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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 12/01/2025, wherein the Amendment amended claims 12-14, 19-20, and 25, and cancelled claim 18.
Claims 12-17, 19-20 and 25 are pending and examined on the merits herein.
Priority
This application claims the following priority:
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REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendments to the claims are sufficient to overcome the objections.
35 U.S.C. § 112(b)
Applicant’s amendments to claims 14, 20 and 25 are sufficient to overcome these rejections.
35 U.S.C. § 102(b)
Applicant’s amendment to independent claim 12 that adds the limitation “wherein the AKR1A1 inhibitor has an AKR1A1 IC50 ≤ 100nm, is sufficient to overcome these rejections.
Double Patenting
The terminal disclaimer filed on 12/01/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patent No. 11,576,900, has been reviewed and is accepted. The terminal disclaimer has been recorded.
REJECTIONS-Maintained, Modified, & New
Applicant’s amendment to independent claim 12 that limits the AKR1A1 inhibitor to a selective or partially selective AKR1A1 inhibition with an IC50 ≤ 100nm, has resulted in the new 112(a) and modified prior art rejections.
Stamler continues to be relied upon as the primary reference.
Claim Objections
(New) Claims 19-20 are objected to because of the following informalities:
-In claim 19, line 3, “Imiristat” should be replaced with - -Imirestat- - , to correct its spelling.
-In claim 20, lines 11-12, following “heteroaryl containing from 5-14 ring atoms” the “or” should be replaced by a comma.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New) Claims 19-20 and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 is indefinite because it depends from a deleted base claim. If the base claim has been canceled, a claim which is directly or indirectly dependent thereon should be rejected as incomplete. MPEP 608.01(n).
In view of compact prosecution, for the purpose of applying prior art, claim 19 is interpreted as dependent from claim 12.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(d)
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.
(New) Claim 20 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 20 depends form claim 19, which recites an imirestat analogue. However, the scope of the generic compounds recited in claim 20 include imirestat, itself. Since imirestat cannot be an analogue of itself, the scope of claim 20 broadens the scope of claim 19, thereby failing to further limit the subject matter of claim 19.
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 § 112(a)-Written Description
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.
(New) Claims 12-17 and 19-20 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 claim(s) contains 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.
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 MPEP 2163.
Independent claim 12 is directed toward a method of treating a subject having or at risk of elevated serum cholesterol levels, comprising administering to the subject a selective or partially selective AKR1A1 inhibitor at an amount(s) effective to reduce serum cholesterol and/or PCSK3 levels in the subject, wherein the AKR1A1 inhibitor has an AKR1A1 IC50 ≤100nm.
However, other than stating AKR1A1 inhibitors having an AKR1A1 IC50 ≤100nm, the instant specification provides no examples of such compounds aside from the twenty-seven species of instant claim 25, which are imirestat analogues, and which share the core structure:
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. It is noted that the AKR1AI IC50 values of these compounds are not provided, but since they are dependent from claim 19, which is dependent from claim 12, it is deduced that these claims have an AKR1A1 IC50 ≤100nm.
And while instant claim 20 further teaches imirestat analogues as AKR1A1 inhibitors, and teaches the following generic imirestat analogues:
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., it does not teach which core structure of these generic compounds imparts the AKR1A1 IC50 ≤ 100nm. In fact, the only teaching of a specific AKR1A1 IC50 appointed to a specific compound, in the instant specification, is that of imirestat:
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, wherein imirestat has a AKR1A1 IC50 of 120nm ([00257]). While this compound is within the scope of instant claim 20, it is outside the scope of the instantly claimed AKR1A1 IC50.
As such, it is impossible to determine a structure-function relationship that is critical to imirestat analogues that imparts an AKR1A1 IC50 of ≤ 100nm, let alone AKR1A1 inhibitors, in general.
Santa Cruz (PTO-892) teaches that the inhibition of AKR1A1 can be achieved through various mechanisms, dependent on the structural characteristics of the inhibitors. Some inhibitors may act by directly binding to the enzyme’s active site, while others may induce conformational changes that reduces the enzymes affinity for its substrate. Structural studies of AKR1A1 inhibitors have revealed a diverse range of molecular frameworks, from small organic molecules to larger, more complex structures. The specificity and potency of these inhibitors are often determined by the precise interactions between the inhibitor and the amino acid residues within the active site of AKR1A1. Understanding these interactions is critical for elucidating the structural requirements for effective inhibition and for exploring the broader implications of AKR1A1’s role in metabolic processes (1st paragraph).
Santa Cruz teaches the following compounds as AKR1A1 inhibitors:
Compound
Structure
Penicillic acid
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ß-Nicotinamide adenine dinucleotide phosphate
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Hydrocortisone
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Insulin
Comprises two polypeptide chains: a 30-residue B chain and a 21-residue A chain, interlinked by two disulfide bonds, with a further disulfide bond located within the A chain.
Resveratrol
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D,L-sulforaphane
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L-Ascorbic acid
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In view of the teachings of Santa Cruz that state that AKR1A1 inhibitors have a diverse range of molecular frameworks from small organic molecules to larger, more complex structures, and the examples of AKR1A1 inhibitor compounds, it is impossible to determine a structure-function relationship amongst AKR1A1 inhibitors that is critical to impart an AKR1A1 IC50 of ≤100nm.
In summary, the recitation of an AKR1A1 inhibitor having an AKR1A1 IC50 of ≤100nm, is broader than what the specification supports. The specification merely provides twenty-seven examples of AKR1A1 inhibitors having an AKR1A1 IC50 of ≤100nm, wherein these compounds share the same core structure, and wherein another compound with the same core structure, imirestat, does not have an AKR1A1 IC50 of ≤100nm; the instant specification does not provide a representative number of species of AKR1A1 inhibitors that encompass the genus, “AKR1A1 inhibitor having an AKR1A1 IC50 of ≤100nm,” nor does the specification provide any structure/function correlation.
The instant patent specification does not 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 MPEP 2163.
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 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.
(Modified) Claims 12-13, 15-17, 19-20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/090373 to Stamler (published 06/09/2016, IDS of 09/06/2023) in view of Zhao (S-nitrosylation of ARH is required for LDL uptake by the LDL receptor, Jn of Lipid Res, published 2013, PTO-892 of 07/30/2025).
Stamler teaches a method of treating disorders associated with NO/SNO deficiency or disorders that benefit from increased SNO in a subject by administering an AKR1A1 inhibitor (pg. 69, claims 1-2; pg. 73, claims 6-7; pg. 73, claims 11-12; pg. 75, claims 16-17), wherein Stamler teaches the AKR1A1 compounds as those of instant claims 20 and 25 ([0020]; pg. 69, claim 4; pg. 71, claim 9; pg. 73, claim 14; pg. 75, claim 19).
Stamler teaches SNO CoA metabolizing enzymes as regulators of cholesterol metabolism and sterol biosynthesis and teaches AKR inhibitors as lowering cholesterol levels ([0008], [0017]).
Regarding claim 12, while Stamler teaches a method of treating disorders associated with NO/SNO deficiency or disorders that benefits from increased SNO by administering an AKR1A1 inhibitor and teaches AKR inhibitors as lowering cholesterol levels, it differs from that of the instantly claimed invention in that it does not exemplify a method of treating a subject having elevated serum cholesterol levels by administering an AKR1A1 inhibitor.
Zhao teaches that S-nitrosylation of autosomal recessive hypercholesterolemia protein (ARH) is required for LDL uptake by the LDL receptor, i.e., ARH requires nitric oxide to support LDL uptake (title, abstract; pg. 1551, 1st full paragraph). Cells that express ARH reduce LDL uptake in response to reductions in nitric oxide (pg. 1557, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select elevated cholesterol as the disorder associated with NO/SNO deficiency in the methods of Stamler, to arrive at instant claim 12. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Stamler teaches a method of treating disorders associated with NO/SNO deficiency by administering AKR1A1 inhibitors,
-Stamler teaches AKR inhibitors as lowering cholesterol levels, and
-Zhao teaches that S-nitrosylation of autosomal recessive hypercholesterolemia protein (ARH) is required for LDL uptake by the LDL receptor, and that cells that express ARH reduce LDL uptake in response to reductions in nitric oxide.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of lowering cholesterol levels by increasing nitric oxide levels to increase LDL uptake in cells.
Further regarding claim 12, and regarding claims 19-20 and 25, while the combination of Stamler and Zhao teaches a method of treating a subject having elevated serum cholesterol levels by administering a selective or partially selective AKR1A1 inhibitor, it differs from that of instant claims 12 and 19-20 and 25, in that it does not teach an AKR1A1 inhibitor with an IC50 ≤100nm, such as
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.
Stamler specifically teaches its compounds as selective or partially selective AKR1A1 inhibitors ([0018]), and teaches the AKR1A1 inhibitors as 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione) (imiretstat) and analogues thereof ([0019]; pg. 69, claim 3; pg. 71, claim 8; pg. 73, claim 13; pg. 75, claim 18).
It would have been prima facie obvious to one ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute a F in
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, 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione , with a Br, to arrive at
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, a 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione) analogue. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione has the structure,
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,
,
-Stamler teaches
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as a 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione analogue,
-Stamler teaches that R2 and R7 can be halogen, and
-Stamler teaches halogen as fluoro, chloro, bromo or iodo.
As such, an artisan having ordinary skill in the art would have been motivated to make such a substitution, to predictably arrive at a AKRA1A inhibitor that is structurally and functionally similar to 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione. Per MPEP 2144.09(I), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).” See also MPEP 2114.08
Regarding claim 13, Stamler teaches cardiovascular disease, heart disease, diabetes, stroke, atherosclerosis as diseases associated with NO/SNO deficiency ([0006]; [0078]; pg. 42, [0068]; [0093]).
While the combination of Stamler and Zhao does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by the combination of Stamler and Zhao would have the same properties since it administers the AKR1A1 inhibitors of instant claims 20 and 25 for the same purpose (lowering cholesterol), to the same patient population (patients in need of lowered cholesterol), in the same dosage amount (Stamler teaches 1µg/kg to 10 g/kg ([0076]), and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Further regarding claim 16, the combination of Stamler and Zhao teaches a method of decreasing LDL-cholesterol.
(Maintained) Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/090373 to Stamler (published 06/09/2016, IDS of 09/06/2023) and Zhao (S-nitrosylation of ARH is required for LDL uptake by the LDL receptor, Jn of Lipid Res, published 2013, PTO-892 of 07/30/2025) as applied to claims 12-13, 15-17, 19-20 and 25 above, and further in view of Fletcher (What should my cholesterol level be at my age, Medical News Today, 02/20/2017, IDS of 09/06/2023).
Stamler and Zhao are applied as discussed above and incorporated herein.
While the combination of Stamler and Zhao teaches a method of lowering cholesterol in subjects by administering AKR1A1 inhibitors, it differs from that of instant claim 14 in that it does not teach patients with LDL levels above 70mg/dL.
Fletcher teaches that LDL cholesterol levels should be less than 100mg/dL (pg. 2). Fletcher teaches that high cholesterol at any age puts a person at risk for heart disease, heart attack, and strokes, and that these risks only increase over time, especially for adults who are not taking action to reduce their cholesterol buildup (pg. 3).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select subjects with LDL cholesterol levels of 100 mg/DL or higher, as the subjects in the combined method of Stamler and Zhao, to arrive at instant claim 14. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Fletcher teaches that LDL levels should be less than 100mg/dL,
-Fletcher teaches that high cholesterol puts a person at risk for heart disease, heart attack and strokes, and
-the combination of Stamler and Zhao teaches methods of decreasing cholesterol.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a method that decreases cholesterol and thus, risk for heart disease, heart attack, and stroke in subjects with elevated LDL’s.
Response to Arguments
On pg. 15, Remarks, Applicant argues that Stamler fails to disclose experimental results showing lowering serum cholesterol and/or PCSK9 levels in a subject with any agent, let alone a selective or partially selective AKR1A1 inhibitor having an AKR1A1 IC50 ≤100nm.
And on pg. 16, Remarks, Applicant argues that Zhao does not describe lowering PCSK9 levels using AKR1A1 inhibitory agents or that a selective or partially selective AKR1A1 inhibitor can lower elevated serum cholesterol levels.
These arguments have been fully considered, but are not found persuasive. It is first noted that it is the combination of Stamler and Zhao that teaches a method of treating a subject having a risk of elevated serum cholesterol by administering an AKR1A1 IC50 ≤100nm; one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As discussed above, Stamler specifically teaches its AKR inhibitors, such as
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, as lowering cholesterol levels, and specifically teaches its compounds as treating disorders associated with NO/SNO deficiency, wherein Zhao teaches that S-nitrosylation of autosomal recessive hypercholesterolemia protein (ARH) is required for LDL uptake by the LDL receptor, and that cells that express ARH reduce LDL uptake in response to reductions in nitric oxide. As such, an artisan having ordinary skill in the art would have been motivated to specifically select elevated cholesterol as the disorder associated with NO/SNO deficiency in its methods, to predictably arrive at a method of lowering cholesterol levels by increasing nitric oxide levels to increase LDL uptake in cells.
Regarding the argument in reference to Stamler not disclosing experimental results showing lowering serum cholesterol land/or PCSK9 levels, it is respectfully pointed out that this rejection is a 35 USC 103, obviousness rejection, and not a 35 USC 102, anticipation rejection. Moreover, it is reasonable to assume that the method taught by the combination of Stamler and Zhao would have the same properties since it administers the AKR1A1 inhibitors of instant claims 20 and 25, such as
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, for the same purpose (lowering cholesterol), to the same patient population (patients in need of lowered cholesterol), in the same dosage amount (Stamler teaches 1µg/kg to 10 g/kg ([0076]), and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties. See also MPEP 2112.02.
The examiner respectfully directs Applicant to MPEP 2145(II), “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. . .’The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.’”
Lastly, regarding independent claim 12, it is respectfully pointed out that lines 4-5 recite “effective to reduce serum cholesterol and/or PCSK9 levels.” Thus, claim 12 is not limited to “reduce serum cholesterol and PCSK9 levels.” This is pointed out because Applicant argues that the references are silent in reference to PCSK9 levels. Moreover, as discussed above, the combination of Stamler and Zhao meet the limitation of “reduce PCSK9 levels”; it is reasonable to assume that the combination of Stamler and Zhao would have the same properties since it teaches administering the same active ingredient, in the same dosage amount, to the same patient population as that of the instantly claimed method. See MPEP 2112.02.
On pg. 16, Remarks, Applicant argues that the examples disclose that serum cholesterol has been lowered in in animal models based on the comparison of AKR1A1 deficient 12-week old mice compared to 12-week old wild-type mice, as well as by use of an AKR1A1 inhibitor in C57BL6J 24-week old male mice.
This argument has been fully considered, but is not found persuasive. Since the combination of Stamler and Zhao teaches the instantly claimed method, it is not clear how this data differentiates the teachings of the combination of Stamler and Zhao from the instantly claimed method. Moreover, it is respectfully pointed out that the data in the instant specification is all directed toward the administration of imirestat, which has an AKR1A1 IC50 of 120nm ([00257, Instant Specification), which is outside the scope of the instantly claimed AKR1A1 inhibitors.
On pg. 16, Remarks, Applicant states that during the prosecution of US Application No. 16/648,737, now Patent No. 11,576,900, an affidavit was submitted illustrating the results of assays for measuring AKR1A1 IC50 of imirestat analogues.
This statement has been fully considered. Applicant is respectfully reminded that affidavits or declarations filed during the prosecution of a prior application do not automatically become part of the instant application. Where it is desired to rely on an earlier-filed affidavit or declaration, the applicant should make the remarks of record in this application and include a copy of the original affidavit or declaration filed in the prior application. See MPEP 201.06(c)(IX.).
Moreover, it is not clear how such data would be relied upon to overcome the rejections of record.
On pg. 18, Remarks, Applicant argues that Fletch fails to make up for the deficiencies of Stamler in view of Zhao and that Fletcher is limited to describing ideal LDL levels.
This argument has been fully considered, but is not found persuasive. Fletcher is a tertiary reference relied upon to teach specific LDL cholesterol levels, to meet the limitations of instant claim 14. As such, Fletcher is not relied upon to teach the limitations of instant independent claim 12.
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 double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., 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); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(Modified) Claims 12-13, 15-17, 19-20 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-15 of U.S. Patent No. 12,098,135 (PTO-892 of 07/30/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘135 claims a method of inhibiting an aldoketoreductase in a subject by administering a compound of instant claim 20,
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. (claims 1, 6, 7).
‘135 claims the subject as having atherosclerotic cardiovascular disease, cerebral stroke, type I or type II diabetes, stroke, and more, wherein subjects with these diseases are at risk of elevated serum cholesterol levels (claim 15).
‘135 claims the compound as a selective or partially selective AKR1A1 inhibitor (claim 8).
‘135 differs from that of instant claims 12 and 25 in that it does not teach a compound with an AKR1A1 IC50 of ≤ 100nm.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to substitute the “H” at
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of ‘135, with “F,” to arrive at
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. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because ‘135 teaches that R5 can be H or a halo group (claims 1, 6).
As such, an artisan having ordinary skill in the art would have been motivated to make such a substitution, to predictably arrive at a AKRA1A inhibitor that is structurally and functionally similar to
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. Per MPEP 2144.09(I), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).” See also MPEP 2114.08
While the combination ‘135 does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by ‘135 would have the same properties since it administers a compound of instant claim 20 for the same purpose (treating subjects with diseases that have or are at risk of elevated serum cholesterol levels), to the same patient population (patients with diabetes, for example), in the same dosage amount (‘135 teaches 1µg/kg to 10 g/kg (Col. 35, lines 35-49) and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
(Modified) Claims 12-13, 15-17, 19-20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-15 of U.S. Patent No. 11,518,748 (PTO-892 of 07/30/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘748 claims a method of inhibiting an aldoketoreductase in a subject by administering a compound of instant claims 20 and 25, such as
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(claims 1-7, 16).
‘748 claims the subject as having atherosclerotic cardiovascular disease, cerebral stroke, type I or type II diabetes, stroke, and more, wherein subjects with these diseases are at risk of elevated serum cholesterol levels (claim 15).
‘748 claims the compound as a selective or partially selective AKR1A1 inhibitor (claim 8).
While‘748 does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by ‘748 would have the same properties since it administers a compound of instant claims 19, 20, and 25 for the same purpose (treating subjects with diseases that have or are at risk of elevated serum cholesterol levels), to the same patient population (patients with diabetes, for example), and in the same dosage amount (‘135 teaches 1µg/kg to 10 g/kg (Col. 35, lines 38-45) and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
(Modified) Claims 12-13, 15-17, 19-20 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,391,703 (published 08/19/2025, PTO-892).
Note: In the previous Office Action, this rejection was made over copending Application No. 17/762,793. However, it was noted that a notice of allowance was mailed in this application and that this provisional rejection would be converted to a non-provisional rejection over the patent once it was published.
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘703 claims a method of increasing S-nitrosylation of proteins in a subject having a disorder associated with NO/SNO deficiency, wherein cerebral stroke, type I and type II diabetes and others are taught as such diseases, by administering a compound of formula
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, such as
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(claims 1,-2, 6, 8, 11).
Patients with stroke and type I and type II diabetes are subjects having or at risk of elevated serum cholesterol levels (see instant claim 13).
‘703 differs from that of instant claim 12 in that it does not teach an AKR1A1 inhibition having an IC50 ≤100nm.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the position of “F”
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of ‘703, with “F,” to arrive at
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. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because ‘703 teaches that R3/R5 can be on any position in the ring (claims 1, 6).
As such, an artisan having ordinary skill in the art would have been motivated to make such a modification, to predictably arrive at a compound that increases S-nitrosylation of proteins, that is structurally and functionally similar to
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. Per MPEP 2144.09(I), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).” And, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
See MPEP 2144.08 and MPEP 2144.09.
Applicant is reminded that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See MPEP 2144 (IV).
While‘703 does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by ‘703 would have the same properties since it administers a compound of instant claims 19-20, and 25 for the same purpose (treating subjects with diseases that have or are at risk of elevated serum cholesterol levels), to the same patient population (patients with diabetes, for example), and in the same dosage amount (‘703 teaches 1µg/kg to 10 g/kg (Col. 18, lines 49-52) and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
(Modified) Claims 12, 15-17, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 3-5 of copending Application No. 17/833,310 (claim set dated 07/08/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other
‘310 claims a method of treating disorders associated with NO/SNO deficiency or benefiting from increased SNO in a subject in need thereof, comprising administering to the subject having a disorder associated with NO/SNO deficiency or benefiting from increased SNO, an AKR1A1 inhibitor at an amount effective to promote S-nitrosylation of proteins in the subject (claim 1).
‘310 teaches heart disease, diabetes, and other diseases as “disorders associated with NO/SNO deficiency” ([0007] Specification ‘310), which are diseases that result in a subject having or at risk of elevated serum cholesterol levels (see instant claim 13).
‘310 claims 2,7-Difluoro-2’H,5’H-spiro[fluorene-9,4’-imidazolidine]-2’5’-dione (imirestat) and analogues thereof (claim 3).
‘310 claims the compounds of instant claim 20 (claim 4), wherein the AKR1A1 inhibitor has an AKR1A1 IC50 ≤25nM.
While ‘310 does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by ‘310 would have the same properties since it administers a compound of instant claims 19-20, and 25, for the same purpose (treating subjects with diseases that have or are at risk of elevated serum cholesterol levels), to the same patient population (patients with stroke, for example), and in the same dosage amount (‘310 teaches 1pg/kg to 10 g/kg ([0075]) and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
This is a provisional nonstatutory double patenting rejection.
(New) Claims 12-13, 15-17, and 19-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 19/303,488 (claim set dated 08/19/2025, reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘488 claims the instantly claimed AKR1A1 inhibitors of instant claims 19-20 (claims 1-7 of ‘488).
‘488 claims these compounds in a pharmaceutical composition (claim 8 of ‘488).
‘488 teaches its compounds for use in a method of lowering cholesterol levels ([0017], [0084]).
Consistent with Sun Pharmaceutical Industries v. Eli Lilly and Col, 611 F. 3d 1381, 1387 (CAFC 2010), it is permissible to use a compound claim to reject a method of use claim where that method of use is disclosed in the specification of the application claiming the compound. According to the Sun Pharma. Court, “[i]t would shock one’s sense of justice if an inventor could receive a patent upon a composition of matter, setting out at length in the specification the useful purposes of such composition, . . .and then prevent the public from making any beneficial use of such product by securing patents upon each of the uses to which it may be adapted. . .”.
Moreover, ‘488 claims the compound for use being administered to a subject in an amount effective to increase S-nitrosylation of proteins, and to treat disorders associated with NO/SNO deficiency or those benefits from increased SNO in a subject (claims 11-12 of ‘488).
‘488 claims treating the disorders recited in instant claim 13 (claims 14-16 of ‘488), which are diseases that result in a subject having or at risk of elevated serum cholesterol levels (see instant claim 13).
While ‘488 does not explicitly teach the functional limitations of claims 15-17, it is reasonable to assume that the method taught by ‘488 would have the same properties since it administers a compound of instant claims 19-20, and 25, for the same purpose (treating subjects with diseases that have or are at risk of elevated serum cholesterol levels), to the same patient population (patients with stroke, for example), and in the same dosage amount (‘488 teaches 1pg/kg to 10 g/kg ([00100]) and the instant specification teaches 1µg/kg-10g/kg [0235]), as that taught by the instant specification and claims. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The above rejections have been modified in view of the amendments to independent claim 12 and dependent claim 19. These modifications have addressed the majority of the arguments present by Applicant. All other arguments mirror those presented in response to the prior art rejections. These arguments have been fully addressed above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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/LAUREN WELLS/Examiner, Art Unit 1622