DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
The status of the claims are as follows:
Claims 1-16 are pending.
Claims 1-16 are rejected.
Claims 1, 9, and 12 are objected to
Response to Election/Restriction Requirement
Applicant's election with traverse of Group I, claims 1-12, drawn to a compound of either Formula I or Formula II in the reply filed on 2026, Jun. 30 is acknowledged. The traversal is on the ground(s) that examination of Group I and Group II would likely be co-extensive and involve such interrelated art that the search and examination of the entire applicant can be made without undue burden. Applicant asserts that the methods of Group II require the specific compounds of Formula I or Formula II, and therefore would necessarily overlap with the search for methods of using those same compounds. This is found persuasive and the restriction requirement has been withdrawn.
Applicant’s election with traverse of Compound No. 21 as the singly elected species in the reply filed on 2026, Jun 30 is acknowledged. The traversal is on the ground(s) that there is a relationship among the claimed species, wherein the same 3,5-substituted piperidine structure with systematic variations at defined positions. Applicant further asserts that that a search for the elected Compound No. 21 would naturally encompass structurally related compounds sharing the same piperidine core and renin inhibitory function. This is found persuasive and the specie election requirement has been withdrawn.
Priority
Acknowledgement is made that Instant Application 18/598,315, filed on 2024, Mar. 07 claims priority from Provisional Application 63,489,882, filed on 2023, Mar. 13.
Informational Disclosure Statement
Applicant has elected not to submit an information disclosure statement for this invention.
Claim Objections
Claims 1, 9, and 12 are objected to because the word “pharmaceutically” should be correctly rewritten as “pharmaceutically”. Appropriate action is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 9 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. Specifically, the claims recite a compound of Formula I or a pharmaceutically acceptable prodrug thereof.”
There is insufficient written description for this claim limitation in the disclosure. M.P.E.P. § 2163 states:
"An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention...one must define a compound by 'whatever characteristics sufficiently distinguish it'. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process."
To provide adequate written description of a claimed genus, the specification must describe sufficient distinguishing identifying characteristics of the prodrug genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, structure/function correlation, methods of making the claimed compounds or any combination thereof. In the instant case, no description of any methods of synthesizing the broad subgenus of prodrugs for instant Formula I is disclosed.
The instant specification defines “pharmaceutically acceptable prodrugs” as “compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure” (page 26, paragraph 0085). Further, the instant specification defines a “prodrug” as a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound of the disclosure (page 26, paragraph 0085). It is generally accepted in the art that formation of a particular prodrug or active metabolite for a given compound or series of compounds is unpredictable. As stated by Stella (Prodrugs: Challenges and Rewards, Part 1, 2007), the personnel and skills needed for a successful prodrug program “are no different from those for analog development – it takes a team. The ideal drug is one that is active, easy to formulate, well absorbed after oral dosing, has an acceptable PK profile, and is both renally cleared and metabolized to 1-2 non-toxic metabolites that are rapidly excreted after being formed. If a prodrug intervention is necessary, obviously this ideal scenario is not met. The ideal prodrug, therefore, is one that readily achieves its desired goal, is non-toxic, and breaks down efficiently and quantitatively to the drug and to known and safe by products. Like the drug discovery process, this goal is not often met.” (Page 24, Paragraph 3).
The instant specification does not provide any working examples of a prodrug of a compound of Formula I. The lack of examples is not considered representative of the exceedingly vast number of possible prodrug combinations that are encompassed by the claims. Therefore, one of ordinary skill in the art would not reasonably conclude that Applicant was in possession of prodrugs of the compound of the structure shown in Formula I at the time of filing.
Accordingly, it is not clear Applicants were in possession of the full scope of the claimed compounds at the time the invention was made. Adequate description requires more than a mere statement, or an incomplete characterization, that prodrugs are part of the invention. The skilled artisan could not “immediately envisage” the claimed prodrugs based on the description provided in the disclosure.
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.
Claim 14 is 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. Specifically, the phrase “a disease associated with” renders the scope of the claim ambiguous.
The phrase “a disease associated with” does not make clear what diseases are or are not covered by the scope of the claim. For example, the renin-angiotensin system is indirectly implicated with Alzheimer’s disease (see Wright), for which there is no written support in the instant disclosure. Furthermore, a skilled artisan cannot discern to what degree of association is needed to reduce the severity of or prevent toxicity of said disease. Accordingly, the above claim is ambiguous.
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.
Claim(s) 1-10 and 12 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Imaeda (US 8,329,691 B2, published 2012, Dec. 11).
The instant claims are directed to compounds of Formula I, or a geometric isomer, a pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof:
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,
wherein
X is a methylene group, an oxygen atom, an amine group, a sulfinyl group, or a sulfonyl group;
n is 0, 1, 2, or 3;
Ring A is an optionally substituted 5- or 6-membered unsaturated heterocycle that contains one or more N, O, S, SO, and SO2, and further defined in claims 2-3 and 5; and
the substituents R1 – R4 are defined in claims 1, 4, and 6-8.
Imaeda teaches renin inhibitors represented by Formula II and their use as an agent for the prophylaxis or treatment of hypertension.
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Specifically, Imaeda teaches example 97 as a preferred embodiment of Formula II:
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.
Example 97 anticipates claims directed to salts of the compounds of instant Formula I as follows:
Instant claim 1 when:
R1 is hydrogen;
n = 0;
X is a methylene group that is substituted by R2 (instant spec, page 4, paragraph 0012);
R2 is a C1 alkoxy group;
Ring A is an optionally substituted 6-membered heterocycle that contains one or more N;
R3 is a C4 alkyl group;
R4 is an a 6-membered heterocycle substituted formyl group, wherein the heterocycle contains one N and one O; and
R5 is hydrogen.
Instant claim 2 when:
Ring A is an optionally substituted 6-membered unsaturated heterocycle containing two atoms selected from N.
Instant claim 3 when:
Ring A is
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, wherein R1’ is hydrogen and R2’ is a C4 alkyl group.
Instant claim 4 when:
R1 and R2 are independently hydrogen.
Instant claim 5 when:
R1’ of Ring A is hydrogen and R2’ of Ring A is a C4 alkyl group.
Instant claim 6 when:
R3 an optionally substituted C3 alkyl group, wherein the substituent is a C1 alkyl group.
Instant claim 7 when:
R4 is a 6-membered heterocycle substituted formyl group, wherein the heterocycle contains one N and one O.
Instant claim 8 when:
R5 is hydrogen.
Instant claim 9 is directed to compounds of Formula III, or a geometric isomer, a pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof,
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,
wherein
R1-R5, X, n, and Ring A are defined as in Formula I; and
R6 and R7 are independently a hydrogen, deuterium, halogen, cyano, hydroxyl, or optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 alkoxy groups.
Instant claim 10 is direct to compounds of Formula II, wherein R6 and R7 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C3 alkoxy, or a C1-C3 haloalkoxy.
Example 97 of Imaeda anticipates claims directed to salts of compounds of Formula III as follows:
Instant claim 9 when:
R1-R5, X, n, and Ring A are defined as described above, and
R6 and R7 are independently hydrogen.
Instant claim 10 when:
R6 and R7 are independently hydrogen.
Claim 12 is directed to a pharmaceutical composition comprising an effective amount of a compound, or a geometric isomer, a pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof of compounds of Formula I, and a pharmaceutically acceptably carrier
Imaeda teaches example 97 can be safely administered as a pharmaceutical composition mixed with pharmaceutically acceptable carriers, for example, a tablet (including a sugar-coated tablet and a film-coated tablet), a film, a powder, a granule, a capsule, a liquid, an emulsion, a suspension, an injectable preparation, a suppository, a sustained release preparation, a patch and the like, either orally or parenterally (e.g., topical, rectal, intravenous administration, etc.) (column 96, lines 18-28).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Imaeda in view of Tokuhara (Discovery of Benzimidazole Derivatives as Orally Active Renin Inhibitors: Optimization of 3,5-Disubstituted Piperidine to Improve Pharmacokinetic Profile. Bioorganic and Medicinal Chemistry, 2018, 26, 3261-3286. Doi: 10.1016/j.bmc.2018.04.051), in view of Dekker (Unlocking Pharmacological Potential: Expanding Fragment-Based Drug Discovery with Cyclobutanes. High-Pressure-Mediated Synthesis of Cyclobutanes for Fragment-Based Drug Discovery, 2022, 13. ISBN 978-94-6506-788-9), and in view of Pauling (Carbon-Carbon Bond Distances. the Electron Diffraction Investigation of Ethane, Propane, Isobutane, Neopentane, Cyclopropane, Cyclopentane, Cyclohexane, Allene, Ethylene, Isobutene, Tetramethylethylene, Mesitylene, and Hexamethylbenzene. Revised Values of Covalent Radii. J Am Chem Soc, 1937, 59, 1223-1236).
Claim 11 is directed to species of compounds of Formula I and Formula III., Specifically, the ninth entry of the claim recites a compound (3S)-{N-(2-methylpropyl), N-{2-tert-butyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine. The compound is also listed as compound 17 in the instant specification (page 17, Table 1), and will hereafter be referred to as “compound 17” (Table 1, top row).
As discussed above, Imaeda teaches example 97 (Table 1, bottom row).
Table 1. Structures of instant compound 17 and Imaeda example 97.
Instant
Compound 17
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Imaeda
Example 97
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The difference between the teaching of Imaeda and compound 17 is that Imaeda fails to teach an embodiment where the N-alkyl substituent of the aniline-type nitrogen is a cyclobutyl group.
However, Tokuhara teaches the X-ray crystal structure and binding mode of example 97 with renin (Figure 1). Example 97 is said to have a low bioavailability in animals (<1% in rats), and therefore structural modifications were necessary to improve its physicochemical properties (abstract; page 3262, left column, paragraph 2). Tokuhara further teaches the isobutyl group has an essential hydrophobic interaction in the S1 site, while the S1’, S3, and S3sp sites are good targets for modification (page 3262, left column, paragraph 2).
Figure 1. X-ray crystal structure of example 97 with renin (left) and binding mode (right).
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Prior to the effective filing date of the current invention, Dekker taught that cyclobutane rings enhance pharmacological activity and druglike properties through conformational restriction, non-planarity, and stereochemical intricacies (abstract and page 20, paragraph 1). Flexible ligands (e.g., the propyl methyl ether group of example 97), can suffer from an entropic penalty upon binding due to rotational restriction of the otherwise flexible bond (page 23, paragraph 1). The use of saturated cyclobutane rings instead of planar aromatic rings typically correlates with stronger binding affinities because saturated molecules better complement spatial arrangements of target proteins, leading to higher water solubility and lower melting points (page 23, paragraph 1). Moreover, cyclobutane can be used to direct key pharmacophore groups, fill a hydrophobic pocket in the target enzyme, prevent cis/trans isomerization, improve metabolic stability, and conformationally restrict (part of) the molecule (page 23, paragraph 1).
Dekker further teaches the 1,3 C-C non-bonding cross-distance of cyclobutane is 2.22 Å (Figure 2) (Dekker Figure 1.4B). This distance is similar to the accepted 1,3 C-C non-bonding cross distance found in n-propane of 2.51 Å, as taught by Pauling (page 1224, right column, paragraph 2).
Figure 2. 3D structure of cyclobutane and Newman projection along the C-C bond.
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Accordingly, one of ordinary skill in the art would have been motivated to combine the teachings of Imaeda with Tokuhara, in view of Dekker, and in view of Pauling to enhance the physicochemical properties of example 97 by incorporating a rigid bioisostere of the n-propane without disrupting the advantageous hydrophobic binding in the S3sp pocket of renin. Therefore, instant compound 17 is rendered prima facie obvious by the combined teachings.
Regarding claims 1-10, the cyclobutane ring is rendered obvious by the combined teachings of Imaeda in view of Tokuhara, in view of Dekker, and in view of Pauling. Therefore, example 97 reads on claims directed to salts of compounds of instant Formula I as follows:
Instant claim 1 when:
R1 is hydrogen;
n = 1;
X is a methylene group that is substituted by R2 (instant spec, page 4, paragraph 0012);
R2 is a C1 alkoxy group;
Ring A is an optionally substituted 6-membered heterocycle that contains one or more N;
R3 is a C4 alkyl group;
R4 is an a 6-membered heterocycle substituted formyl group, wherein the heterocycle contains one N and one O; and
R5 is hydrogen.
Instant claims 2-10 as discussed above, when n=1.
Claim 12 is directed to a pharmaceutical composition comprising an effective amount of a compound, or a geometric isomer, a pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof of compounds of Formula I, and a pharmaceutically acceptably carrier
Imaeda teaches example 97 can be part of a pharmaceutical composition mixed with pharmaceutically acceptable carriers, for example, a tablet (including a sugar-coated tablet and a film-coated tablet), a film, a powder, a granule, a capsule, a liquid, an emulsion, a suspension, an injectable preparation, a suppository, a sustained release preparation, a patch and the like, either orally or parenterally (e.g., topical, rectal, intravenous administration, etc.) (column 96, lines 18-28).
Claims 13-16 are directed to methods for inhibiting renin activity in a subject in need thereof and treating a disease associated with renin activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound for Formula (I), wherein the disease is hypertension, cardiovascular disease, diabetic kidney disease, or heart failure.
Imaeda teaches example 97 acts as a renin inhibitory drug in mammals (e.g., rats, mice, humans, etc.), and is useful for the prophylaxis or treatment of various diseases caused by the RA system, including hypertension (column 93, lines 8-13). The method comprises administering to the subject individually, or according to ordinary methods (e.g., methods described in the Japanese Pharmacopeia, etc.), as a pharmaceutical composition mixed with pharmaceutically acceptable carriers (column 96, lines 18-28).
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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