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 106-109,111 and 117-129 are pending. Note that the amendment of claims and introduction of new claims have necessitated this final office action. In the office action, the claimed compound SSR125543, a known CRF1 antagonist Crinecerfont.
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Applicant elected without traverse, the steroid species hydrocortisone
hydrocortisone (11 β, 17α,21-trihydroxypregn-4-ene-3,20-dione),
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Information Disclosure Statement
The information disclosure statements (IDS) submitted April 3, 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 and amendments, filed April 3, 2026, with respect to the rejection of Claims 106-125 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (scope of enablement), have been fully considered and are persuasive. The rejection of claims 106-125 has been withdrawn.
Applicant’s arguments and amendments, filed April 3, 2026, with respect to the rejection of Claims 106-111, 119-121 and 124-125 under 35 U.S.C. 102(a)(1) as being
anticipated by Grigoriadis (aka US 877) (U.S. 2017/0020877), have been fully considered and are persuasive. The rejection of claims 106-125 has been withdrawn.
Applicant's arguments filed April 3, 2026, have been fully considered but they are not persuasive. The rejection of claims 106-121 and 123-125 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US20170020877) is maintained over the remaining pending and new claims detailed below. The rejection of previously pending claims 106-109,111 and 117-125 and new claims 126-1129 is detailed below.
Claim Rejections - 35 USC § 112b (Indefiniteness)
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 106 and 117 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 106 recites the limitation "the glucocorticoid" between lines 5-6. There is insufficient antecedent basis for this limitation in the claim. An amendment of claim 106 to delete “a steroid” in line 5, and replace with “a glucocorticoid” will overcome this rejection.
Claim 117 is indefinite for depending from canceled claim 112. Further claim 117 recites the limitation of a “steroid,” where it is noted that Applicant intended to amend the claims to recite a “glucocorticoid” rather than a “steroid.” An amendment to have claim 117 depend properly from a pending claim and replace “steroid” with “glucocorticoid” will overcome this rejection.
Claim Rejections - 35 USC § 112 (4th paragraph)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 117 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 117 depends from canceled claim 112 and further claim 117 recites “wherein the steroid” where it is clear Applicant intended to replace “steroid” with “glucocorticoid” in claim 106. Claim 117 is reasonably interpreted as intended to depend from claim 111, where the glucocorticoid is said to be HCT among others. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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 106-109, 111 and 117-126 and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US20170020877).
Claim 106 is a method of treating congenital adrenal hyperplasia (CAH) in a subject, comprising administering to the subject a therapeutically effective amount of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-l-yl)thiazol-2-amine (SSR125543) or salt thereof, at a frequency of at least twice per day, and a steroid or a pharmaceutically acceptable salt thereof, wherein the glucocorticoid or pharmaceutically acceptable salt thereof is administered at a reduced dosage compared to a dosage of the glucocorticoid or a pharmaceutically acceptable salt thereof administered alone, wherein the reduced dosage is in a 5 mg hydrocortisone equivalent, wherein the 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.
Regarding claim 106, US 877 teaches the claimed CRF1 antagonist, SSR-125543, i.e. Crinecerfont to treat CAH patients in need. See claims 1, 13 and 18; and paragraphs 13 and 54. US 877 teaches treatment of CAH includes efforts to normalize cortisol deficiency with glucocorticoid (GC) as claimed, (hydrocortisone in children) and the need to monitor treatment (as claimed) so as to avoid side effects of the steroids. See paragraphs 47 and fully detailed in paragraph 50.
Regarding the subject in need where the subject in need is receiving a combination of CRF1 antagonist and glucocorticoid (GC), requires less glucocorticoid than one receiving monotherapy of glucocorticoid, 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.
Further, 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.
As required by claim 106 and reduction of doses of a glucocorticoid (GC) in 5 mg increments, in an adult CAH patient, US 877 teaches, a GC dose, such as the dose of hydrocortisone (HC), among others, 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]. . . .” See paragraph 30.
While US 877 teaches the method of claim 106 as detailed above, it does not explicitly recite the species of method where the subject has steroid hormones levels of ACTH, A4, 17-OHP, that is less than two times an upper limit of a reference range of the at least one steroid hormone level.
In terms of claim interpretation, it is pointed out that elevated reference ranges to slightly elevated above normal reference range of adrenocorticotropic hormone (ACTH), androstenedione (A4), 17-hydroxyprogesterone (17-OHP), levels would be well within the claimed limitations of less than twice the upper limit of said A4 and ACTH as per claim 106.
Regarding claim 106, 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.
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. 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.
Regarding the limitation of at least twice a day dosing of Crinecerfont, 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. 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 Crinecerfont, if necessary to of at least twice a day dosing, on a as needed basis.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of the teachings of US 877 with regard to co-administering a CRF1 antagonist (at least twice a day) with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, combining prior art elements, 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, according to known methods (i.e. less than twice the upper limit of said range, but still above a normal reference range). MPEP 2143 (a)2
The PHOSITA would have had a reasonable expectation of success because the prior 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.
Regarding claim 107, US 877 teaches the dose reduction of glucocorticoid (GC), as claimed, by at least 10% to 60% from the recommended daily dose of GC, within 24 hours, as claimed, such as hydrocortisone. See paragraph 30.
Regarding claims 108-109, US 877 teaches CAH patients are considered to be treated for either, classic or non-classic CAH as claimed. See paragraph 4. While Figure 1 of US 877 teaches treatment of classical CAH in terms of 11-beta hydroxylase deficiency, a PHOSITA would readily envisage treatment of non-classical CAH, as guided by paragraph 4, as CAH is either one of the two, classic or non-classic.
Regarding claims 111 and 129 and the administration of the GC, hydrocortisone, 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. 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]. See paragraph 30.
Regarding claims 117-118 and the levels of steroid hormone determined from biological samples (blood, blood fraction/serum, urine etc.), US 877 teaches a blood sample is used to test 17-OHP. See paragraph 41. Also see paragraph 91, where it is taught 16-hour post dose blood samples were collected in the clinical study where biomarkers such as 17-OHP, ACTH and androstenedione (A4) were noted to be of interest.
Regarding claims 119-121 claiming SSR125543 total daily doses administered of about 50 mg to about 200 mg, about 200 mg or about 100 mg, 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. See paragraph 63.
Regarding claim 122, US 877 teaches tablets and capsules thereof. See paragraph 73.
Regarding claim 123 and the testing of ACTH in the morning, US 877 teaches that ACTH release is typically at 1-2 AM. See paragraph 66. Therefore, a PHOSITA would routinely test for ACTH in the morning, either at the time of release or shortly thereafter.
Regarding claims 124-125 and the treatment of adult and pediatric patients, US 877 teaches treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. See paragraph 44.
Regarding claim 126 and whether a subject is in a fed state, as a subject can be only in a fed state or non-fed state, it would be obvious to treat a subject in either state.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response argues US 877 (Grigoriadis) alone or in combination with Dhoot, does not disclose the claimed frequency of twice daily dosing.
In response, as detailed above, US 877 teaches based on the treated subject’s response to a combination of Crinecerfont, it is well within the purview of a PHOSITA to adjust dosing to achieve optimal clinical response. See paragraphs 40-42,44-45, 63-64 and 70 of US 877 as detailed above.
The Attorney response states its Example 1 has recognized distinct subgroups of CAH patients based on levels of A4 and ACTH, where the inclusion of 17-OHP (another biomarker associated with CAH) as an input occluded the identification of clear subgroups which was non-obvious (citing to paragraph 191 of the specification).
The Attorney response states it identified patient treatment groups as a “good disease control” group (normal/near normal levels of A4/ACTH) and “poor disease control” group (elevated levels of A4/ACTH), referencing Figures 2-4, where both groups had elevated 17-OHP levels.
The Attorney response states that co-administration of CRF1 antagonist to subjects with highly elevated levels of A4 and ACTH (poor disease control group) does not necessarily result in the same outcome as those subjects with normal or near-normal levels of A4 and ACTH (good disease control group). The Attorney response concludes this outcome between the two groups provides “a basis for different, yet sequential methods of treatment” as well as prophetic Example 3 overcomes the prima facie case of obviousness.
In response, while Applicant argues its identification of both good and poor response patient groups rebuts the rejection, it is noted both A4 and ACTH biomarkers are recognized as determining factors in guiding CAH treatment with a combination of a CRF1 antagonist and a glucocorticoid (HCT) as detailed above in US 877. Accordingly, the rejection of claims are maintained and new applied as detailed above.
Claims 106-109, 111 and 117- 129 are rejected under 35 U.S.C. 103 as being unpatentable over Grigoriadis (aka US 877) (US20170020877 in 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.
Jha is listed on the PTO-892 form.
As detailed above, US 877 teaches the method of claims 106-109, 111, 117-126 and 129 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 127-128.
Regarding claims 127 claiming a reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches reference range of ACTH 5-46 (see Abstract), an obvious overlap between the art range and that claimed per MPEP 2144.05.
Regarding claim 128 claiming a 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 between the claimed range per MPEP 2144.05.
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 106-109,111, 117-126 and 129 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 3-21 of US Patent 12115166 B2 (reference patent) in view of Grigoriadis (aka US 877) (US20170020877).
The disclosure of claim 106 is discussed above.
Regarding claim 106, the reference patent claims treatment of CAH as claimed with a CRF1 antagonist and glucocorticoid, where a second glucocorticoid (GC) dose is reduced in combination with the CRF1 antagonist (lowered GC dose as claimed), noting reductions in ACTH and A4 levels from a baseline. See claim 1.
While teaching the claimed subject treated with CRF1 antagonist glucocorticoid, Crinecerfont, the reference patent does not teach the claimed CRF1 antagonist, Crinecerfont aka SSR125543, twice a day and the limitations of A4 and ACTH levels that are less than two times an upper reference range of such.
To address the first deficiency, US 877 teaches the claimed CRF1 antagonist administered, SSR-125543, i.e. Crinecerfont to treat the claimed CAH patients in need. See claims 1, 13 and 18; and paragraphs 13 and 54.
Regarding the limitation of at least twice a day dosing of Crinecerfont and hormone levels of ACTH and A4 that is less than two times an upper limit, 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 Crinecerfont, if necessary to twice a day dosing, on a as needed basis.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of the teachings of the reference patent and US 877 with regard to co-administering a CRF1 antagonist (at least twice a day) with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, combining prior art elements, 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, according to known methods (i.e. less than twice the upper limit of said range, but still above a normal reference range). MPEP 2143 (a)
The PHOSITA would have had a reasonable expectation of success because the prior 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.
Regarding claims 107, 108-109, and limitations therein, US 877 teaches SSR-125543, i.e. Crinecerfont to treat the claimed CAH patients in need. See claims 1, 13 and 18; and paragraphs 13 and 54; US 877 teaches CAH patients are treated for classic or non-classic CAH as claimed. See paragraph 4;
Regarding claims 111 and 129, the reference patent teaches various glucocorticoids, including hydrocortisone, etc. See claim 12.
Regarding claims 117-118 with regard to biological plasma samples from the subject patient, the reference patent teaches reduction of a plasma concentration of biomarkers from the subject (A4 and ACTH) from a baseline. See claims 1-9.
Regarding claims 119-121 claiming SSR125543 total daily doses administered of about 50 mg to about 200 mg, about 200 mg or about 100 mg, 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. See paragraph 63.
Regarding claim 122, US 877 teaches tablets and capsules thereof. See paragraph 73.
Regarding claim 123 and the testing of ACTH in the morning, US 877 teaches that ACTH release is typically at 1-2 AM. See paragraph 66. Therefore, a PHOSITA would routinely test for ACTH in the morning, either at the time of release or shortly thereafter.
Regarding claims 124-125 and the treatment of adult and pediatric patients, US 877 teaches treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. See paragraph 44.
Regarding claim 126 and whether a subject is in a fed state, as a subject can be only in a fed state or non-fed state, it would be obvious to treat a subject in either state.
Claims 106-109, 111, and 117-129 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of US Patent 12115166 B2 (reference patent) 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. Jha is listed on the PTO-892 form.
As detailed above, the reference patent and US 877 teach the method of claims 106-109, 111, 117-126 and129 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 127-128.
Regarding claims 127 claiming a reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches reference range of ACTH 5-46 (see Abstract), an obvious overlap between the art range and that claimed per MPEP 2144.05.
Regarding claim 128 claiming a 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 between the claimed range per MPEP 2144.05.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the reference patent and 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.
Claims 106-109, 111, and 117-129 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 6, 13-14, 19, 46-48, 54-55, 58-61, 66, 78-81, 86, 106, and 108-109 of copending Application No. 17578149 in view of Grigoriadis (aka US 877) (US20170020877).
The disclosure of claim 106 is discussed above.
Regarding claim 106, the reference application claims treatment of a CAH patient as claimed with a group CRF1 antagonists, including SSR125543 (Crinecerfont) as claimed, and glucocorticoid (GC) dose is reduced in combination with the CRF1 antagonist (lowered GC dose as claimed), claiming reductions of A4 and ACTH levels that are less than two times an upper reference range of such. See claim 1. See also claims 6, and 13-14 for levels of ACTH and A4 of two times, and less than two times the reference level.
Regarding 5 mg reductions of glucocorticoid in 5 mg HCT equivalents, the reference application this limitation. See claim 19.
It is noted that the reference application does not teach the limitation of dosing Crinecerfont at least twice a day as claimed.
Regarding the limitation of twice a day dosing of Crinecerfont, 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 Crinecerfont, if necessary to twice a day dosing, on a as needed basis.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of the teachings of the reference application and US 877 with regard to co-administering a CRF1 antagonist (at least twice a day) with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, combining prior art elements, 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, according to known methods (i.e. less than twice the upper limit of said range, but still above a normal reference range). MPEP 2143 (a)
The PHOSITA would have had a reasonable expectation of success because the prior 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.
Regarding claim 107, US 877 teaches the dose reduction of glucocorticoid (GC), as claimed, by at least 10% to 60% from the recommended daily dose of GC, within 24 hours, as claimed, such as hydrocortisone. See paragraph 30.
Regarding claims 108-109 (classic and non-classic CAH); 111 and 129 (the glucocorticoid hydrocortisone (HC)) and the limitations therein, the reference application teaches classic and non-classic CAH. See claim 86; the reference application teaches the use of HC and HC equivalents. See claim 19.
Regarding claims 117-118 and the levels of steroid hormone determined from biological samples (blood, blood fraction/serum, urine etc.), US 877 teaches a blood sample is used to test 17-OHP. See paragraph 41. Also see paragraph 91, where it is taught 16-hour post dose blood samples were collected in the clinical study where biomarkers such as 17-OHP, ACTH and androstenedione (A4) were noted to be of interest.
Regarding claims 119-121 claiming SSR125543 total daily doses administered of about 50 mg to about 200 mg, about 200 mg or about 100 mg, the reference application teaches dose ranges and doses at claims 47-48.
Regarding claim 122 US 877 teaches tablets and capsules thereof. See claims 60-61 and 66.
Regarding claim 123 and the testing of ACTH in the morning, US 877 teaches that ACTH release is typically at 1-2 AM. See paragraph 66. Therefore, a PHOSITA would routinely test for ACTH in the morning, either at the time of release or shortly thereafter.
Regarding claims 124-125 and adult and pediatric patients in need, US 877 teaches treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. See paragraph 44.
Regarding claim 126 and whether a subject is in a fed state, as a subject can be only in a fed state or non-fed state, it would be obvious to treat a subject in either state.
Regarding claims 127-128 and the ACTH and A4 reference ranges therein, these are taught by the reference application, see claims 108-109 below.
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Claims 106-109, 111, 117-126 and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No.19650165 in view of Grigoriadis (aka US 877) (US20170020877).
The disclosure of claim 106 is discussed above.
Regarding claim 106, the reference application claims treatment of a CAH patient as claimed with a group CRF1 antagonists, including SSR125543 (Crinecerfont) as claimed, and glucocorticoid (GC) dose is reduced in combination with the CRF1 antagonist (lowered GC dose as claimed), claiming reductions of A4 and ACTH levels that are less than two times an upper reference range of such. See claims 1-4. The reference application teaches twice daily dosing. See claim 6.
It is noted that the reference applications do not teach the limitation of reduction of doses of glucocorticoid in HCT 5 mg increments.
As required by claim 106 and reduction of doses of a glucocorticoid in 5 mg increments, 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.” See paragraph 30.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of the reference application and US 877 with regard to co-administering a CRF1 antagonist (at least twice a day) with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, combining prior art elements, 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, according to known methods (i.e. less than twice the upper limit of said range, but still above a normal reference range). MPEP 2143 (a)
The PHOSITA would have had a reasonable expectation of success because the prior 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.
Regarding claim 107, the reference application teaches SSR-125543, i.e. Crinecerfont. See claims 1-3. Regarding claim 107, US 877 teaches the dose reduction of glucocorticoid (GC), as claimed, by at least 10% to 60% from the recommended daily dose of GC, within 24 hours, as claimed, such as hydrocortisone. See paragraph 30.
Regarding claims 108-109, US 877 teaches CAH patients are considered to be treated for either, classic or non-classic CAH as claimed. See paragraph 4.
Regarding claims 111 and 129 and the glucocorticoids claimed, the reference application teaches various glucocorticoids, including hydrocortisone, etc. See claim 4.
Regarding claims 117-118 with regard to biological samples from the subject patient (plasma), to measure biomarkers ACTH and A4. These are taught by reference application claims 15-18. See also US 877 teaches a blood sample is used to test 17-OHP. See paragraph 41. Also see US 866 paragraph 91, where it is taught 16-hour post dose blood samples were collected in the clinical study where biomarkers such as 17-OHP, ACTH and androstenedione (A4) were noted to be of interest.
Regarding claims 119-121 claiming SSR125543 total daily doses administered of about 50 mg to about 200 mg, about 200 mg or about 100 mg, the reference application teaches overlapping doses. See claims 7-10.
Regarding claim 122, the reference application teaches capsules. See claim 14.
Regarding claim 123 and the testing of ACTH in the morning, US 877 teaches that ACTH release is typically at 1-2 AM. See paragraph 66. Therefore, a PHOSITA would routinely test for ACTH in the morning, either at the time of release or shortly thereafter.
Regarding claims 124-125 and the treatment of adult and pediatric patients, the reference application teaches treatment of adults. See claim 5. US 877 teaches treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. See paragraph 44.
Regarding claim 126 and whether a subject is in a fed state, as a subject can be only in a fed state or non-fed state, it would be obvious to treat a subject in either state. This is a provisional nonstatutory double patenting rejection.
Claims 106-109, 111, 117-126 and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19650188 in view of Grigoriadis (aka US 877) (US20170020877).
The disclosure of claim 106 is discussed above.
Regarding claim 106, the reference application claims treatment of a fed CAH patient as claimed comprising administering (twice daily) a glucocorticoid and a pharmaceutical composition comprising a CRF1 antagonist, (SSR125543 aka Crinecerfont) as claimed, where glucocorticoid (GC) dose is reduced (as claimed), claiming A4 and ACTH levels that are less than two times an upper reference range of such, where the subject is fed and on a glucocorticoid regimen. See claims 1-4 and 7-8.
It is noted that reference application claim 1 does not teach the limitations of A4 and ACTH levels that are less than two times an upper reference range of such.
However such limitation is taught by reference application claim 2.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of the teachings of the reference application and US 877 with regard to co-administering a CRF1 antagonist (at least twice a day) with reduced levels of concomitant steroid (hydrocortisone) relative to a patient not taking the CRF1 antagonist, combining prior art elements, 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, according to known methods (i.e. less than twice the upper limit of said range, but still above a normal reference range). MPEP 2143 (a)
The PHOSITA would have had a reasonable expectation of success because the prior 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.
Regarding claim 107, the reference application teaches SSR-125543, i.e. Crinecerfont. See claims 1-3 and 7-8. Regarding claim 107, US 877 teaches the dose reduction of glucocorticoid (GC), as claimed, by at least 10% to 60% from the recommended daily dose of GC, within 24 hours, as claimed, such as hydrocortisone. See paragraph 30.
As required by claim 106 and reduction of doses of a glucocorticoid in 5 mg increments, 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.” See paragraph 30.
Regarding claim 107, the reference application SSR-125543, i.e. Crinecerfont. See claims 1-3. Regarding claim 107, US 877 teaches the dose reduction of glucocorticoid (GC), as claimed, by at least 10% to 60% from the recommended daily dose of GC, within 24 hours, as claimed, such as hydrocortisone. See paragraph 30.
Regarding claims 108-109, US 877 teaches CAH patients are considered to be treated for either, classic or non-classic CAH as claimed. See paragraph 4.
Regarding claims 111 and 129 and the administration of the GC, hydrocortisone, 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 claims 117-118 with regard to biological samples from the subject patient (plasma), to measure biomarkers ACTH and A4. These are taught by reference application claims 15-18.
Regarding claims 119-121 claiming SSR125543 total daily doses administered of about 50 mg to about 200 mg, about 200 mg or about 100 mg, the reference application teaches overlapping doses. See claims 7-10.
Regarding claim 122, the reference application teaches capsules. See claim 14.
Regarding claim 123 and the testing of ACTH in the morning, US 877 teaches that ACTH release is typically at 1-2 AM. See paragraph 66. Therefore, a PHOSITA would routinely test for ACTH in the morning, either at the time of release or shortly thereafter.
Regarding claims 124-125 and the treatment of adult and pediatric patients, the reference application teaches treatment of adults. See claim 5. US 877 teaches treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood. See paragraph 44.
Regarding claim 126 and whether a subject is in a fed state, as a subject can be only in a fed state or non-fed state, it would be obvious to treat a subject in either state. This is a provisional nonstatutory double patenting rejection.
Claims 106-109, 111, and 117-129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-18 of copending Application No 19650165
claims 1-16 of copending Application No. 19650188
all three applications 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. Jha is listed on the PTO-892 form.
As detailed above, the reference application(s) and US 877 teach the method of claims 106-109, 111, 117-126 and 129 as detailed above, but they do not necessarily teach the species of the specific reference ranges of ACTH and androstenedione A4 of claims 127-128.
Regarding claims 127 claiming a reference range of ACTH is about 7 to 63.3 pg/mL, Jha teaches reference range of ACTH 5-46 (see Abstract), an obvious overlap between the art range and that claimed per MPEP 2144.05.
Regarding claim 128 claiming a 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 between the claimed range per MPEP 2144.05.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the reference application and 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. 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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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 17/578,149 01/18/2022
17/578,149 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
2 (a) combining prior art elements according to known methods to yield predictable results;
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