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, 46-48, 54-55, 58-61, 66, 78-81, 86, 88, 90, 96, 98, 106, 107, 108 and 109 are pending. Claims 88, 90, 96, and 98 are withdrawn.
Claims 1, 6, 13-14, 19, 46-48, 54-55, 58-61, 66, 78-81, 86, 106, 107, of Group I, elected without traverse and new claims 108 and 109, are under examination. The elected species are:
Species of glucocorticoid/steroid, hydrocortisone
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Species of CRF1 antagonist Compound 3
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Information Disclosure Statement
The information disclosure statement (IDS) submitted 04/03/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicant’s arguments, filed April 3, 2026, with respect to the rejection of Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 under 35 U.S.C. § 112(a) (written description) have been fully considered and are persuasive. The rejection of claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 has been withdrawn.
Applicant’s amended claims and arguments, filed April 3, 2026, with respect to the rejections of
Claims 1, 6, 13-14, 19, 47-48, 58-61, 66, 68, 78-81, 86, and 106 under 35 U.S.C. § 103 as being unpatentable over US 2017/0020877 (hereafter "Grigoriadis")
Claims 1, 6, 13-14, 19, 38, 44, 46, 47-48, 58-61, 66, 68, 78-81, 86, 106, and 107 under 35 U.S.C. § 103 as being unpatentable over Grigoriadis in view of US 8,030,304B2 (hereinafter "Chen")
Claims 1, 6, 13-14, 19, 47-48, 54-55, 58-61, 66, 68, 78-81, 86, and 106 under 35 U.S.C. § 103 as being unpatentable over Grigoriadis in view of US 2006/0078623 Al (hereinafter "Dhoot") have been fully considered and are persuasive.
However, upon further search and consideration new obviousness rejections have been issued as detailed below.
Applicant’s amended claims and arguments, filed April 3, 2026, with respect to the rejections of Claims 1, 6, 13-14, 19, 38, 44, 46-48, 54-55, 58-61, 66, 68, 78-81, 86, 106, and 107 for nonstatutory obviousness double patenting over
US 11,311,549 B2 in view of Grigoriadis
US 11,344,557 B2 in view of Grigoriadis
US 11,351,177 B2 in view of Grigoriadis
US 12,115,166 B2 in view of Grigoriadis have been fully considered and are persuasive.
However, upon further search and consideration new obviousness rejections have been issued as detailed below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 46-48, 58-61, 66, 78-81, 86, 106 and 107 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US 20170020877) 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.
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wherein the CRF1 antagonist is Compound 3 among others.
US 877 teaches a method of treating CAH by administering to a subject in need thereof a CRF1 receptor antagonist having a dissociation half-life in excess of 30 minutes. See claim 1. 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
US 877 teaches CRF1 antagonists have the potential to directly inhibit ACTH release (per the limitation to monitor ACTH) in CAH patients, thereby allowing normalization of androgen production while using lower, more physiologic doses of hydrocortisone (lowering glucocorticoid (GC) dose administered with a CRF1 antagonist vs. GC monotherapy), and reducing treatment-associated side effects. See paragraph 6. US 877 teaches the glucocorticoid, hydrocortisone. See abstract, and paragraphs 6, 30 and 70.
US Pub 877 teaches the need to measure A4 in a CAH patient (per the limitation to monitor ACTH), where it discloses screening tests to measure androstenedione (A4) to cortisol (naturally occurring form of HCT). See paragraph 42. See also paragraph 45 disclosing the need of monitoring steroid (glucocorticoid) therapy to avoid side effects.
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 limitation where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC), requires less GC than one receiving monotherapy of GC, 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, hydrocortisone (HC), among others, i.e. prednisone etc., 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 GC and CRF1 antagonist, monitoring the levels of ACTH and A4 related with such therapy and noting the reduction of a subject’s GC levels taking the CRF1 antagonist, it does not specifically recite the limitations of where the monitored A4 and ACTH levels are less than a two times an upper limit of a reference range of A4 or ACTH.
However, based on the teachings of US 877,
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. See paragraph 60.
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.
Further, although US 877 generally teaches CRF1 receptor antagonists for the treatment of CAH, US 877 did not specifically teach the claimed Compound 3, as instantly recited.
The 304 patent (Chen) 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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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 GC (hydrocortisone) treatment to avoid concomitant side effects, especially where established by US 877, co-administration of a CRF1 antagonist (such as Compound 3 per Chen 304 patent) 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 glucocorticoids, 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 US 877 with regard to co-administering a CRF1 antagonist with reduced levels of concomitant GC (hydrocortisone) relative to a patient not taking the CRF1 antagonist (Compound 3 per Chen 304 patent), 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).
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 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.
Further, 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.
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 GC administered in the subject receiving the combination therapy, vs. the subject receiving monotherapy of GC.
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 claim 46 and the disclosure of the elected species of CRF1 antagonist, Compound 3
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, the 304 patent (Chen) teaches Compound 3, see above.
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 rendering it obvious. MPEP 2144.05 A5
Regarding claims 58-61 and 66, US 877 teaches pharmaceutical compositions such as tablets and gelatin capsules. See paragraph 73-74.
Regarding claims 78 and 79, of concurrent administration (optionally a single pharmaceutical composition) of a CRF1 antagonist and GC, 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 GC 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 (GC) 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, 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, 46-48, 54-55, 58-61, 66, 78, 79, 80, 81, 86, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (US 877) (US20170020877) in view of Chen et al. (aka 304 Pat) (US Pat 8030304 B2) in further 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. The 304 Pat is cited on the IDS dated Mar 20 2023, US Pat Doc 001. US Pat Doc 016. US 623 is cited on the IDS dated Mar 20 2023, US Pat Doc 010.
As detailed above, US 877 in view of 304 patent (Chen) teaches the method of claims 1, 6, 13-14, 19, 47-48, 58-61, 66, 78, 79, 80, 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 and the 304 patent generally taught CRF1 receptor antagonists (Compound 3) for the treatment of CAH, they 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.
Claims 1, 6, 13-14, 19, 46-48, 58-61, 66, 78, 79, 80, 81, 86, 106 and 108-109 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) in further view of Jha et al. SUN-371 Successful Induction of Fertility with Low-Dose Dexamethasone in a Patient with Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumor, Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract.
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. Jha is listed on the PTO-892 form.
As detailed above, US 877 in view of 307 patent (Chen) teaches the method of claims 1, 6, 13-14, 19, 47-48, 58-61, 66, 78, 79, 80, 81, 86, 106 as detailed above, but does not necessarily recite the species of the claims already rejected, i.e. reciting the specific reference ranges of ACTH and androstenedione A4 recited in claims 108-109.
Regarding claims 108 claiming reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches a male patient suffering from CAH, with an elevated level of ACTH 866 pg/ml (reference: 5-46), (see Abstract) an obvious overlap between the claimed reference range and that claimed per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level of ACTH 13.5 pg/ml. See abstract.
Regarding claim 109 wherein the reference range of A4 is about 50 to 220
ng/dL, among other disclosed ranges, Jha teaches an androstenedione A4 reference range of ng/dl 26- 125, (see Abstract) an obvious overlap with the claimed range per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level A4 16 ng/ dL. See abstract.
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 antagonist SSR125543, modified by the teachings of Jha and its teachings of overlapping reference ranges.
The PHOSITA would have had a reasonable expectation of success because both the claimed method and the method of Jha have overlapping reference ranges of ACTH and A4 in the context of treatment of a subject in need suffering from CAH.
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, 46-48, 54-55, 58-61, 66, 78, 79, 80, 81, 86, 106 and 108-109 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) and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract
over Claims 1-21 of U.S. Patent No. 11351177 B2 in view of Grigoriadis (aka US 877) (US20170020877) and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract
Claims 1-21 of U.S. Patent No. 12,115,166 B2 in view of Grigoriadis (aka US 877) (U.S.2017/0020877), and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract in further view of Dhoot et al (US 623) (US 2006/0078623. A1) and
Claims 1-27 of U.S. Patent No. 11,344,557 B2 in view of Chen et al. (aka 304 Pat) (US Pat 8030304 B2), Grigoriadis (aka US 877) (US20170020877), and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract in further view of Chen et al (aka 304 Pat) (US Pat 8030304 B2).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference patents are directed to the CRF1 antagonist Compound 3 as claimed.
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Note with regard to the 557 patent, it does not teach compound 3. However, it is pointed out that the Chen 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.
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The reference patents’ 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/GC administered is less with a combination of CRF1 antagonist and GC, vs. GC 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 Pub 877 teaches the need to measure and monitor ACTH, 17-OHP and A4 in a CAH subject in need, so as to avoid side effects. See paragraphs 40-42 and 44-45. The basis to do so would be monitoring levels of these steroid hormones to adjust doses of steroid (such as hydrocortisone) in 5 mg increments as claimed. See paragraph 70. See also paragraph 70 of US 877 noting adjustment of A4 and ACTH levels treated with CRF1 antagonists would be in the purview of a PHOSITA, where subjects are generally monitored for therapeutic effectiveness via known assays by determining the level of a compound in a biological fluid. See paragraphs 63-64. Accordingly, such monitoring of ACTH, A4 in a subject in need, will necessitate a PHOSITA to adjust dosing of CR1 antagonist, if necessary to twice a day dosing, on a as needed basis.
Note, with regard to micronized particles and Applicant’s claims 54-55, the ’166 patent does not teach this limitation.
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.
Regarding claims 108 claiming reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches a male patient suffering from CAH, with an elevated level of ACTH 866 pg/ml (reference: 5-46), (see Abstract) an obvious overlap between the claimed reference range and that claimed per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level of ACTH 13.5 pg/ml. See abstract.
Regarding claim 109 wherein the reference range of A4 is about 50 to 220
ng/dL, among other disclosed ranges, Jha teaches an androstenedione A4 reference range of ng/dl 26- 125, (see Abstract) an obvious overlap with the claimed range per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level A4 16 ng/ dL. See abstract.
It would have been prima facie obvious to a PHOSITA to include, within the issued claims of the reference patents, 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, 46-48, 54-55, 58-61, 66, 78, 79, 80, 81, 86, 106 and 108-109 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over
claims 106-109, 111, and 117-129 of copending Application No. 18438060 (reference application) in view of Chen et al (aka 304 Pat) (US Pat 8030304 B2), Grigoriadis (aka US 877) (US20170020877) and Dhoot et al (US 623) (US 2006/0078623 A1)
claims 1-18 of copending Application No.19650165 (reference application) in view of Chen et al (aka 304 Pat) (US Pat 8030304 B2), Grigoriadis (aka US 877) (US20170020877) and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract
claims 19650176 of copending Application No. 19650176 (reference application) in view of Chen et al (aka 304 Pat) (US Pat 8030304 B2), Grigoriadis (aka US 877) (US20170020877) and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract
claims 1-15 of copending Application No. 19650188 (reference application) in view of Chen et al (aka 304 Pat) (US Pat 8030304 B2), Grigoriadis (aka US 877) (US20170020877) and Jha et al., Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, SUN-371, Abstract.
Although the claims at issue are not identical, they are not patentably distinct from each of the reference applications.
Initially it is noted the reference applications teach the CRF1 antagonist, SSR125543, as recited in examined claim 1. The reference application claims recite all the features instantly recited for the treatment of CAH including the limitation where the ACTH and A4 levels is less than two times an upper limit of a reference range except for the species of Compound 3.
To address this, the Chen 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.
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Note with regard to the dependent claims, the reference application teaches the reduced levels of ACTH and A4 of an upper limited of a reference range; a 5 mg reduction of a HCT (glucocorticoid) equivalent; the claimed dose ranges; pharmaceutical composition (tablet or capsule); either concurrent or simultaneous co-administration (as there can only be one or the other, it would be obvious to do either) as well as the claimed reference range of ACTH is about 7 to 63.3 pg/m (per new claim 108) and the claimed reference ranges of A4 (per claim 109).
Although the reference application teaches the claimed method it does not teach CRF1 antagonists microparticles in the claimed size as per claims 54-55.
Dhoot 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.
With regard to claims 108-109, the ACT and A4 limitations are taught by Application 18438060, see claims 128-129.
With regard to claims 109-109, they are not taught by the balance of reference applications, but are obvious in view of Jha.
Regarding claims 108 claiming reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches a male patient suffering from CAH, with an elevated level of ACTH 866 pg/ml (reference: 5-46), (see Abstract) an obvious overlap between the claimed reference range and that claimed per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level of ACTH 13.5 pg/ml. See abstract.
Regarding claim 109 wherein the reference range of A4 is about 50 to 220
ng/dL, among other disclosed ranges, Jha teaches an androstenedione A4 reference range of ng/dl 26- 125, (see Abstract) an obvious overlap with the claimed range per MPEP 2144.05. Similar to the claimed method, Jha teaches an improvement in CAH with a level A4 16 ng/ dL. See abstract.
This is a provisional nonstatutory double patenting rejection.
Conclusion and Correspondence
In summary, 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.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
1 CONTINUING DATA
This application is a CON of PCT/US2020/042820 07/20/2020
PCT/US2020/042820 has PRO 63/047,822 07/02/2020
PCT/US2020/042820 has PRO 62/876,176 07/19/2019
This application has published as US 20220133742.
2 CAS Registry Number: 1014983-00-6
3-[4-Chloro-2-(4-morpholinyl)-5-thiazolyl]-7-(1-ethylpropyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (ACI)
3-[4-Chloro-2-(morpholin-4-yl)thiazol-5-yl]-7-(1-ethylpropyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine
LY 2371712
SPR 001
Tildacerfont
3 US 877 teaches pituitary hormone ACTH, under control of hypothalamic corticotropin-releasing factor (CRF), drives steroidgenesis in the adrenal gland, where CAH resulting from mutations or deletions in CYP21A2 gene, result in overproduction of steroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP). “Plasma levels of 17-OHP can reach 10-1000 times the normal concentration in these cases. These increases result in the overproduction of androgens, specifically androstenedione, testosterone, and dihydroxytestosterone causing virilization in female. In addition, 21-hydroxylase deficiency in CAH causes insufficient biosynthesis of glucocorticoids and mineralocorticoids, specifically cortisol and aldosterone. Cortisol is a critical negative feedback regulator of hypothalamic CRF secretion and pituitary ACTH release. The lack of glucocorticoid synthesis and release eliminates the restraint on the hypothalamus and pituitary, which causes ACTH levels to increase. The excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting in adrenal hyperplasia.” See paragraph 50 of US 877.
4 See also general formula at [col 2, lines 15-31], where R1 and R2 were independently ethyl, R3 is Cl and R4 is morpholin-4-yl).
5 In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists.
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