate support or enablement for one or more claims of the instant invention, as defined below in Restrictions / Election of Species, and in the manner provided by 35 U.S.C. § 112(a), the first Office action on the merits of all relevant claims drawn to the instant invention will be prosecuted according to the earliest effective filing date afforded this invention, which is that of International Application No. PCT/CA2022/050355, filed March 10, 2022.
Restrictions / Election of Species
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The forthcoming first Office action and prosecution on the meris includes (1) claims 1-26 and 32, drawn to substituted 1,6-naphthyridines of the formula (I), shown to the right, and/or a pharmaceutical composition thereof; (2) claim 33, drawn to a method of inhibiting DNA-PK activity, comprising contacting DNA-PK with… a substituted 1,6-naphthyridine of the formula (I), shown to the right above; (3) claim 34, drawn to a method, comprising administering… a substituted 1,6-naphthyridine of the formula (I), shown to the right above; (4) claims 35 and 36, drawn to a method of treating cancer, comprising administering… a substituted 1,6-naphthyridine of the formula (I), shown to the right above; (5) claims 37, 38 and 41-43, drawn to a method of repairing a DNA break in one or more target genomic regions via a homology directed repair (HDR) pathway,… comprising administering… a substituted 1,6-naphthyridine of the formula (I), shown to the right above; and (6) claims 39 and 40, drawn to a method of modifying expression of one or more genes or proteins,… comprising administering… a substituted 1,6-naphthyridine of the formula (I), shown to the right above, respectively.
Thus, a first Office action and prosecution on the merits of claims 1-26 and 32-43 is contained within.
Specification Objection - Disclosure
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(c). Revisions should particularly address bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
Specification Objection - Title
The inventor or joint inventor is reminded of the proper content of the title of the invention.
The title of the invention should be brief, but technically accurate and descriptive and should contain fewer than 500 characters. See 37 CFR 1.72(a) and MPEP § 606.
The title of the invention is not technically accurate and descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. In the revised title, the examiner suggests additionally identifying a particular utility for the substituted 1,6-naphthyridines of the formula (I).
The following title is suggested: SUBSTITUTED 1,6-NAPHTHYRIDINES AS DNA-PK INHIBITORS.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
A compound of formula (I):
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(I)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R1a is H or C1-C6 alkyl;
R1b is C1-C6 alkyl, C(O)R7, C(O)NR6R7, C(O)OR7, NR6R7, S(O)R7, S(O)2R7, S(O)2NR6R7, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected R8 substituents;
each R8 is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl;
each R2 is independently halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, OR5, NR6R7, or 5- to 10-membered heteroaryl;
m is 0, 1, 2, or 3;
each R6 is independently H or C1-C6 alkyl;
each R7 is independently H, C1-C6 alkyl, C(O)C1-C6 alkyl, C(O)OC1-C6 alkyl, C(O)C3-C8 cycloalkyl, C(O)-(3- to 8-membered heterocycloalkyl), C(O)-(5- to 10-membered aryl), C(O)-(5- to 10-membered heteroaryl), S(O)2C1-C6 alkyl, S(O)2C3-C8 cycloalkyl, S(O)2-(3- to 8-membered heterocycloalkyl), S(O)2-(5- to 10-membered aryl), S(O)2-(5- to 10-membered heteroaryl), C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected R9 substituents;
each R9 is independently halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C(O)NR10R10, C(O)OR10, NR10R10, OR5, S(O)2NR10R10, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein each C1-C6 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected R11 substituents;
each R5 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or OC1-C6 alkyl;
each R11 is independently NR10R10;
each R10 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or S(O)2C1-C6 alkyl;
R3 is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl;
each R4 is independently C1-C6 alkyl or C1-C6 haloalkyl; and
n is 0, 1, 2, 3, or 4.
Appropriate correction is required. See MPEP § 2173.02.
Claim 2 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0.
Appropriate correction is required. See MPEP § 2173.02.
Claim 4 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1a is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 5 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1a is CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 6 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1b is NR6R7.
Appropriate correction is required. See MPEP § 2173.02.
Claim 7 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1b is 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected R8 substituents.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is NH2; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 9 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is CN; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 10 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is halo; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 11 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is OH; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 12 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is NHS(O)2C1-C6 alkyl; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 13 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is N(CH3)S(O)2C1-C6 alkyl; and
m is 1.
Appropriate correction is required. See MPEP § 2173.02.
Claim 14 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is H.
Appropriate correction is required. See MPEP § 2173.02.
Claim 15 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is halo.
Appropriate correction is required. See MPEP § 2173.02.
Claim 16 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 1, wherein the compound is of formula (Ia):
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(Ia)
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R7 is C(O)C1-C6 alkyl, C(O)OC1-C6 alkyl, C(O)C3-C8 cycloalkyl, C(O)-(3- to 8-membered heterocycloalkyl), C(O)-(5- to 10-membered aryl), C(O)-(5- to 10-membered heteroaryl), S(O)2C1-C6 alkyl, S(O)2C3-C8 cycloalkyl, S(O)2-(3- to 8-membered heterocycloalkyl), S(O)2-(5- to 10-membered aryl), S(O)2-(5- to 10-membered heteroaryl), C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected R9 substituents.
Claim 17 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is 5- to 10-membered heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 18 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is 5-membered heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Appropriate correction is required. See MPEP § 2173.02.
Claim 19 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is 6-membered heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 20 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is C(O)-(5- to 10-membered aryl).
Appropriate correction is required. See MPEP § 2173.02.
Claim 21 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is C(O)-(5- to 10-membered heteroaryl).
Appropriate correction is required. See MPEP § 2173.02.
Claim 22 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The compound of Claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is S(O)2-(5- to 10-membered aryl).
Appropriate correction is required. See MPEP § 2173.02.
Claim 23 is objected to because of the following informalities: a) for clarity and precision, The compound of Claim 1, wherein the compound is selected from: should be replaced with The compound of Claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ; and b) for clarity and precision, , or a pharmaceutically acceptable salt thereof should be inserted before the period. Appropriate correction is required. See MPEP § 2173.02.
Claim 24 is objected to because of the following informalities: a) for clarity and precision, The compound of Claim 1, wherein the compound is selected from: should be replaced with The compound of Claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ; and b) for clarity and precision, , or a pharmaceutically acceptable salt thereof should be inserted before the period. Appropriate correction is required. See MPEP § 2173.02.
Claim 25 is objected to because of the following informalities: a) for clarity and precision, The compound of Claim 1, wherein the compound is selected from: should be replaced with The compound of Claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ; and b) for clarity and precision, , or a pharmaceutically acceptable salt thereof should be inserted before the period. Appropriate correction is required. See MPEP § 2173.02.
Claim 32 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 33 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation(s):
33. A method for inhibiting DNA-dependent protein kinase (DNA-PK) activity in a cell, wherein the method comprises contacting the cell containing the DNA-dependent protein kinase (DNA-PK) with a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
44. A method for inhibiting DNA-dependent protein kinase (DNA-PK) activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 35 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 36 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of Claim 35, wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of any one of (a), (b), or (c):
(a) radiotherapy; or
(b) a DNA damaging chemotherapeutic agent; or
(c) radiotherapy and a DNA damaging chemotherapeutic agent.
Appropriate correction is required. See MPEP § 2173.02.
Claim 37 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A method for repairing a DNA break in at least one target genomic region in a cell, wherein the method comprises contacting the cell that contains at least one target genomic region with a therapeutically effective amount of a genome editing system and a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein the genome editing system interacts with a nucleic acid of at least one target genomic region in the cell, resulting in a DNA break; and
wherein the DNA break in at least one target genomic region in the cell is repaired at least in part via a homology directed repair (HDR) pathway.
Appropriate correction is required. See MPEP § 2173.02.
Claim 38 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of Claim 37, wherein the efficacy of the repair of the DNA break in at least one target genomic region in the cell at least in part via a HDR pathway is increased as compared to the efficacy of the repair of the DNA break in at least one target genomic region in the cell at least in part via a HDR pathway in the absence of the compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 39 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
A method for modifying expression of at least one gene or protein in a cell having at least one target genomic region, wherein the method comprises contacting the cell having at least one target genomic region and at least one gene or protein with a therapeutically effective amount of a genome editing system and a compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein the genome editing system interacts with a nucleic acid of at least one target genomic region of a target gene in the cell having at least one target genomic region, resulting in editing at least one target genomic region of the target gene in the cell having at least one target genomic region; and
wherein the genomic editing of at least one target genomic region of the target gene in the cell having at least one target genomic region results in any one of (a), (b), or (c):
(a) modification of the expression of at least one downstream gene associated with the target gene; or
(b) modification of the expression of at least one downstream protein associated with the target gene; or
(c) modification of the expression of at least one downstream gene associated with the target gene and modification of the expression of at least one downstream protein associated with the target gene.
Appropriate correction is required. See MPEP § 2173.02.
Claim 40 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of Claim 39, wherein the efficacy of the genomic editing of at least one target genomic region of the target gene in the cell having at least one target genomic region is increased as compared to the efficacy of the genomic editing of at least one target genomic region of the target gene in the cell having at least one target genomic region in the absence of the compound of Claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 41 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
The method of Claim 37, wherein the genome editing system is selected from the group consisting of a clustered regularly interspaced short palindromic repeats (CRISPR)-based system, a meganuclease based system, a Natronobacterium gregoryi Argonaute (NgAgo)-based system, a transcription activator-like effector-based nuclease (TALEN) system, and a zinc finger nuclease (ZFN) based system.
Appropriate correction is required. See MPEP § 2173.02.
Claim 42 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of Claim 41, wherein the genome editing system is a clustered regularly interspaced short palindromic repeats (CRISPR)-based system.
Appropriate correction is required. See MPEP § 2173.02.
Claim 43 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of Claim 42, wherein the clustered regularly interspaced short palindromic repeats (CRISPR)-based system is a CRISPR-Cas system or a CRISPR-Cpf system.
Appropriate correction is required. See MPEP § 2173.02.
Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
Prodrugs of substituted 1,6-naphthyridines of the formula (I)
Claims 1 and 26 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted 1,6-naphthyridines of the formula (I), does not reasonably provide enablement for prodrugs of substituted 1,6-naphthyridines of the formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. Prodrugs of substituted 1,6-naphthyridines of the formula (I), as recited in claims 1 and 26, respectively, have not been adequately enabled in the specification to allow any person having ordinary skill in the art, at the time this invention was made, to make and/or use prodrugs of substituted 1,6-naphthyridines of the formula (I).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the instant invention, are summarized as follows:
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(a) Breadth of the claims - the breadth of the claims includes substituted 1,6-naphthyridines of the formula (I), shown to the right, as well as the myriad of potential prodrugs formulated from these substituted 1,6-naphthyridines of the formula (I), shown to the right, respectively;
(b) Nature of the invention - the nature of the invention is evaluation of substituted 1,6-naphthyridines of the formula (I), shown to the right above, and/or prodrugs thereof, and the pharmacokinetic behavior of these substances as DNA-dependent protein kinase (DNA-PK) inhibitors;
(c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Moreover, WO 21/050059, as provided in the file, cited on the IDS, and cited on the International Search Report (ISR), illustrates a synthesis of the instantly recited substituted 1,6-naphthyridines of the formula (I) {Minchinton, et al. WO 21/050059, 2021};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted 1,6-naphthyridines of the formula (I), and/or prodrugs thereof, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is unclear based on the combination of the instant specification and Minchinton, et al. in WO 21/050059, as provided in the file, cited on the IDS, and cited on the International Search Report (ISR), whether the instantly recited prodrugs of substituted 1,6-naphthyridines of the formula (I) are enabled. Moreover, the following excerpt is taken from Burger’s, with respect to the synthesis of prodrugs of 1,6-naphthyridines of the formula (I) {Wolff, Manfred E., Ed. Burger’s Medicinal Chemistry and Drug Discovery - Fifth Edition, Volume 1: Principles and Practice, New York: John Wiley & Sons, 1994, 975-977}:
The design of prodrugs in a rational manner requires that the underlying causes which necessitate or stimulate the use of the prodrug approach be defined and clearly understood. It may then be possible to identify the means by which the difficulties can be overcome. The rational design of the prodrug can thus be divided into three basic steps: (1) identification of the drug delivery problem; (2) identification of the physiochemical properties required for optimal delivery; and (3) selection of a prodrug derivative that has the proper physiochemical properties and that will be cleaved in the desired biological compartment.
The difficulty of extrapolating data from animal to humans encountered during toxicokinetic and toxicologic studies with drugs is amplified with prodrugs, since not only metabolism of the active moiety might differ, but also its availability from the prodrug. As a matter of fact, there is presently no published rational for the conduct of animal and human pharmacokinetic programs during prodrug research and development.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using prodrugs of substituted 1,6-naphthyridines of the formula (I);
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted 1,6-naphthyridines of the formula (I); however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited prodrugs of substituted 1,6-naphthyridines of the formula (I). The specification lacks working examples of prodrugs of substituted 1,6-naphthyridines of the formula (I).
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure - predicting whether a recited compound, and/or a prodrug thereof, is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Similarly, the specification, as originally filed, including any references incorporated therein, fails to provide the necessary support required by 35 U.S.C. § 112(a) to enable the instantly recited prodrugs of substituted 1,6-naphthyridines of the formula (I). Thus, it is unclear, based on the guidance provided by the specification, whether a prodrug of a substituted 1,6-naphthyridine of the formula (I), such as acetic 4-(5-(((trans)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)oxy)-3-((4-nitrobenzyl)oxy)-1,6-naphthyridin-7-yl)morpholine, shown to the left above, is either synthetically feasible or possesses utility as a DNA-dependent protein kinase (DNA-PK) inhibitor.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using prodrugs of substituted 1,6-naphthyridines of the formula (I) is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 112(b)
The following is a quotation of the second paragraph of 35 U.S.C. § 112:
(b) CONCLUSION. The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or joint inventor regards as the invention.
Claim 33 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that claim 33 fails to explicitly recite a target population for the method of inhibiting DNA-PK activity, comprising contacting DNA-PK with… a substituted 1,6-naphthyridine of the Formula (I), which renders the claim indefinite. Similarly, the inventor or joint inventor should further note that the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Likewise, the inventor or joint inventor should further note that the specification, on page 32, fails to disclose a cell or a subject as a target population. Moreover, the inventor or joint inventor should further note that neither the specification, nor the claim explicitly limits the invention to any particularly disclosed or recited embodiments. Consequently, the inventor or joint inventor should further note that the method of inhibiting DNA-PK activity, comprising contacting DNA-PK with… a substituted 1,6-naphthyridine of the Formula (I) has been rendered indefinite by the lack of a target population.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 34 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that claim 34 fails to explicitly recite an activity for the instantly recited method, which renders the claim indefinite. Similarly, the inventor or joint inventor should further note that the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Likewise, the inventor or joint inventor should further note that the specification, on page 32, fails to disclose any acttivity effected by the instantly recited method. Moreover, the inventor or joint inventor should further note that neither the specification, nor the claim explicitly limits the invention to any particularly disclosed or recited embodiments. Consequently, the inventor or joint inventor should further note that the method, comprising administering… a substituted 1,6-naphthyridine of the Formula (I) has been rendered indefinite by the lack of an activity effected by the method.
The examiner suggests cancelling the claim, to overcome this rejection.
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.
Claims 1, 3, 4, 7, 10, 14 and 32-43 are rejected under 35 U.S.C. § 102(a)(1) and/or 35 U.S.C. § 102(a)(2) as being anticipated by Minchinton, et al. in WO 21/050059.
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The inventor or joint inventor should note that the instant invention recites a substituted 1,6-naphthyridine of the formula (I), shown to the left, where m = 1; n = 0; R1a = -H; R1b = -5- to 10-membered heteroaryl, optionally substituted with R8, wherein R8 = -C1-C6 alkyl; R2 = -halo; and R3 = -H, respectively, and/or a pharmaceutical composition thereof, as a DNA-dependent protein kinase (DNA-PK) inhibitor.
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Similarly, the inventor or joint inventor should further note that Minchinton, et al. (WO 21/050059), as provided in the file, cited on the IDS, and cited on the International Search Report (ISR), teaches a substituted 1,6-naphthyridine of the formula (I), shown to the right, where m = 1; n = 0; R1a = -H; R1b = -pyrazol-4-yl, substituted at N1 with R8, wherein R8 = -CH3; at C-3, R2 = -Br; and R3 = -H, respectively, and/or a pharmaceutical formulation thereof, as a DNA-dependent protein kinase (DNA-PK) inhibitor {p. 102, Table 19, compound 59; and pharmaceutical formulations - p. 24, ¶[0071]}.
Likewise, the inventor or joint inventor should further note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}.
Next, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}.
Then, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}.
Moreover, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}.
Furthermore, the inventor or joint inventor should also note that, although not explicitly discussed herein, this reference contains additional species that may anticipate the instantly recited substituted 1,6-naphthyridines of the formula (I). Consequently, any amendments to the claims and/or arguments formulated to overcome rejections rendered under 35 U.S.C. § 102 should address this reference as a whole and should not be limited to the species discussed or disclosed explicitly herein.
Also, the inventor or joint inventor should further note that in the event the determination of the status of the invention as subject to AIA 35 U.S.C. § 102 (or as subject to pre-AIA 35 U.S.C. § 102) is incorrect, any correction of the statutory basis for the instant 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.
Claim Rejections - Obviousness-type Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute), so as to prevent the unjustified or improper timewise extension of the right to exclude granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined invention claim is not patentably distinct from the reference claims because the examined invention claim is either anticipated by, or would have been obvious over, the reference claims. {See In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969)}.
US Application No. 18/279,379
Consequently, at least claims 1, 3, 4, 7, 10, 14 and 32-43 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over at least claims 1, 3, 12 and 29-40 of copending US Application No. 18/279,379. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in the copending invention recites substituted 1,6-naphthyridines of the formula (II), where R1 = -5- to 10-membered heteroaryl; m = 1; R2 = -halo; R3 = -H; and n = 0, respectively, which provide overlapping subject matter with respect to the instantly recited substituted 1,6-naphthyridines of the formula (I), where R1a = -H; R1b = -5- to 10-membered heteroaryl; m = 1; R2 = -halo; R3 = -H; and n = 0, respectively.
The inventor or joint inventor should note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}.
Similarly, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}.
Likewise, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}.
Next, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}.
Moreover, the inventor or joint inventor should further note that this is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
US Application No. 17/641,813
At least claims 1, 3, 4, 10, 14 and 32-43 are provisionally further rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over at least claims 1, 5, 7, 8, 20, 21, 27 and 33-36 of copending US Application No. 17/641,813. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in the copending invention recites substituted 1,6-naphthyridines of the formula (I), where R4 = -L1-L2-R9a, wherein L1 is absent, L2 is absent, and R9a = -C3-C8 cycloalkyl, substituted with R10d, where R10d = -C1-C6 alkyl; Y = -O-; m = 1; R3 = -halo; R2 = -H; and n = 0, respectively, which provide overlapping subject matter with respect to the instantly recited substituted 1,6-naphthyridines of the formula (I), where R1a = -H; R1b = -C1-C6 alkyl; m = 1; R2 = -halo; R3 = -H; and n = 0, respectively.
The inventor or joint inventor should note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}.
Similarly, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}.
Likewise, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}.
Next, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}.
Then, the inventor or joint inventor should further note that this is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Moreover, the inventor or joint inventor should further note that a timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 37 CFR 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground, provided the conflicting invention or patent either is shown to be commonly owned with this invention, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Furthermore, the inventor or joint inventor should also note that the USPTO internet Web site contains terminal disclaimer forms which may be used, and the inventor or joint inventor is encouraged to visit http://www.uspto.gov/forms/, where (i) the filing date of the invention will determine what form should be used, and (ii) a web-based eTerminal Disclaimer may be filled out completely online using web-screens, respectively.
Also, the inventor or joint inventor should further note that an eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission.
Finally, for more information about eTerminal Disclaimers, the inventor or joint inventor should refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624