DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application, filed 25 April, 2023, is a national stage application of PCT/US2021/056499, filed 25 October, 2021, which claims the benefit of U.S. Provisional Application N° 63/223,719, filed 20 July, 2021, and Provisional Application N° 63/105,745, filed 26 October, 2020.
Information Disclosure Statement
Four information disclosure statements (IDS) submitted on 25 April, 2023; 12 May, 2023; 20 December, 2023; and 16 October, 2025 are acknowledged and have been considered.
Election/Restrictions
Applicant’s election without traverse of the compound of Formula A in the reply filed on 5 December, 2023 is acknowledged.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 5 December, 2023, in the matter of Application N° 18/250,402. Said documents have been entered on the record.
Claims 5-6, 8-11, 13-16, 19, 22, 24, 30, 32 and 34-35 are amended. Claims 3, 7, 12, 17-18, 20-21, 23, 25-29, 31, 33 and 36 are canceled. No new matter was introduced.
Claim 10 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim, as Formula A is a 1,2,4-triazine, requiring X and Y to both equal N.
Thus, Claims 1-2, 4-6, 8-9, 11, 13-16, 19, 22, 24, 30, 32, and 34-35 represent all claims currently under consideration.
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 8 and 34 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Although the specification describes Formula A as selective for CYB11B2 inhibition and recites the same Ki ratio as in the claims (instant Specification Para 0069), the application does not disclose experimental data, assay conditions, methods for determining inhibition constants, or comparative enzyme inhibition studies. As a result, the specification does not enable a person of ordinary skill in the art to determine or achieve the claimed selectivity ratio without undue experimentation.
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.
Claims 8, 15, 22, and 34-35 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.
The phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim. See MPEP § 2173.05(c) and (d).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 30 is rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena without significantly more.
The claim recites the steps of measuring BP and evaluating plasma renin activity and aldosterone concentrations. This judicial exception is not integrated into a practical application because the association with plasma renin activity, plasma aldosterone concentration, and hypertension involves natural phenomenon. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because measuring BP and evaluating plasma renin and aldosterone are so routine in the art they don’t add significantly more to the judicial exception. See MPEP 2106.04(d).
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.
Claims 1-2, 4-6, 8-9, 11, 13-16, 19, 22, 24, 30, 32, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Ushirogochi et al. (US Patent 10,029,993, published 24 July, 2018, cited in IDS), hereinafter Ushirogochi.
Regarding Claims 1, 9, 11 and 35, Ushirogochi teaches method for preventing or treating various diseases or conditions associated with aldosterone, comprising administering a therapeutically effective amount of a compound of the above formula [I] or a pharmacologically acceptable salt thereof (‘993, Col 6, Lines 35-39), wherein a compound of formula I is Example 48 (‘993, Col 71, Table 5; which is also instant Formula A, instant Claims 11 and 35, the elected Species, which is a 1,2,4-triazine compound as in instant Claims 9 and 35), which has an excellent inhibitory activity against aldosterone synthetase (Cyp11B2) and therefore, it is useful for preventing or treating various diseases and/or disease states evoked by an increased level of aldosterone and/or overproduction of aldosterone, such as hypertension (‘993, Col 6, Lines 56-61), treatment-resistant hypertension (‘993, Col 38, Lines 61-62.)
Regarding Claim 2, Ushirogochi teaches can be used in combination with one or more other medicaments including one more medicaments selected from the group consisting of an antihypertensive drug such as an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a calcium antagonist, a B-blocker, an A/B-blockers; (2) a diuretic, etc. (‘993, Col 40, Lines 7-16.) Because Ushirogochi teaches administering the compound Example 48 in combination with other antihypertensive agents and expressly discloses use in treatment-resistant hypertension (‘993, Col 38, Lines 61-62), it would have been obvious to treat subjects who are taking or have taken additional antihypertensive medications.
Regarding Claims 4-6, although Ushirogochi does not explicitly disclose the particular plasma renin activity or aldosterone concentration threshold recited in the dependent claims, Ushirogochi teaches treating aldosterone-associated hypertension with the same compound. A person of ordinary skill in the art would understand that aldosterone-associated hypertension is clinically characterized by low PRA and elevated aldosterone levels, and that measuring those parameters is a routine part of standard hypertension evaluation. Selecting a patient subgroup using routine laboratory criteria, and choosing particular numerical thresholds within the clinically accepted ranges, constitutes routine optimization of known diagnostic parameters and would have been obvious in identifying those subjects most likely to benefit from the treatment already taught in the prior art.
Regarding Claims 8 and 34, Ushirogochi teaches a compound [I] of the present invention includes a compound which exhibits high selectivity to Cyp11B2. For example, the IC50 value (nM) of the compound described in Example 22 against human Cyp11B2 is 500 times higher than those against human Cyp11B1 because of high selectivity to human Cyp11B2 (‘993, Col 39, Lines 26-34.)
Regarding Claims 13-14, Ushirogochi teaches in oral administration, the dosage is generally 0.01-100 mg/kg/day, (‘993, Col 40, Lines 3-4.)
Regarding Claim 15, the limitation requiring that administration of the compound of Formula A “does not inhibit the activity of 11B-hydroxylase as demonstrated by a lack of a clinically meaningful reduction in cortisol production in an ACTH (Cortrosyn) Stimulation test” represents a biological result of administering the same selective CYP11B2 inhibitor disclosed by Ushirogochi. The prior art teaches the identical compound for treating hypertension via CYP11B inhibition. A compound’s inherent biological properties, including its selectivity profile and the resulting endocrine response, necessarily flow from administration of that compound. “The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)”, see MPEP §2112(I). The claimed functional outcome is an inherent property of the known compound when used as taught in the prior art.
Similarly, regarding Claims 16, 19, 22, and 24 Ushirogochi teaches administering the same Cyp11B2 hydroxylase inhibitor (instant Formula A) to treat hypertension by selectively inhibiting aldosterone synthase. The pharmacodynamic outcomes recited – including suppression of aldosterone production, increases in serum potassium and plasma renin activity, lack of cortisol suppression, and absence of 11-DOC and 11-deoxycortisol accumulation – are inherent or predictable consequences of administering a selective Cyp11B2 inhibitor. These physiological effects necessarily flow from the enzyme selectivity and mechanism of action disclosed in the prior art, even if the art did not explicitly measure them. See MPEP §2112.
Regarding Claims 30 and 32, Ushirogochi teaches treating hypertension, including aldosterone-associated hypertension, using the same compound. A subject having systolic blood pressure >130 mmHg and diastolic pressure >90 mmHg is, by definition, hypertensive, and evaluating plasma renin activity and aldosterone levels to identify aldosterone-driven or low-renin hypertension is routine clinical practice. Selection of an appropriate patient subgroup for a known treatment is considered obvious absent evidence of unexpected results.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to administer Example 48 (instant Formula A) to treat hypertensive patients meeting the recited physiological characteristics, and to identify such patients using routine clinical measurements, as taught or suggested by Ushirogochi.
Ushirogochi discloses treating hypertension, including aldosterone-associated forms, with the same compound via Cyp11B2 inhibition. Subjects exhibiting elevated systolic and/or diastolic blood pressure, low plasma renin activity, and elevated aldosterone levels represent an art-recognized subtype of aldosterone-driven hypertension. Measurement of blood pressure, plasma renin activity, and plasma aldosterone levels constitutes routine clinical evaluation for characterizing hypertensive patients and selecting candidates for aldosterone-targeted therapy. Identifying and treating this patient subgroup is therefore an obvious selection of appropriate subjects for the known therapeutic method. In re Woodruff.
Administration of a selective Cyp11B2 inhibitor inherently and predictable results in the pharmacodynamic outcomes recited in the dependent claims , including suppression of aldosterone production, increases in serum potassium and plasma renin activity, and lack of cortisol suppression of 11-DOC/11-deoxycortisol accumulation. These effects are natural consequences of inhibiting aldosterone synthase while sparing Cyp11B2, and thus constitute expected results of administering the same compound disclosed by Ushirogochi. In re Best; In re Papesch.
Furthermore, the dose amounts, dose ranges, and dosing frequencies (once daily or twice daily oral administration) fall within, or are routine optimizations of, the oral dosing ranges taught by Ushirogochi (e.g., 0.01-100 mg/kg/day.) Adjusting dose and schedule to achieve the desired endocrine and blood-pressure effects represents routine optimization of known parameters with predictable results. In re Aller.
Accordingly, the claimed methods of identifying hypertensive subjects and/or treating those subjects with Example 48 (instant Formula A) represent nothing more than the obvious application of known diagnostic practices and routine clinical optimization applied to a known compound for a known therapeutic indication.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627