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 .1
Status of Claims
Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 88, 90, 96, and 98, 106, and 107 are pending.
Election/Restrictions
Applicant’s election of Group I (Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107) and species in the reply filed on 8/27/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 88, 90, 96, and 98 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/27/2025. The species elected are the following:
hydrocortisone (11 β, 17α,21-trihydroxypregn-4-ene-3,20-dione),
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Compound 3 (3-( 4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5- dimethylpyrazolo(l,5-a )pyrimidine ( or alternatively 4-( 4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl )pyrazolo[ 1,5-a ]pyrimidin-3-yl)thiazol-2-yl)morpholine) ),
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Compound 3 has been identified as CAS Registry Number: 1014983-00-6,
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.2
For purposes of the office action, the elected CRF1 antagonist will be referred to as Compound 3.
Information Disclosure Statement
The information disclosure statements (IDS)s submitted on 03/20/2023, 10/10/2023, 03/12/2024, 07/18/2024, 08/23/2024 and 11/12/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 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 claims contain 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.
The Claimed Invention
The claimed invention (e.g. claim 1) is broadly directed to any and all steroids and any and all CRF1 antagonists. Certain narrower embodiments of the claimed invention are presented in various dependent claims. Some of these claims are limited to narrower embodiments such as the elected species of steroid, hydrocortisone (claim 19) and various claims limited to generic structure Formula I (claim 38), and elected species of CRF1 antagonist
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, among others (see the multiple CRF1 antagonists recited in claims 44 and 107).
The Supporting Disclosure
Applicants’ supporting disclosure contains certain descriptions and embodiments of the claimed invention. See paragraph 6 of the specification which essentially repeats the ACTH and A4 limitations recited in claims 1, 6, 13 and 14.
Example 3 (Phase 2 Clinical Studies) is a prophetic example (at least at the time of filing the Application) said to be “involving a up to 52 weeks treatment multiple-dose
study of Compound 3 and a glucocorticoid for the treatment of adults with classic CAH.” See paragraph 203.
The balance of Example 3 merely states prophetic instructions regarding this prophetic clinical study, no presentation of data is provided.
In summary, Example 3 treating CAH patients with Compound 3 and an unidentified glucocorticoid fail to provide adequate written description to convey to one skilled in the art that the inventors had possession of the claimed invention over the full scope of genre of CRF1 antagonists and steroids, as instantly claimed.
Claim Rejections - 35 USC § 103
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, 6, 13-14, 19, 47-48, 58-61, 66, 68, 78-81, 86, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US20170020877), cited on IDS dated Mar 20 2023, US Pat Doc 016.
A method of treating Congenital Adrenal Hyperplasia (CAH), comprising administering a steroid, or a pharmaceutically acceptable salt thereof, and a corticotropin-releasing factor type-1(CRF1) antagonist, or a pharmaceutically acceptable salt thereof, to a subject, wherein when said subject has a level of androstenedione (A4) that is less than two times an upper limit of a reference range of A4 and a level of adrenocorticotropic hormone (ACTH) that is less than two times an upper limit of a reference range of ACTH,
a dose of said steroid, or a pharmaceutically acceptable salt thereof, is reduced compared to a dose of said steroid, or a pharmaceutically acceptable salt thereof, administered to a CAH patient that does not receive said CRF 1 antagonist, or a pharmaceutically acceptable salt thereof.
Regarding claim 1, US 877 teaches a method of treating CAH by administering to a o a subject in need thereof a CRF1 receptor antagonist having a dissociation half-life in excess of 30 minutes. See claim 1.
Regarding claim 1 and the limitation of administering a steroid, US 877 teaches treatment of CAH includes efforts to normalize cortisol deficiency with glucocorticoids (hydrocortisone in children) and the need to monitor treatment so as to avoid side effects of the steroids. See paragraph 47. See paragraph 50 for full detail.3
Regarding claim 1 and the limitations of a CAH subject in need, the need to monitor ACTH levels and reducing levels of steroid in a patient (vs. a patient not taking a CRF1 antagonist), US 877 teaches CRF1 antagonists have the potential to directly inhibit ACTH release in patients with CAH, thereby allowing normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and reducing treatment-associated side effects. See paragraph 6.
Regarding claim 1 and the limitation of measuring androstenedione (A4) in a subject in need so as to reduce the amount of hydrocortisone (synthetic pharmaceutical grade of the naturally occurring cortisol) administered to said subject, US Pub 877 teaches the need to measure A4 in a CAH subject in need, where it discloses screening tests to measure androstenedione (A4) to cortisol. See paragraph 42. See also paragraph 45 disclosing the need of monitoring steroid (glucocorticoid) therapy to avoid side effects, inclusive of monitoring A4.
In terms of claim interpretation, it is pointed out that elevated reference ranges to slightly elevated above normal reference range of ACTH and androstenedione (A4) levels would be well within the claimed limitations of less than twice, 1.75 times, 1.5 times, 1.25 times and one time, the upper limit of said A4 and ACTH as claimed (claims 1, 6, 13 and 14).
Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC) steroid, requires less steroid than one receiving monotherapy of steroid, US 877 teaches “methods for treating CAH by administering a CRF1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.” See paragraph 70. In an adult CAH patient, US 877 teaches, the dose of a GC, such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC [hydrocortisone] ; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.” Id.
While the art recognizes the claimed subject and claimed method administering a steroid and CRF1 antagonist, monitoring the levels of ACTH and A4 related with such therapy and noting the reduction of steroid levels in a subject taking the CRF1 antagonist, it does not specifically recite the limitations of where the monitored A4 and ACTH levels less than a two times an upper limit of a reference range of A4 or ACTH.
However, based on the teachings of US 877, the
treatment of CAH, CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol [naturally occurring equivalent of synthetic steroid hydrocortisone]. Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol [naturally occurring hydrocortisone] and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
US 877 teaches in treating CAH patients,
Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. In general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
The dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art. See paragraphs 63-64.
As stated above, a person having ordinary skill in the art (PHOSITA) recognizes what would be above reference standards of ACTH and A4 levels in the CAH afflicted subject in need, and would recognize the necessity of lowering concurrent steroid (hydrocortisone) treatment to avoid concomitant side effects, especially where established by US 877, co-administration of a CRF1 antagonist would achieve this goal. A PHOSITA would readily recognize that ACTH and A4 levels under twice the upper limit of a reference range inclusive of a range above normal reference range is a logical clinical target in CAH patients in need, so reduce concomitantly administered steroids, known to have adverse side effects..
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the teachings of US 877 with regard to co-administering a CRF1 antagonist with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, modified with other teachings of US 877 noting the ordinary skill level of a PHOSITA (physician) in order to treat patients with above normal reference ranges of ACTH and A4 (i.e. less than twice the upper limit of said range, but still above a normal reference range).
The PHOSITA would have had a reasonable expectation of success because the art recognizes the treatment of CAH with steroids with side effects, and an effort to reduce such side effects by co-administering a CRF1 antagonist, where a clinical goal is to reduce administered steroids to treat CAH subject with above normal reference range of ACTH and A4, such those patients with ACTH and A4 levels while less than twice the upper limit of a normal reference range, but still above a normal reference range.
As required by claims 6, 13, and 14, and the limitations of ACTH and A4 levels less than two times, less than 1.75 times, less than 1.5 times, less than 1.25 times, or less than one time an upper limit of a reference range of both, as discussed above, a PHOSITA would no doubt optimize doses of steroid and ACTH antagonist in a CAH subject in need experiencing ACTH and A4 levels less than the claimed multipliers but still above a normal reference range, while simultaneously reducing the levels of hormone administered in the subject receiving the combination therapy, vs. the subject receiving monotherapy of hormone.
Regarding claim 19 and the reduction of hydrocortisone in 5mg increments, US 877 teaches hydrocortisone dose reduction in increments of 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day hydrocortisone. See paragraph 70, where a PHOSITA would readily recognize a reduction in 5 mg increments of hydrocortisone, i.e. a 30% reduction of a 15 mg dose, is approximately 5 mg. Similarly, a 40% reduction of a 20 mg HC dose is 5 mg.
Regarding claims 47 and 48 and the limitations of administering the CRF1 antagonist in a dose of about 50 mg to about 20 mg or (about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg) total daily dose to the subject, US 877 teaches “[in] general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred.” See paragraph 63. The taught range overlaps the claimed range, where in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A
Regarding claims 58-61 and 66, wherein the CRF1 antagonist and/or steroid are in the form of pharmaceutical compositions such as (hard or soft gelatin) capsules or tablets, US 877 teaches pharmaceutical compositions such as tablets and gelatin capsules. See paragraph 73-74.
Regarding claim 68, US 877 teaches the steroid is a glucocorticoid, such as hydrocortisone. See abstract, and paragraphs 6, 30 and 70.
Regarding claims 78 and 79, where the CRF1 antagonist and steroid are administered concurrently and/or in one pharmaceutical composition, US 877 teaches “[f]or oral formulations, at least one of the compounds described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules. “ See paragraph 70. The formulation of CRF1 antagonist and steroid into one pharmaceutical composition necessarily entails concurrent administration of both.
Regarding claims 80 and 81 and the limitation of concurrent, separate pharmaceutical compositions or sequential administration, as US 877 teaches concurrent and single pharmaceutical compositions of CRF1 antagonist and steroid, the only other optional and obvious choices of a combination of CRF1 antagonist and steroid are alternatively, non-concurrent (sequential) and separate pharmaceutical compositions.
Note that US 877 teaches at least one of the compounds can be used alone in pharmaceutical compositions. See paragraph 70. Also US 877 teaches a clinical study, where a particular CRF1 antagonist was administered and the steroid treatment (usually administered in the morning, was delayed until after 16 hours of post dose blood samples (i.e. sequentially). See paragraph 91.
Regarding claim 86 and the limitations therein, US 877 teaches the necessity to treat both classic and non-classic CAH. See paragraphs 4-5.
Claim 106 wherein the CRF1 antagonist, or pharmaceutically acceptable salt thereof, is administered in a dose of about 50 mg to about 400 mg total daily dose to the subject, US 877 teaches “[in] general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred.” See paragraph 63. The claim is prima facie obvious due to the overlap in ranges. See MPEP 2144.05 A.
Claims 1, 6, 13-14, 19, 38, 44, 46 47-48, 58-61, 66, 68, 78-81, 86, 106, and 107 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US20170020877) in view of Chen et al (aka 304 Pat) (US Pat 8030304 B2).
US 877 is cited on the IDS dated Mar 20 2023, US Pat Doc 016. The 304 Pat is cited on the IDS dated Mar 20 2023, US Pat Doc 001.
As detailed above, US 877 teaches the method of claims ) 1, 6, 13-14, 19, 47-48, 58-61, 66, 68, 78-81, 86 and 106 as detailed above, but does not necessarily recite the species of the claimed method (of claim 1 and dependent claims) with regard to claims 38, 44, and 46 and 107 and the disclosure of the elected species of CRF1 antagonist, Compound 3
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Although US 877 generally taught CRF1 receptor antagonists for the treatment of CAH, US 877 did not specifically teach the claimed Compound 3, as instantly recited.
The 304 patent teaches a method of treating CAH in a patient (e.g., human at [col 3, line 52]) in need thereof [col 2, lines 56-62], comprising administering a therapeutically effective amount [col 3, lines 47-53] of a CRF1 receptor antagonist [abstract], wherein the CRF1 receptor antagonist was: (e.g., specific compound at [Example 16]), i.e. Compound 3 as claimed.4
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Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference US 877 to treat CAF with lesser doses of steroids due to the combination therapy with CRF1 antagonists, modified by the teachings of the 304 Patent to choose Compound 3 as the CRF1 antagonist. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its art-recognized suitability for its intended use. See MPEP 2144.07.
The PHOSITA would have had a reasonable expectation of success because Chen teaches a method of treating CAH with CRF1 antagonists, such as Compound 3/Example 16, where it would be obvious to incorporate it into US 877’s method of treating CAH with the composition comprising a CRF1 antagonist and steroid.
Claims 1, 6, 13-14, 19, 47-48, 54-55, 58-61, 66, 68, 78-81, 86, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (US 877) (US20170020877) in view of Dhoot et al (US 623) (US 2006/0078623 A1).
US 877 is cited on the IDS dated Mar 20 2023, US Pat Doc 016. US 623 is cited on the IDS dated Mar 20 2023, US Pat Doc 010.
As detailed above, US 877 teaches the method of claims 1, 6, 13-14, 19, 47-48, 58-61, 66, 68, 78-81, 86 and 106 as detailed above, but does not necessarily recite the species of the claimed method (of claim 1 and dependent claims) with regard to claims 54-55 and the disclosure of the particular species CRF1 antagonist in the form of microparticles, wherein the average size of the microparticles is between about 1 μm to about 20 μm.
Although US 877 generally taught CRF1 receptor antagonists for the treatment of CAH, US 877 did not specifically teach CRF1 antagonists microparticles in the claimed size as per claims 54-55.
US 623 teaches a method of treating that the small size of microparticles allows for greater bioavailability of the active agent, since the size permits the particles to pass from the stomach to the small intestine, where dissolution and drug absorption is best [0004].
Active agents at a particle size of about 1 to about 999 micrometers were disclosed [0007]. This range of particle size, overlaps the claimed range of 1-20 μm, where a prima facie case of obviousness is established due to the overlap. See MPEP 2144.05 A.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference US 877 to treat CAF with lesser doses of steroids due to the combination therapy with CRF1 antagonists, modified by the teachings of US 623 to formulate US 877 active CRF1 antagonists as microparticles as taught by US 623.
The PHOSITA would have had a reasonable expectation of success because by micronizing US 877’s actives at 1-999 microns, at this said diameter, the particles more
freely pass through the stomach and into the small intestine, as taught by US 623.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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.
Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-21 of U.S. Patent No. 11,311,549 B2 in view of Grigoriadis (aka US 877) (US20170020877). The 549 patent is cited on the IDS dated Mar 20 2023, US Pat Doc 005.
Although the claims at issue are not identical, they are not patentably distinct from each other. The reference patent claims recite all of the features instantly recited for the treatment of congenital adrenal hyperplasia except for reduction from baseline in the level of the limitation of measuring ACTH and androstenedione (A4) (ACTH and A4 that is less than two times, less than 1. 7 5 times, less than 1.5 times, less than 1.25 times, or less than one time an upper limit of a reference range) in a subject in need so as to reduce the amount of hydrocortisone synthetic pharmaceutical grade of the naturally occurring cortisol) administered to said subject.
Such a limitation of ACTH and A4 reference range less than the multiplier times the upper limit of reference range, where the steroid administered is less with a combination of CRF1 antagonist and steroid, vs. steroid monotherapy, is not taught by the issued claims, but is otherwise obvious in view US 877. Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC) steroid, requires less steroid than one receiving monotherapy of steroid, US 877 teaches “methods for treating CAH by administering a CRF1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.” See paragraph 70. In an adult CAH patient, US 877 teaches, the dose of a GC, such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC [hydrocortisone] ; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.” Id.
US 877 teaches treatment of CAH, CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol [naturally occurring equivalent of synthetic steroid hydrocortisone]. Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol [naturally occurring hydrocortisone] and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
US 877 teaches in treating CAH patients, “
Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. In general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
The dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art. See paragraphs 63-64.
It would have been prima facie obvious to a PHOSITA to include, within the issued claims of U.S.P. 11,311,549, treating patients with the claimed ACTH and A4 (elevated), so as to reduce the levels of steroid co-administered with CRF1 antagonist, as suggested by US 877.
Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-27 of U.S. Patent No. 11,344,557 B2 in view of Grigoriadis (aka US 877) (US20170020877). The 557 patent is cited as US Pat Doc 006 on IDS dated 3/20/23.
Although the claims at issue are not identical, they are not patentably distinct from each other. The reference patent claims recite all of the features instantly recited for the treatment of congenital adrenal hyperplasia except for reduction from baseline in the level of the limitation of measuring ACTH and androstenedione (A4) (ACTH and A4 that is less than two times, less than 1. 7 5 times, less than 1.5 times, less than 1.25 times, or less than one time an upper limit of a reference range) in a subject in need so as to reduce the amount of hydrocortisone synthetic pharmaceutical grade of the naturally occurring cortisol) administered to said subject.
Such a limitation of ACTH and A4 reference range less than the multiplier times the upper limit of reference range, where the steroid administered is less with a combination of CRF1 antagonist and steroid, vs. steroid monotherapy, is not taught by the issued claims, but is otherwise obvious in view US 877. Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC) steroid, requires less steroid than one receiving monotherapy of steroid, US 877 teaches “methods for treating CAH by administering a CRF1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.” See paragraph 70. In an adult CAH patient, US 877 teaches, the dose of a GC, such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC [hydrocortisone] ; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.” Id.
US 877 teaches treatment of CAH, CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol [naturally occurring equivalent of synthetic steroid hydrocortisone]. Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol [naturally occurring hydrocortisone] and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
US 877 teaches in treating CAH patients, “
Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. In general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
The dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art. See paragraphs 63-64.
It would have been prima facie obvious to a PHOSITA to include, within the issued claims, treating patients with the claimed ACTH and A4 (elevated), so to reduce the levels of steroid co-administered with CRF1 antagonist, as suggested by US 877.
Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-21 of U.S. Patent No. 11351177 B2 in view of Grigoriadis (aka US 877) (US20170020877). The 177 patent is cited as US Pat Doc 007 on the 3/20/23 IDS.
Although the claims at issue are not identical, they are not patentably distinct from each other. The reference patent claims recite all of the features instantly recited for the treatment of congenital adrenal hyperplasia except for reduction from baseline in the level of the limitation of measuring ACTH and androstenedione (A4) (ACTH and A4 that is less than two times, less than 1. 7 5 times, less than 1.5 times, less than 1.25 times, or less than one time an upper limit of a reference range) in a subject in need so as to reduce the amount of hydrocortisone synthetic pharmaceutical grade of the naturally occurring cortisol) administered to said subject.
Such a limitation of ACTH and A4 reference range less than the multiplier times the upper limit of reference range, where the steroid administered is less with a combination of CRF1 antagonist and steroid, vs. steroid monotherapy, is not taught by the issued claims, but is otherwise obvious in view US 877. Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC) steroid, requires less steroid than one receiving monotherapy of steroid, US 877 teaches “methods for treating CAH by administering a CRF1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.” See paragraph 70. In an adult CAH patient, US 877 teaches, the dose of a GC, such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC [hydrocortisone] ; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.” Id.
US 877 teaches treatment of CAH, CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol [naturally occurring equivalent of synthetic steroid hydrocortisone]. Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol [naturally occurring hydrocortisone] and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
US 877 teaches in treating CAH patients, “
Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. In general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
The dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art. See paragraphs 63-64.
It would have been prima facie obvious to a PHOSITA to include, within the issued claims, treating patients with the claimed ACTH and A4 (elevated), so to reduce the levels of steroid co-administered with CRF1 antagonist, as suggested by US 877.
Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-21 of U.S. Patent No. 12,115,166 B2 in view of Grigoriadis (aka US 877) (U.S.2017/0020877).
Although the claims at issue are not identical, they are not patentably distinct from each other. The reference patent claims recite all of the features instantly recited for the treatment of congenital adrenal hyperplasia except for reduction from baseline in the level of the limitation of measuring ACTH and androstenedione (A4) (ACTH and A4 that is less than two times, less than 1. 7 5 times, less than 1.5 times, less than 1.25 times, or less than one time an upper limit of a reference range) in a subject in need so as to reduce the amount of hydrocortisone synthetic pharmaceutical grade of the naturally occurring cortisol) administered to said subject.
Such a limitation of ACTH and A4 reference range less than the multiplier times the upper limit of reference range, where the steroid administered is less with a combination of CRF1 antagonist and steroid, vs. steroid monotherapy, is not taught by the issued claims, but is otherwise obvious in view US 877. Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC) steroid, requires less steroid than one receiving monotherapy of steroid, US 877 teaches “methods for treating CAH by administering a CRF1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.” See paragraph 70. In an adult CAH patient, US 877 teaches, the dose of a GC, such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC [hydrocortisone] ; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.” Id.
US 877 teaches treatment of CAH, CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol [naturally occurring equivalent of synthetic steroid hydrocortisone]. Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol [naturally occurring hydrocortisone] and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
US 877 teaches in treating CAH patients, “
Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. In general, the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject. In certain embodiments, a single dose is about 50-1000 mg. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
The dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art. See paragraphs 63-64.
It would have been prima facie obvious to a PHOSITA to include, within the issued claims, treating patients with the claimed ACTH and A4 (elevated), so to reduce the levels of steroid co-administered with CRF1 antagonist, as suggested by US 877.
Conclusion
In summary, no claims are allowed.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623