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 present application claims priority to the application, 63/495,649, with effective filing dates of 12 April 2023
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 28 August 2026.
Applicant’s election without traverse of Group I (claims 1-6, 9, 11-12, 17, 19-20, 22, 30, 33-35, and 41) and Compound A10 (
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) as the species in the reply filed on 28 August 2026 is acknowledged.
Claims 42-43 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected group (Group II: claims 42-43), there being no allowable generic or linking claim.
Claims 11, 19, 30, and 33-34 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species, there being no allowable generic or linking claim. Claim 11 recites R5 is unsubstituted, which does not read on the elected species. Claim 19 recites R2 is CHF2 or CF3, which does not read on the elected species. Claim 30 recites that R3 is CHF2 and R4 is methyl, which does not read on the elected species. Claim 33 recites R1 is H or hydroxy, R2 is methyl, R3 is CHF2, R4 is methyl, X is a bond, and R5 is a 4-6-membered heterocycle, which does not read on the elected species. Claim 34 recites X is C1-6(alkylene)-C(O), R5 is azetidinyl, R1 is H or hydroxy, R2 is C1-3 alkyl, R3 is CHF2, and R4 is methyl.
Claims 1-6, 9, 12, 17, 20, 22, 35, and 41 are under consideration in the instant office action.
The Examiner notes that the amendment for claims 9, 22, and 35 has support in the specification at [0022], [0025], [0031], and [0044].
Information Disclosure Statement
The Information Disclosure Statements filed 23 Aug 2024, 1 Oct 2024, and 25 Mar 2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
1. Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 recites a structure of Formula (II):
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, wherein CA and CB represent carbon stereocenters having the same or opposite stereochemistry. Claim 1 (the claim upon which claim 4 depends) recites a compound of Formula (I):
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, which is stereo-ambiguous (stereogenic) and has two unassigned stereocenters, thus making the total possible number of stereoisomers: 22 = 4. In other words, claim 1 does not specify the stereochemistry of the two stereocenters and is necessarily understood to encompass all stereocenters, which are the four isomers: (R,R), (S,S), (R,S), and (S,R).
Claim 4 recites that the stereocenters of the compound of Formula (II) have either the same stereochemistry (i.e. (R,R) or (S,S)) or opposite stereochemistry (i.e. (R,S) or (S,R)), all four of which are already encompassed in claim 1. Accordingly, claim 4 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the 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.
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.
2. Claim(s) 1-6, 9, 12, 17, 20, 22, and 41* are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Coates (US 2020/0392118, published 17 Dec 2020; see IDS filed 25 Mar 2026).
*While Applicant elected the species of Compound A10:
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, Coates applies to the broader genus, and the rejection over the broader genus is made in favor of compact prosecution. However, the Examiner notes that the full genus was not searched.
Coates teaches ketohexokinase (KHK) inhibitors and pharmaceutical compositions thereof for treating type 2 diabetes mellitus, heart failure, diabetic kidney disease, and non-alcoholic steatohepatitis ([0001]). Coates teaches that KHK is also referred to as fructokinase and is the rate-limiting enzyme involved in fructose metabolism ([0002]). Coates teaches that KHK exists in two alternatively spliced isoforms: KHK-C (expressed primarily in the liver, kidney, and intestine) and KHK-A (expressed ubiquitously; [0003]). Coates teaches that increased consumption of fructose and more precisely increased fructose metabolism may play an important role in the development of certain disorders, including metabolic syndrome, type 2 diabetes mellitus, heart failure, diabetic kidney disease, and NAFLD/NASH ([0004]). Coates teaches that there is a need for compounds that are potent KHK inhibitors with advantageous properties, such good oral bioavailability to support once daily dosing and a lack of carboxylic acid moiety (which carry the risk of acyl glucuronide metabolite formation; [0006]-[0007]). Coates teaches the compound, Example 35:
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([0233]), which falls into Formula (I). Mapping shown below:
18/634,193 Formula (I) Components
18/634,193 Formula (I)
Example 35 (Coates)
R1
OH
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R2
C1-6 alkyl (Me)
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R3
C1-6 haloalkyl (CF3)
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R4
H
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A
5-membered heteroaryl having 2 N ring atoms
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X
a bond
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R5
4-membered heterocycloalkyl having 1 ring atom and substituted with C1-6 alkyl (Me)
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Accordingly, Coates teaches a compound of Formula (I) ([0233]). Additionally, the Examiner notes that Examples 1, 4, 13-15, and 29-34 in Coates also fall into Formula (I).
Regarding claim 1, Coates teaches the compound, Example 35:
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([0233]), wherein R1 is OH, R2 is methyl, R3 is CF3, R4 is H, A is pyrazole, X is a bond, and R5 is azetidine substituted with a methyl.
Regarding claim 2, Coates teaches the compound, Example 35:
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([0233]), wherein A is a pyrazolyl.
Regarding claim 3, Coates teaches the compound, Example 35:
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([0233]), wherein the compound is a structure of Formula Ix:
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.
Regarding claim 4, Coates teaches the compound, Example 35:
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([0233]), wherein the compound is a structure of Formula (II):
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.
Regarding claim 5, Coates teaches the compound, Example 35:
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([0233]), wherein CA has the stereochemical assignment of (R) and CB has the stereochemical assignment of (S).
Regarding claim 6, Coates teaches the compound, Example 35:
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([0233]), wherein A is pyrazolyl.
Regarding claim 9, Coates teaches the compound, Example 35:
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([0233]), wherein R5 is a 4-membered heterocycloalkyl having 1 ring nitrogen atom (azetidine) substituted with 1 C1-6 alkyl (methyl).
Regarding claim 12, Coates teaches the compound, Example 35:
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([0233]), wherein R5 is substituted with 1 C1-6 alkyl (methyl).
Regarding claim 17, Coates teaches the compound, Example 35:
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([0233]), wherein R2 is methyl.
Regarding claim 20, Coates teaches the compound, Example 35:
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([0233]), wherein R3 is CF3.
Regarding claim 22, Coates teaches the compound, Example 35:
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([0233]), wherein R4 is H.
Regarding claim 41, Coates teaches a pharmaceutical composition of a compound or salt thereof and a pharmaceutically acceptable excipient ([0001]; [0071]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
3. Claim(s) 1-6, 9, 12, 17, 20, 22, 35, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Dowling (US 9,809,579, issued 7 Nov 2017; see IDS filed 23 Aug 2024) in view of Coates (US 2020/0392118, published 17 Dec 2020; see IDS filed 25 Mar 2026).
Dowling teaches ketohexokinase (KHK) inhibitors for treating type 2 diabetes and NAFLD/NASH, which are major public health concerns (abstract; column 1, lines 22-23; column 1, lines 31-35; column 1, lines 43-46; column 1, lines 54-56). Dowling teaches that fructose significantly elevates de novo lipid synthesis compared to glucose and that elevated lipid synthesis is a distinct characteristic of patients with NAFLD (column 1, lines 56-61). Dowling teaches that short term fructose feeding causes increases in hepatic triglycerides and that removal of fructose consumption can reverse hepatic triglyceride accumulation (column 1, lines 61-65). Dowling teaches that the high prevalence of type 2 diabetes, obesity, and NAFLD/NASH and associated comorbidities has led to increased desire for both preventative care and therapeutic interventions (column 2, lines 7-10). Dowling teaches that inhibiting KHK metabolism of fructose offers a novel alternative to current treatment strategies (column 2, lines 16-18). Dowling teaches that KHK is the principle enzyme in fructose metabolism and catalyzes the conversion of fructose to fructose-1-phsophate (F1P) and that KHK is expressed as two alternative mRNA splice variants: KHK-A and KHK-C (column 2, lines 20-23). Dowling additionally teaches that a more severe condition involved in fructose metabolism is Hereditary Fructose Intolerance, which is caused be defects in aldolase B, which is the enzyme responsible for breaking down F1P and is immediately downstream of the KHK step in the pathway (column 2, lines 37-44). Dowling teaches that there remains a need for an easily administered treatment for cardiometabolic and associated diseases (column 3, lines 19-20). Dowling teaches Examples 5 and 40:
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and
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, respectively (column 61 and Figure 3). Dowling teaches that Examples 5 and 40 have an IC50 values in Assay A of 24.7 nM and 11.1 nM, respectively, against KHK-C (Table 3, column 75; Table 4, column 79).
Regarding claim 1, Dowling fails to teach
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.
Coates teaches ketohexokinase (KHK) inhibitors and pharmaceutical compositions thereof for treating type 2 diabetes mellitus, heart failure, diabetic kidney disease, and non-alcoholic steatohepatitis ([0001]). Coates teaches that KHK is also referred to as fructokinase and is the rate-limiting enzyme involved in fructose metabolism ([0002]). Coates teaches that KHK exists in two alternatively spliced isoforms: KHK-C (expressed primarily in the liver, kidney, and intestine) and KHK-A (expressed ubiquitously; [0003]). Coates teaches that increased consumption of fructose and more precisely increased fructose metabolism may play an important role in the development of certain disorders, including metabolic syndrome, type 2 diabetes mellitus, heart failure, diabetic kidney disease, and NAFLD/NASH ([0004]). Coates teaches that there is a need for compounds that are potent KHK inhibitors with advantageous properties, such good oral bioavailability to support once daily dosing and a lack of carboxylic acid moiety (which carry the risk of acyl glucuronide metabolite formation; [0006]-[0007]). Coates teaches the compound, Example 35:
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([0233]), which has the IC50 values of 2.63 nM against KHK-C and 1.59 nM against KHK-A (Table 6, page 37). Coates further teaches that Example 35 has a HepG2 IC50 value of 6.41 nM, which measures inhibition of metabolism of fructose to F1P in HepG2 cells (Table 7, page 37; [0245]).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify Example 5 of Dowling to 1) incorporate a chloro moiety to increase potency as taught in Example 40 of Dowling; and 2) substitute the eastern fragment of a pyrrolidine-cyclopropyl bicycle-carboxylic acid fragment to a pyrazole-azetidine fragment as taught by Coates to simplify the eastern fragment, optimize potency, and remove the carboxylic acid as taught by Coates. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Dowling teaches ketohexokinase (KHK) inhibitors for treating type 2 diabetes and NAFLD/NASH, which are major public health concerns,
-Dowling teaches that fructose significantly elevates de novo lipid synthesis compared to glucose and that elevated lipid synthesis is a distinct characteristic of patients with NAFLD,
-Dowling teaches that short term fructose feeding causes increases in hepatic triglycerides and that removal of fructose consumption can reverse hepatic triglyceride accumulation,
-Dowling teaches that the high prevalence of type 2 diabetes, obesity, and NAFLD/NASH and associated comorbidities has led to increased desire for both preventative care and therapeutic interventions,
-Dowling teaches that inhibiting KHK metabolism of fructose offers a novel alternative to current treatment strategies,
-Dowling teaches that KHK is the principle enzyme in fructose metabolism and catalyzes the conversion of fructose to fructose-1-phsophate (F1P) and that KHK is expressed as two alternative mRNA splice variants: KHK-A and KHK-C,
-Dowling additionally teaches that a more severe condition involved in fructose metabolism is Hereditary Fructose Intolerance, which is caused be defects in aldolase B, which is the enzyme responsible for breaking down F1P and is immediately downstream of the KHK step in the pathway,
-Dowling teaches that there remains a need for an easily administered treatment for cardiometabolic and associated diseases,
-Dowling teaches Examples 5 and 40:
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and
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, respectively,
-Dowling teaches that Examples 5 and 40 have an IC50 values in Assay A of 24.7 nM and 11.1 nM, respectively, against KHK-C,
-Coates teaches ketohexokinase (KHK) inhibitors and pharmaceutical compositions thereof for treating type 2 diabetes mellitus, heart failure, diabetic kidney disease, and non-alcoholic steatohepatitis,
-Coates teaches that KHK is also referred to as fructokinase and is the rate-limiting enzyme involved in fructose metabolism,
-Coates teaches that KHK exists in two alternatively spliced isoforms: KHK-C (expressed primarily in the liver, kidney, and intestine) and KHK-A (expressed ubiquitously),
-Coates teaches that increased consumption of fructose and more precisely increased fructose metabolism may play an important role in the development of certain disorders, including metabolic syndrome, type 2 diabetes mellitus, heart failure, diabetic kidney disease, and NAFLD/NASH,
-Coates teaches that there is a need for compounds that are potent KHK inhibitors with advantageous properties, such good oral bioavailability to support once daily dosing and a lack of carboxylic acid moiety (which carry the risk of acyl glucuronide metabolite formation),
-Coates teaches the compound, Example 35:
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, which has the IC50 values of 2.63 nM against KHK-C and 1.59 nM against KHK-A, and
-Coates further teaches that Example 35 has a HepG2 IC50 value of 6.41 nM, which measures inhibition of metabolism of fructose to F1P in HepG2 cells.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a
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.
Regarding claim 2, Coates teaches the compound, Example 35:
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([0233]), wherein A is a pyrazolyl.
Regarding claim 3, Coates teaches the compound, Example 35:
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([0233]), wherein the compound is a structure of Formula Ix:
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.
Regarding claim 4, Coates teaches the compound, Example 35:
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([0233]), wherein the compound is a structure of Formula (II):
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.
Regarding claim 5, Coates teaches the compound, Example 35:
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([0233]), wherein CA has the stereochemical assignment of (R) and CB has the stereochemical assignment of (S). Additionally, Dowling teaches Example 5:
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(column 61), wherein CA has the stereochemical assignment of (R) and CB has the stereochemical assignment of (S).
Regarding claim 6, Coates teaches the compound, Example 35:
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([0233]), wherein A is pyrazolyl.
Regarding claim 9, Coates teaches the compound, Example 35:
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([0233]), wherein R5 is a 4-membered heterocycloalkyl having 1 ring nitrogen atom (azetidine) substituted with 1 C1-6 alkyl (methyl).
Regarding claim 12, Coates teaches the compound, Example 35:
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([0233]), wherein R5 is substituted with 1 C1-6 alkyl (methyl).
Regarding claim 17, Coates teaches the compound, Example 35:
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([0233]), wherein R2 is methyl. Additionally, Dowling teaches Example 5:
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(column 61), wherein R2 is methyl.
Regarding claim 20, Coates teaches the compound, Example 35:
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([0233]), wherein R3 is CF3. Additionally, Dowling teaches Example 5:
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(column 61), wherein R3 is CF3.
Regarding claim 22, Coates teaches the compound, Example 35:
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([0233]), wherein R4 is H. Additionally, Dowling Example 40:
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(Figure 3). wherein R4 is chloro.
Regarding claim 35, Dowling teaches Examples 5 and 40:
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and
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, respectively (column 61 and Figure 3). Coates teaches the compound, Example 35:
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([0233]). Accordingly, the combination of Dowling and Coates teaches Compound A10:
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.
Regarding claim 41, Coates teaches a pharmaceutical composition of a compound or salt thereof and a pharmaceutically acceptable excipient ([0001]; [0071]).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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