UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`NEUROCRINE BIOSCIENCES, INC.
`Petitioner
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`v.
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`SPRUCE BIOSCIENCES, INC.
`Patent Owner
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`Case PGR2022-00025
`U.S. Patent 11,007,201
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`PETITION FOR POST GRANT REVIEW OF
`U.S. PATENT NO. 11,007,201
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`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`TABLE OF CONTENTS
`
`V. 
`
`I. 
`II. 
`
`INTRODUCTION ........................................................................................... 1 
`REQUIREMENTS FOR PGR UNDER 37 C.F.R. § 42.204 .......................... 3 
`A.  Grounds for Standing Under 37 C.F.R. § 42.204(a)................................. 3 
`B.  Challenge Under 37 C.F.R. § 42.204(b) and Relief Requested ............... 3 
`III.  BACKGROUND OF THE TECHNOLOGY .................................................. 6 
`A.  Congenital Adrenal Hyperplasia (“CAH”) ............................................... 6 
`B.  The Use of CRF1 Receptor Antagonists to Treat CAH ......................... 10 
`IV.  THE ’201 PATENT AND ITS PROSECUTION HISTORY ....................... 12 
`A.  The ’201 Patent Disclosure ..................................................................... 12 
`B.  The ’201 Patent Claims ........................................................................... 16 
`C.  The ’201 Patent Prosecution History ...................................................... 18 
`LEGAL STANDARDS ................................................................................. 24 
`A.  Anticipation ............................................................................................. 24 
`B.  Obviousness ............................................................................................ 25 
`1. 
`Level of Ordinary Skill in the Art ................................................. 26 
`VI.  CLAIM CONSTRUCTION UNDER 37 C.F.R. §§ 42.204(b)(3) ................ 27 
`A.  “Baseline”/ “From Baseline” .................................................................. 27 
`B.  “A Human”/“The Human” ...................................................................... 28 
`C.  “Maintained at a Reduced Level Post 24 Hours”, “Maintained at a
`Reduced Level Post 4 Weeks”, “Maintained at a Reduced Level Post 6
`Weeks” .................................................................................................... 29 
`VII.  THE CLAIMS OF THE ’201 PATENT ARE UNPATENTABLE .............. 30 
`A.  Grigoriadis .............................................................................................. 31 
`1.  Grigoriadis’ Disclosure of Crinecerfont (SSR-125543) ............... 32 
`2.  Grigoriadis’ Disclosure of NBI-77860 .......................................... 39 
`B.  Turcu 2016 .............................................................................................. 40 
`C.  Romano ................................................................................................... 41 
`D.  Ground 1: Grigoriadis’ Disclosure of Crinecerfont Anticipates Claims
`1-4, 7-9, 11-15, and 18. ........................................................................... 42 
`1. 
`The use of crinecerfont to treat CAH, as disclosed in Grigoriadis,
`inherently results in an A4 reduction from baseline that is
`maintained post 24 hours as recited in claim 1. ............................ 42 
`2.  Grigoriadis discloses all of the limitations of dependent claims 2-
`4, 7-9, 11-15, and 18. .................................................................... 45 
`E.  Ground 2: Claims 10, 16-17, and 19 Would Have Been Obvious in
`View of Grigoriadis’ Disclosure of Crinecerfont and the Knowledge of a
`Skilled Artisan. ....................................................................................... 51 
`1. 
`Claim 10 ........................................................................................ 51 
`
`i
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`

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`2. 
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`Claims 16-17 ................................................................................. 52 
`2. 
`Claim 19 ........................................................................................ 53 
`3. 
`F.  Ground 3: Claims 5-6 Would Have Been Obvious in View of
`Grigoriadis’ Disclosure of Crinecerfont in Combination with Romano
`and the Knowledge of a Skilled Artisan. ................................................ 55 
`G.  Ground 4: Claims 1-4 and 7-19 Would Have Been Obvious in View of
`Grigoriadis’ and Turcu 2016’s Disclosure of NBI-77860 and the
`Knowledge of a Skilled Artisan. ............................................................. 57 
`1. 
`Claim 1 would have been obvious in view of Grigoriadis’ and
`Turcu 2016’s disclosure of NBI-77860 reducing A4 in a patient
`compared to placebo measurement ............................................... 57 
`Claim 2-4 and 7-19 would have been obvious in view of
`Grigoriadis’ and Turcu 2016’s disclosure of NBI-77860 and the
`knowledge of a skilled artisan ....................................................... 62 
`H.  Ground 5: Claims 5-6 Would Have Been Obvious in View of
`Grigoriadis and Turcu 2016 in Combination with Romano and the
`Knowledge of a Skilled Artisan. ............................................................. 73 
`I.  Ground 6: Claims 1-19 of the ’201 Patent are Unpatentable for Lack of
`Written Description. ................................................................................ 75 
`VIII.  DISCRETIONARY DENIAL IS NOT WARRANTED ............................... 79 
`IX.  PAYMENT OF FEES – 37 C.F.R. § 42.203 ................................................. 81 
`X. 
`CONCLUSION .............................................................................................. 81 
`XI.  MANDATORY NOTICES UNDER 37 C.F.R § 42.8(a)(1) ......................... 82 
`A.  Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) .............................. 82 
`B.  Related Matters Under 37 C.F.R. § 42.8(b)(2) ....................................... 82 
`C.  Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ................... 82 
`D.  Service Information ................................................................................ 83 
`
`
`
`ii
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`

`

`Petitioner
`Exhibit Number
`1001
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`1002
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`1003
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`1004
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`1005
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`1006
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`1007
`
`1008
`
`1009
`
`1010
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`1011
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`1012
`1013
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`
`EXHIBITS
`
`Exhibit Description
`
`U.S. Patent No. 11,007,201 to Alexis Howerton, et al. (“the
`’201 patent”).
`U.S. Prosecution History of the ’201 Patent.
`
`Application No. PCT/US2018/046760.
`
`U.S. Provisional Application Serial No. 62/545,406.
`
`Declaration of Robert M. Carey, M.D.
`
`U.S. Patent Application Publication No. 2017/0020877 to
`Grigoriadis et al. (“Grigoriadis”).
`U.S. Patent Application Publication No. 2005/0209250 to
`Romano (“Romano”).
`Turcu et al., “Single-Dose Study of a Corticotropin-
`Releasing Factor Receptor-1 Antagonist in Women With 21-
`Hydroxylase Deficiency,” J. Clin. Endocrinol. Metab.,
`101(3):1174–1180 (March 2016) (“Turcu 2016”).
`Auchus et al., “Crinecerfont Lowers Elevated Hormone
`Markers in Adults With 21-Hydroxylase Deficiency
`Congenital Adrenal Hyperplasia,” J. Clin. Endocrinol.
`Metab. (2021) (“Auchus 2021”).
`U.S. Patent Application Publication No. 2006/0078623 to
`Dhoot et al. (“Dhoot”).
`“Spruce Biosciences Presents Phase 1 and 2 Data for
`Tildacerfont in Adults with Congenital Adrenal Hyperplasia
`from Endocrine Society’s 2021 Annual Meeting,” Spruce
`Biosciences (Mar. 17, 2021) (“Spruce March 17, 2021 Press
`Release”).
`U.S. Patent No. 8,030,304 to Chen et al. (“Chen”).
`Speiser et al., “Congenital Adrenal Hyperplasia Due to
`Steroid 21-Hydroxylase Deficiency: An Endocrine Society
`Clinical Practice Guideline,” J. Clin. Endocrinol. Metab.,
`95(9):4133–4160 (2010) (“Speiser 2010”)
`
`iii
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`

`

`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`Turcu A.F. & Auchus R.J., “The Next 150 Years of
`Congenital Adrenal Hyperplasia,” J. Steroid. Biochem. Mol.
`Biol. 153:63–71 (Sep. 2015) (“Turcu & Auchus 2015”).
`El Maouche et al., “Congenital Adrenal Hyperplasia,”
`Lancet 390:2194–210 (2017) (“El Maouche 2017”).
`Merke D.P. & Bornstein S.R., “Congenital Adrenal
`Hyperplasia,” Lancet 365:2125–36 (2005) (“Merke &
`Bornstein 2005”).
`Speiser et al., “Congenital Adrenal Hyperplasia Due to
`Steroid 21-Hydroxylase Deficiency: An Endocrine Society
`Clinical Practice Guideline,” J. Clin. Endocrinol. Metab.,
`103(11):4043–4088 (2018) (“Speiser 2018”).
`Fahmy et al., “Structure and Function of Small Non-Peptide
`CRF Antagonists and their Potential Clinical Use,” Curr.
`Mol. Pharmacol. 10(4): 270–281 (2017) (“Fahmy 2017”).
`Griebel et al., “4-(2-Chloro-4-methoxy-5-methylphenyl)-N-
`[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-
`methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride
`(SSR125543A), a Potent and Selective Corticotrophin-
`Releasing Factor1 Receptor Antagonist. II. Characterization
`in Rodent Models of Stress-Related Disorders,” J.
`Pharmacol. Exp. Ther. 301(1):333–345 (2002) (“Griebel
`2002”).
`Gully et al., “4-(2-Chloro-4-methoxy-5-methylphenyl)-N-
`[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-
`methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride
`(SSR125543A): A Potent and Selective Corticotrophin-
`Releasing Factor1 Receptor Antagonist. I. Biochemical and
`Pharmacological Characterization,” J. Pharmacol. Exp.
`Ther. 301(1):322-332 (2002) (“Gully 2002”).
`Merke D.P. & Cutler G.B., “New Ideas for Medical
`Treatment of Congenital Adrenal Hyperplasia,” Endocrinol.
`Metab. Clin. North. Am. 30(1):121–135 (2001) (“Merke &
`Cutler 2001”).
`Merke et al., “Future Directions in the Study and
`Management of Congenital Adrenal Hyperplasia due to 21-
`Hydroxylase Deficiency,” Ann. Intern. Med. 136:320–334
`(2002) (“Merke 2002”).
`
`iv
`
`

`

`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`“Microparticles Formulation as a Targeting Drug Delivery
`System,” J. Nanomed. Res. 6(2):00151, 1–4 (2017)
`(“Microparticles Formulation 2017”).
`Merke D.P. & Auchus R.J., “Congenital Adrenal
`Hyperplasia Due to 21-Hydroxylase Deficiency,” N. Engl. J.
`Med. 383(13):1248–1261 (2020) (“Merke & Auchus 2020”).
`Turcu A.F. & Auchus R.J., “Novel Treatment Strategies in
`Congenital Adrenal Hyperplasia,” Curr. Opin. Endocrinol.
`Diabetes Obes. 23(3):225–232 (June 2016) (“Turcu &
`Auchus 2016”).
`Webb E.A. & Krone N., “Current and Novel Approaches to
`Children and Young People with Congenital Adrenal
`Hyperplasia and Adrenal Insufficiency,” Best Pract. Res.
`Clin. Endocrinol. Metab. 29:449–468 (2015) (“Webb &
`Krone 2015”).
`“Neurocrine Biosciences to Present New Data Analyses for
`Crinecerfont in Adults with Classical Congenital Adrenal
`Hyperplasia at ENDO 2021,” Neurocrine Biosciences (Mar.
`20, 2021) (“Neurocrine March 20, 2021 Press Release”).
`“Neurocrine Biosciences Reports Positive Phase II Data for
`Crinecerfont in Adults with Congenital Adrenal Hyperplasia
`at ENDO Online 2020,” Neurocrine Biosciences (June 8,
`2020) (“Neurocrine June 8, 2020 Press Release”).
`Williams, “Corticotropin-Releasing Factor 1 Receptor
`Antagonists: A Patent Review,” Expert Opin. Ther. Pat.
`23(8):1057–68 (2013) (“Williams 2013”).
`Zorrilla E.P. & Koob G.F., “Progress in Corticotropin-
`Releasing Factor-1 Antagonist Development,” Drug
`Discovery Today 15(9/10):371–383 (2010) (“Zorrilla &
`Koob 2010”).
`Kehne J.H. & Cain C.K., “Therapeutic Utility of Non-
`Peptidic CRF1 Receptor Antagonists in Anxiety, Depression,
`and Stress-Related Disorders: Evidence from Animal
`Models,” Pharmacol. Ther. 128(3):460–487 (2010). (“Kehne
`& Cain 2010”).
`Goodman & Gilman’s The Pharmacological Basis of
`Therapeutics (Brunton L.L. ed., 12th ed. 2011) (“Goodman
`& Gilman 2011).
`
`v
`
`

`

`1033
`
`1034
`
`1035
`
`1036
`
`1037
`1038
`
`1039
`
`1040
`
`
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`Shargel L. & Yu A., Applied Biopharmaceutics &
`Pharmacokinetics (7th ed. 2016) (“Shargel & Yu 2016”).
`Shargel et al., Applied Biopharmaceutics &
`Pharmacokinetics (6th ed. 2012) (“Shargel 2012”).
`Bale et al., “Overview on Therapeutic Applications of
`Microparticulate Drug Delivery Systems,” Crit. Rev. Ther.
`Drug Carrier Syst. 33(4):309-361 (2016).
`U.S. Patent No. 10,849,908 to Alexis Howerton, et al. (“the
`’908 patent”).
`U.S. Prosecution History of the ’908 Patent.
`Fuqua et al., “Duration of Suppression of Adrenal Steroids
`after Glucocorticoid Administration,” International Journal
`of Pediatric Endocrinology (2010) (“Fuqua 2010”).
`Sarafoglou et al., “Tildacerfont in Adults with Classic
`Congenital Adrenal Hyperplasia: Results from Two Phase 2
`Studies,” Journal of Clinical Endocrinology & Metabolism
`(2021) (“Sarafoglou 2021”).
`Reif et al., “Mechanisms Involved in Placebo and Nocebo
`Responses and Implications for Drug Trials,” Clinical
`Pharmacology and Therapuetics (2011) (“Reif 2011”).
`
`
`vi
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`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`
`I.
`INTRODUCTION
`Neurocrine Biosciences, Inc. (“Petitioner” or “Neurocrine”) petitions for
`
`Post Grant Review (“PGR”) under 35 U.S.C. §§ 321–326 and 37 C.F.R. § 42 of
`
`claims 1-19 (“the Challenged Claims”) of U.S. Patent No. 11,007,201 (“the ’201
`
`patent;” Ex. 1001) assigned to Spruce Biosciences (“Spruce”). As explained in
`
`this petition, it is more likely than not that Neurocrine will prevail with respect to
`
`at least one of the Challenged Claims.
`
`Neurocrine is an innovator in the area of treatments for congenital adrenal
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`hyperplasia (“CAH”), a group of genetic disorders impacting hormone production,
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`and was the first company to study CRF1 receptor antagonists to treat CAH.
`
`Neurocrine is currently developing a specific CRF1 receptor antagonist,
`
`crinecerfont, as a treatment for CAH, and previously studied NBI-77860, a
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`different CRF1 receptor antagonist, as a treatment for CAH. Later, Spruce began
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`to develop treatments for CAH as well, and is currently studying a third CRF1
`
`receptor antagonist, tildacerfont, to treat CAH. Spruce, however, has not been
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`content to patent only its own work, and instead has filed serial applications
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`claiming the use of a class of CRF1 receptor antagonists to treat CAH. The ’201
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`patent issued from one such application. These actions have the potential to
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`artificially constrict the choices of patients and doctors in the treatment of this very
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`1
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`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`
`challenging disease.
`
`The ’201 patent broadly claims the use of CRF1 receptor antagonists to treat
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`CAH, but the specification describes only a single CRF1 receptor antagonist,
`
`tildacerfont, which it repeatedly characterizes as “the invention.” The ’201 patent
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`claims are unpatentable because of this insufficient disclosure, and because
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`Neurocrine’s own work on the use of CRF1 receptor antagonists to treat CAH,
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`which is prior art to the ’201 patent, anticipates Spruce’s broad claims or renders
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`those claims obvious.
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`With respect to Neurocrine’s prior work, Published Application No. US
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`2017/0020877 (Ex. 1006; “Grigoriadis”) was published in January 2017, and
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`discloses the use of a number of CRF1 receptor antagonists to treat CAH,
`
`including crinecerfont. The administration of crinecerfont to a patient inherently
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`results in a reduced androstenedione level of the patient compared to baseline,
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`which is maintained post 24 hours, as recited in the ’201 patent claims, and thus
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`anticipates the claims.
`
`Grigoriadis also discloses the use of NBI-77860, the compound Neurocrine
`
`previously studied as a CAH treatment. Neurocrine’s work studying NBI-77860 as
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`a treatment for CAH was also published in 2016 (Ex. 1008; “Turcu 2016”). These
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`disclosures would render the ’201 patent claims obvious to a person of ordinary
`
`skill in this art.
`
`2
`
`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`The broad ’201 patent claims are also unpatentable under 35 U.S.C. § 112 in
`
`view of its limited disclosure. Although the patent claims the use of CRF1
`
`receptor antagonists, the entire disclosure relates to only a single CRF1 receptor
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`antagonist, tildacerfont. The ’201 patent repeatedly characterizes “the invention”
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`as relating to this particular compound. The patent’s disclosure does not allow
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`persons of ordinary skill in the art to recognize that the inventor invented what is
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`claimed (the use of a class of compounds).
`
`Neurocrine respectfully submits that a PGR should be instituted, and that the
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`Challenged Claims should be canceled as unpatentable.
`
`II. REQUIREMENTS FOR PGR UNDER 37 C.F.R. § 42.204
`A. Grounds for Standing Under 37 C.F.R. § 42.204(a)
`Neurocrine certifies that the ’201 Patent is available for PGR. The present
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`petition is being filed within nine months of the issuance of the ’201 patent on May
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`18, 2021. Neurocrine has not filed a civil action challenging the validity of any
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`claim of the ’201 patent. Neurocrine is not barred or estopped from requesting this
`
`review challenging claims 1-19 on the below-identified grounds.
`
`B. Challenge Under 37 C.F.R. § 42.204(b) and Relief
`Requested
`Neurocrine requests a PGR of the Challenged Claims on the grounds set
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`forth in the table shown below, and requests that each of the Challenged Claims be
`
`found unpatentable.
`
`3
`
`

`

`
`
`’201 Patent Claims
`Ground
`Ground 1 1-4, 7-9, 11-15, 18
`
`Ground 2 10, 16-17, 19
`
`Ground 3 5-6
`
`Ground 4 1-4, 7-19
`
`Ground 5 5-6
`
`Ground 6 1-19
`
`
`
`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`
`Basis for Rejection
`Anticipation under 35 U.S.C. § 102 by
`the disclosure of crinecerfont in
`Grigoriadis et al., US 2017/0020877
`(Ex. 1006; “Grigoriadis”)
`Obviousness under 35 U.S.C. § 103 by
`the disclosure of crinecerfont in
`Grigoriadis in view of the knowledge of
`a skilled artisan
`Obviousness under 35 U.S.C. § 103 by
`the disclosure of crinecerfont in
`Grigoriadis in combination with US
`2005/0209250 (Ex. 1007; “Romano”)
`and the knowledge of a skilled artisan
`Obviousness under 35 U.S.C. § 103 by
`the disclosure of NBI-77860 in
`Grigoriadis and Turcu 2016 (Ex. 1008),
`in view of the knowledge of a skilled
`artisan
`Obviousness under 35 U.S.C. § 103 by
`the disclosure of NBI-77860 in
`Grigoriadis and Turcu 2016 in
`combination with Romano and the
`knowledge of a skilled artisan
`Lack of written description under 35
`U.S.C. § 112
`
`Grigoriadis (Ex. 1006) qualifies as prior art under 35 U.S.C § 102(a).
`
`Specifically, Grigoriadis is a patent application that published on January 26, 2017,
`
`names a different inventor than the inventors named on the ’201 patent, and was
`
`published before August 14, 2017, which is the earliest possible effective filing
`
`4
`
`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`date to which claims 1-19 of the ’201 patent could be entitled.1
`
`Turcu 2016 (Ex. 1008) qualifies as prior art under 35 U.S.C. § 102(a).
`
`Specifically, Turcu 2016 is a printed publication that first published online on
`
`January 11, 2016,2 names different authors than the inventors named on the ’201
`
`patent, and was published more than one year before the ’201 patent’s earliest
`
`effective filing date of August 14, 2017. Thus, Turcu 2016 is prior art to the ’201
`
`patent.
`
`Romano (Ex. 1007) qualifies as prior art under 35 U.S.C § 102(a).
`
`Specifically, Romano is a patent application that published on September 22, 2005,
`
`names a different inventor than the inventors named on the ’201 patent, and was
`
`published more than one year before the ’201 patent’s earliest effective filing date
`
`of August 14, 2017. Thus, Romano is prior art to the ’201 patent.
`
`
`
`
`1 Claims 1-19 are entitled to an effective filing date no earlier than April 18, 2019,
`
`which is the date its parent application, U.S. App. No. 16/388,620, was filed. The
`
`claims are not entitled to claim priority to Provisional App. No. 62/545,406, filed
`
`on August 14, 2017. However, for purposes of this Petition it is not necessary to
`
`reach the priority issue.
`
`2 Ex. 1008 at 1174.
`
`
`5
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`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`III. BACKGROUND OF THE TECHNOLOGY
`A. Congenital Adrenal Hyperplasia (“CAH”)
`Congenital adrenal hyperplasia (“CAH”) refers to a group of disorders
`
`
`
`encompassing enzyme deficiencies that impair a patient’s ability to synthesize
`
`cortisol.3 Cortisol is a hormone that plays an important role in regulating blood
`
`sugar, immune responses, metabolism of fat, protein, and carbohydrates, and
`
`regulation of bone formation.4
`
`
`
`Patients suffering from CAH typically have lower levels of cortisol than
`
`needed. These deficient cortisol levels cause the hypothalamus to increase
`
`production of a hormone called corticotropin-releasing factor (“CRF”).5 The
`
`production of CRF signals the pituitary gland to secrete another hormone,
`
`adrenocorticotropic hormone (“ACTH”).6 ACTH stimulates the production of a
`
`number of precursor hormones, in particular 17-α-hydroxyprogesterone (“17-
`
`OHP”), that ultimately lead to the production of both cortisol and androstenedione
`
`
`3 Ex. 1005, ¶ 13; Ex. 1013, 4134.
`
` 4
`
` 5
`
` 6
`
`
`
` Ex. 1005, ¶ 14.
`
` Ex. 1005, ¶ 16; Ex. 1014, 1.
`
` Id.
`
`6
`
`

`

`Attorney Docket No. 47291-0005PS1
`PGR of U.S. Patent No. 11,007,201
`(“A4”), which is a common precursor of the androgen sex hormones.7 Androgens
`
`are a group of hormones, such as testosterone, that regulate the development of
`
`male characteristics and reproductive activity. CAH patients cannot convert 17-
`
`OHP to cortisol.8 As a result, CAH patients produce excess 17-OHP that cannot be
`
`converted to cortisol. 9 Because CAH patients can convert 17-OHP to A4, the
`
`excess 17-OHP is sent down this pathway, resulting in the overproduction of A4
`
`and the downstream androgens that A4 converts to, testosterone and
`
`dihydroxytestosterone.10 The overproduction of androgens in CAH patients leads
`
`to a number of physiological problems, including abnormalities in growth and
`
`development in children, hirsutism (excessive hair growth), and in females,
`
`irregular or absent menstrual cycles and infertility.11
`
`
`
`Moreover, the continued cortisol deficiency in these patients creates a
`
`feedback loop whereby the body continues to produce CRF and ACTH, which
`
`
`7 Ex. 1005, ¶¶ 14-16; Ex. 1014, 1.
`
` 8
`
` 9
`
` Id.
`
` Ex. 1005, ¶ 16; Ex. 1015, 2195-2196.
`
`
`10 Ex. 1005, ¶¶ 16-17; Ex. 1015, 2195-2196.
`
`11 Ex. 1005, ¶ 20; Ex. 1016, 2130-2132.
`
`
`7
`
`

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`Attorney Docket No. 47291-0005PS1
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`results in the continued overproduction of 17-OHP, the continued overproduction
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`of A4 and downstream androgens, and a continued cortisol deficiency.12
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`The objectives of CAH treatment are two-fold: to correct cortisol hormone
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`deficiency and to control excess androgen production caused by elevated ACTH,
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`17-OHP, and A4 hormones.13 Correcting cortisol deficiency while also controlling
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`excess androgen production caused by elevated ACTH is challenging.14
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`Treating cortisol deficiency in CAH patients involves providing
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`supplemental hormones, called glucocorticoids, as replacement for the cortisol.15
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`Glucocorticoid therapy can correct cortisol deficiency in CAH patients. However,
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`the amount of glucocorticoids needed to replace deficient cortisol levels is often
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`not sufficient to reduce ACTH in CAH patients, and thus control excess A4 and
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`downstream androgen production.16 This is particularly true in the early morning
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`12 Ex. 1005, ¶¶ 15-16.
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`13 Ex. 1001, 11:1-5; Ex. 1005, ¶ 18; Ex. 1014, 7-8.
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`14 Ex. 1005, ¶¶ 19-21.
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`15 Ex. 1001, 11:1-5; Ex. 1005, ¶ 18; Ex. 1017, 4056; Ex. 1013, 4147.
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`16 Ex. 1001, 11:41-48; Ex. 1005, ¶ 19; Ex. 1006, ¶ [0066]; Ex. 1014, 8.
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`hours, because ACTH and A4 production follows a circadian pattern where the
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`highest ACTH and A4 production occurs in the early morning.17
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`
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`To address the issue of excessive ACTH, and subsequently excessive
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`downstream A4 and androgen, production in the early morning hours, physicians
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`often prescribe higher glucocorticoid doses than is needed to replace the cortisol
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`deficiency.18 However, increased glucocorticoid dosing over the long term can
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`lead to increased cardiovascular risk, weight gain, increased blood pressure,
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`glucose intolerance, and bone loss in CAH patients.19 High glucocorticoid dosing
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`can also result in elevated cortisol levels and Cushing’s syndrome, a disease
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`characterized by obesity and an increased risk of heart attack, stroke, blood clots,
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`bone loss, and type 2 diabetes.20
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`
`17 Id.
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`18 Ex. 1005, ¶ 19; Ex. 1014, 8.
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`19 Ex. 1001, 11:45-48; Ex. 1005, ¶ 19; Ex. 1014, 8.
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`20 Ex. 1005, ¶ 19; Ex. 1006, ¶ [0045].
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`There is no single standard treatment regimen for all CAH patients—the
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`types of glucocorticoid treatments, and dosing of those treatments, vary according
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`to a patient’s age, symptoms, and the severity of androgen excess.21
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`B.
`The Use of CRF1 Receptor Antagonists to Treat CAH
`As discussed above, CRF is a hormone that activates the synthesis and
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`release of ACTH from the pituitary gland.22 The CRF receptor has two main
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`subtypes, CRF1 and CRF2.23 By 2002, the literature had reported CRF as the main
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`regulator of the release of ACTH from the pituitary gland.24
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`A CRF type 1 (“CRF1”) receptor antagonist is a specific type of antagonist
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`that binds the CRF receptor and blocks or reduces the actions of CRF. By doing
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`so, CRF1 receptor antagonists can directly inhibit ACTH synthesis and secretion.25
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` Researchers proposed the use of CRF1 receptor antagonists as a potential
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`treatment for CAH before the effective filing date of the ’201 patent. For example,
`
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`21 Ex. 1001, 11:12-15; Ex. 1005, ¶ 18; Ex. 1017, 4056-57; Ex. 1013, 4140, 4147-
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`4148.
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`22 Ex. 1005, ¶ 22; Ex. 1006, ¶ [0006], Fig. 1.
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`23 Ex. 1005, ¶ 22; Ex. 1018, 270.
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`24 Ex. 1005, ¶ 22; Ex. 1019, 333; Ex. 1020, 322.
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`25 Ex. 1005, ¶ 23; Ex. 1006, ¶¶ [0006], [0040].
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`in 2001, several researchers suggested that CRF1 receptor antagonists could
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`decrease CRF and ACTH secretion, and thus eliminate the need to rely solely on
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`glucocorticoid negative feedback to prevent excessive adrenal androgen production
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`in CAH patients.26 These researchers made similar observations in journal articles
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`published in 2002 and 2005.27 Beginning in 2013, Petitioner Neurocrine
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`Biosciences embarked on an examination of the utility of CRF1 receptor
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`antagonists for the treatment of CAH.
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`Neurocrine has developed and tested two CRF1 receptor antagonists, NBI-
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`77860 and crinecerfont, for their ability to treat CAH by decreasing elevated
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`ACTH, 17-OHP, A4, and downstream adrenal androgens.
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`Neurocrine’s Phase I clinical study, published in 2016, demonstrated that
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`administration of 300 mg and 600 mg NBI-77860 reduced ACTH in the 6-10 a.m.
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`timeframe (referred to as the “morning window” to note the time of peak ACTH
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`elevation in CAH patients) by a mean of 43% and 41%, respectively, compared to
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`placebo.28 Administration of 600 mg NBI-77860 reduced mean 17-OHP levels by
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`26 Ex. 1005, ¶ 24; Ex. 1021, 130-131.
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`27 Ex. 1005, ¶ 24; Ex. 1022, 331; Ex. 1016, 2132.
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`28 Ex. 1005, ¶ 25; Ex. 1008, 1177.
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`27% compared to placebo.29 Administration of 300 mg or 600 mg of NBI-77860
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`also reduced mean A4 levels in six of the eight patients studied.30
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`Neurocrine’s Phase II study demonstrated that compared to a pre-dose
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`baseline, administering crinecerfont daily for 14 days reduced median ACTH and
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`17-OHP levels in the morning window between 53% to 66% in four dosing
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`cohorts.31 Administration of crinecerfont daily for 14 days reduced median A4
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`levels in the morning window between 21% and 64% in four dosing cohorts.32
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`IV. THE ’201 PATENT AND ITS PROSECUTION HISTORY
`A. The ’201 Patent Disclosure
`The ’201 patent discloses the use of a single CRF1 receptor antagonist, 3-4-
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`Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-
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`dimethylpyrazolo(1,5-a) pyrimidine or “Compound 1,” for treating CAH. This
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`compound is also known as tildacerfont.33 Spruce is developing tildacerfont as a
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`29 Ex. 1005, ¶ 25; Ex. 1008, 1177.
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`30 Ex. 1005, ¶¶ 25, 58; Ex. 1008, Table 3.
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`31 Ex. 1005, ¶ 52; Ex. 1009, Fig. 3.
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`32 Ex. 1005, ¶ 52-55; Ex. 1009, Fig. 3.
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`33 The ’201 patent discloses two chemical names that can be referred to as
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`“Compound 1.” Ex. 1001, 14:15-42. These two chemical names are alternative
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`Attorney Docket No. 47291-0005PS1
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`potential treatment for CAH.34 U.S. Patent No. 8,030,304 (Ex. 1012, “the ’304
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`patent”), which issued on October 4, 2011, claims tildacerfont and discloses CRF1
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`receptor antagonists as useful for treating various psychiatric and neuroendocrine
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`disorders, neurological diseases, and metabolic syndromes, including CAH.35
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`The ’201 patent repeatedly characterizes the “present invention” or “present
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`disclosure” as relating to Compound 1, i.e. tildacerfont. For example, the Abstract
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`states:
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`The present invention provides novel pharmaceutical
`compositions comprising [3]-(4-Chloro-2-(morpholin-4-yl)thiazol-5-
`yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a) pyrimidine and
`methods of using the same for the treatment of Congenital adrenal
`hyperplasia (CAH).36
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`The Summary of the Invention states:
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`The present invention provides novel pharmaceutical
`compositions comprising 3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-
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`names for the same compound, tildacerfont. See
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`https://pubchem.ncbi.nlm.nih.gov/compound/Tildacerfont; Ex. 1005, ¶ 31.
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`34 Ex. 1011, 1.
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`35 Ex. 1005, ¶ 27; Ex. 1012, 2:10-62, 44:7-10.
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`36 Ex. 1001, Abstract (emphasis added).
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`yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a) pyrimidine and
`methods using such pharmaceutical compositions for treating
`congenital adrenal hyperplasia (CAH).
`In one aspect, the present disclosure provides a method of
`treating congenital adrenal hyperplasia (CAH) in a subject in need
`thereof, comprising administering a pharmaceutical composition
`comprising Compound 1 . . . .37
`* * *
`In one aspect, the present disclosure provides a method of
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`treating congenital adrenal hyperplasia (CAH) in a subject in need
`thereof, the method comprising (i) measuring a hormone level in the
`subject in need thereof; (ii) administering Compound 1 . . . or a
`pharmaceutically acceptable salt or solvate thereof; and (iii) repeating
`steps (i) and (ii) until the hormone level reaches a pre-determined
`range followed by a maintenance therapy of a daily dosing of
`compound 1.38
`
`* * *
`In one aspect, the present disclosure provides a method of
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`improving hyperandrogenic symptoms in a subject in need thereof
`comprising administering a pharmaceutical composition comprising
`Compound 1 . . . .39
`
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`37 Ex. 1001, 1:32-40 (emphasis added).
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`38 Id., 4:45-5:2 (emphasis added).
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`39 Id., 8:37-40 (emphasis added).
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`* * *
`In one aspect, the present disclosure provides a method of
`
`treating menstrual irregularity, ovulatory dysfunction or infertility, in
`a subject in need thereof, comprising administering a pharmaceutical
`composition comprising Compound 1 . . . .40
`* * *
`In one aspect, the present disclosure provides a method of
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`improving metabolic symptoms in a subject in need thereof,
`comprising administering a pharmaceutical composition comprising
`Compound 1 . . . .41
`
`* * *
`In one aspect, the p