UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEUROCRINE BIOSCIENCES, INC.
`Petitioner
`
`v.
`
`SPRUCE BIOSCIENCES, INC.
`Patent Owner
`
`U.S. Patent 12,115,166
`
`DECLARATION OF MAYA LODISH, M.D.
`
`IN SUPPORT OF PETITION FOR POST GRANT REVIEW OF U.S.
`PATENT NO. 12,115,166
`
`1
`
`NEUROCRINE-1003
`
`

`

`I, Maya Lodish, M.D., of San Francisco, California, declare that:
`
`I.
`
`QUALIFICATIONS AND BACKGROUND INFORMATION
`1. My curriculum vitae is attached hereto as Appendix A.
`
`2.
`
`I earned a B.A. degree in Biochemistry and Molecular Biology at
`
`Dartmouth College in 1998. I then earned an M.D. from Yale University School of
`
`Medicine in 2003. I also hold a Masters in Health Science from Duke University,
`
`which I earned in 2013. After receiving my M.D., I completed my internship and
`
`residency in pediatrics at John Hopkins Hospital in Baltimore, Maryland from
`
`2003 to 2006. I then completed a fellowship in pediatric endocrinology at the
`
`National Institutes of Health in Bethesda, Maryland from 2006 to 2009.
`
`3.
`
`I am currently a Professor of Clinical Pediatrics and hold the Selna
`
`Kaplan Distinguished Professorship in Pediatric Endocrinology/Diabetes at the
`
`University of California, San Francisco (UCSF), a position I have held since 2018.
`
`Since 2019, I have also served as the Chief of the Division of Endocrinology at
`
`UCSF. Prior to these positions, I served as a Deputy Program Director, Staff
`
`Clinician, Program Director, and Associate Research Physician at the Eunice
`
`Kennedy Shriver National Institute of Child Health and Human Development
`
`(NICHD), positions I held from 2009 to 2018.
`
`4.
`
`As part of my position at UCSF, I teach medical students, residents,
`
`and fellows in formal courses, including foundational courses/lectures on the
`
`2
`
`

`

`thyroid; lectures on disorders of the adrenal glands, pituitary glands, and
`
`hypothalamus; lectures on diabetes; as well as lead small groups of students on a
`
`variety of topics. I lecture to students, residents, nursing students, and pediatric
`
`endocrinology fellows, as well adult endocrinology and reproductive
`
`endocrinology fellows. I also helped to draft the curriculum content guidelines for
`
`the American Board of Pediatrics subspecialty content in Pediatric Endocrinology.
`
`I have had the privilege of serving as a mentor to over 40 students, fellows in
`
`training, and junior faculty members, many of whom have had first author
`
`publications and gone on to successful academic careers.
`
`5.
`
`I am and have been certified by the American Board of Pediatrics
`
`since 2006, as well as the American Board of Pediatrics Sub-board of Pediatric
`
`Endocrinology since 2009. I am currently licensed to practice medicine in
`
`California. I have also held licenses to practice medicine in Maryland and Virginia.
`
`6.
`
`In addition to teaching, I attend in the pediatric endocrinology clinic
`
`and on the inpatient pediatric endocrinology consult service (with medical
`
`students, residents, and fellows). I collaborate with the UCSF hereditary cancer
`
`clinic for management of children with a predisposition to endocrine tumors. I
`
`also collaborate with the division of pediatric oncology, to provide endocrine care
`
`to survivors of childhood cancer and to neuro-oncology patients.
`
`3
`
`

`

`7.
`
`In my career, I have been invited by numerous universities and
`
`institutions around the world to present lectures on pediatric endocrinology. I have
`
`authored or co-authored over 140 scientific articles, 8 book chapters, and 3 books.
`
`8.
`
`At UCSF, I am the principal clinical investigator for studies of novel
`
`therapeutics in pediatric endocrinology, including four active protocols. These
`
`include a phase II study of the use of osilodrostat in children with Cushing’s
`
`disease, a phase III study of a once-yearly GnRH agonist in children with
`
`precocious puberty, a phase IV study of long-acting growth hormone in children
`
`with short stature, and a randomized comparative study between liquid and tablet
`
`formulations of levothyroxine in neonates and infants with congenital
`
`hypothyroidism. I previously served as a co-investigator on an efficacy and safety
`
`study of palovarotene for the treatment of fibrodysplasia ossificans progressive.
`
`9.
`
`During my time at the NIH, I was the primary investigator of a study
`
`evaluating mifepristone in children with refractory Cushing’s disease, as well as
`
`primary investigator of a study evaluating the safety and efficacy of pegvisomant
`
`in children with growth hormone excess. I was also a co-investigator on a clinical
`
`trial studying the use of vandetanib to treat children and adolescents with
`
`medullary thyroid cancer.
`
`10.
`
`I have a been a Principal Investigator in numerous clinical trials. I
`
`helped to design the Phase III clinical trial design of crinecerfont in pediatric CAH
`
`4
`
`

`

`patients and went on to serve as a Principal Investigator. I am an author of the New
`
`England Journal of Medicine article reporting the result of that study. See EX1053.
`
`I continue to serve as primary investigator in the open label extension of this trial.
`
`11.
`
`I currently serve as a reviewer for various medical journals including
`
`the Journal of the American Medical Association, Lancet, Thyroid, Endocrine,
`
`Endocrinology, Diabetes and Metabolism Case Reports, the Journal of Pediatrics,
`
`Molecular and Cellular Endocrinology, and others. I have previously served on
`
`the editorial board of the Journal of Clinical Endocrinology & Metabolism.
`
`12.
`
`I am a member of the Endocrine Society and the Pediatric Endocrine
`
`Society, where I have served on various committees and subcommittees.
`
`II.
`
`COMPENSATION
`13.
`I am being compensated at my customary rate of $550 per hour for
`
`my work in this matter. My compensation is in no way based on the outcome of
`
`this matter and has not influenced my views in this matter.
`
`III.
`
`MATERIALS CONSIDERED
`14.
`In writing this Declaration, I have relied on my background,
`
`education, and experience as physician, both in treating patient with endocrine
`
`disorders, including CAH, and studying the treatment of such disorders in clinical
`
`trials. I have also considered, in whole or in part, the following documents in
`
`forming my opinion in this matter.
`
`5
`
`

`

`Exhibit No.
`
`1001
`
`1002
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1013
`
`1014
`
`1015
`
`1016
`
`Exhibit Description
`U.S. Patent No. 12,115,166 to Alexis Howerton, et al. (“the
`’166 patent”).
`U.S. Prosecution History of the ’166 Patent.
`Part 1, 1-624
`Part 2, 625-1248
`Part 3, 1249-1872
`Part 4, 1873-2182
`Part 5, 2183-2495
`Part 6, 2496-2119
`Final Written Decision, Paper 64, Neurocrine Biosciences, Inc.
`v. Spruce Biosciences, Inc., No. PGR2021-00088 (PTAB Nov.
`27, 2024).
`U.S. Patent Application Publication No. 2017/0020877 to
`Grigoriadis et al. (“Grigoriadis”).
`Final Written Decision, Paper 62, Neurocrine Biosciences, Inc.
`v. Spruce Biosciences, Inc., No. PGR2022-00025 (PTAB Nov.
`26, 2024).
`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):1174-80
`(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. 1-12 (2021) (“Auchus
`2021”).
`Speiser et al., “Congenital Adrenal Hyperplasia Due to Steroid
`21-Hydroxylase Deficiency: An Endocrine Society Clinical
`Practice Guideline,” J. Clin. Endocrinol. Metab., 95(9):4133-60
`(2010) (“Speiser 2010”).
`Turcu A.F. & Auchus R.J., “The Next 150 Years of Congenital
`Adrenal Hyperplasia,” J. Steroid. Biochem. Mol. Biol., 153:63-
`71 (Sept. 2015) (“Turcu & Auchus 2015”).
`El Maouche et al., “Congenital Adrenal Hyperplasia,” Lancet
`390:2194-10 (2017) (“El Maouche 2017”).
`Merke D.P. & Bornstein S.R., “Congenital Adrenal
`Hyperplasia,” Lancet, 365:2125-36 (2005) (“Merke & Bornstein
`2005”).
`
`6
`
`

`

`Exhibit No.
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1024
`
`1025
`
`1026
`
`Exhibit Description
`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-
`88 (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):333-45 (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):322-32
`(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):121-35 (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., 136:320-34 (2002) (“Merke
`2002”).
`Merke D.P. & Auchus R.J., “Congenital Adrenal Hyperplasia
`Due to 21-Hydroxylase Deficiency,” N. Engl. J. Med.
`383(13):1248-61 (2020) (“Merke & Auchus 2020”).
`Turcu A.F. & Auchus R.J., “Novel Treatment Strategies in
`Congenital Adrenal Hyperplasia,” Curr. Opin. Endocrinol.
`Diabetes Obes., 23(3):225-32 (June 2016) (“Turcu & Auchus
`2016”).
`Webb E.A. & Krone N., “Current and Novel Approaches to
`Children and Young People with Congenital Adrenal
`
`7
`
`

`

`Exhibit No.
`
`1027
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1035
`
`1039
`
`1041
`
`1044
`
`1045
`
`Exhibit Description
`Hyperplasia and Adrenal Insufficiency,” Best Pract. Res. Clin.
`Endocrinol. Metab., 29:449-68 (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 (March
`20, 2021) (“Neurocrine March 20, 2021, 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):371-83 (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):460-87 (2010). (“Kehne & Cain 2010”).
`Deore et al., “The Stages of Drug Discovery and Development
`Process,” Asian J. Pharm. R. & D., 7(6):62-67 (2019)
`(“Deore”).
`National Center for Biotechnology Information (2025),
`PubChem Compound Summary for CID 5282340, Crinecerfont.
`Retrieved February 4, 2025, from
`https://pubchem.ncbi.nlm.nih.gov/compound/Crinecerfont.
`U.S. Provisional Application Serial No. 62/545,406.
`Sarafoglou et al., “Interpretation of Steroid Biomarkers in 21-
`Hydrozylase Deficiency and Their Use in Disease
`Management,” J. Clin. Endocrinol. Metabol. 108:2154-75
`(March 2023) (“Sarafoglou 2023”).
`Sarafoglou et al., “Tildacerfont in Adults With Classic
`Congenital Adrenal Hyperplasia: Results from Two Phase 2
`Studies,” J. Clin. Endocrinol. Metabol. 106(11):e4666-79
`(2021) (“Sarafoglou 2021”).
`“Spruce Biosciences Announces Topline Results from
`CAHmelia-203 in Adult Classic CAH and CAHptain-205 in
`Pediatric Classic CAH,” Spruce Biosciences (March 13, 2024)
`(“Spruce March 13, 2024, Press Release”).
`“Spruce Biosciences Announces Topline Results from
`CAHmelia-204 in Adult CAH and CAHptain-205 in Adult and
`
`8
`
`

`

`Exhibit No.
`
`1046
`
`1047
`
`1048
`
`1049
`
`1052
`
`1053
`
`1058
`
`1059
`
`1065
`
`1066
`
`
`
`Exhibit Description
`Pediatric CAH,” Spruce Biosciences (December 10, 2024)
`(“Spruce December 10, 2024, Press Release”).
`Turcu A.F. & Auchus R.J, “Adrenal Steroidogenesis and
`Congenital Adrenal Hyperplasia,” Endocrinol. Metabol. Clin. N.
`Am., 44:275-96 (2015) (“Turcu & Auchus 2015a”).
`Mallappa A. & Merke D.P., “Management challenges and
`therapeutic advances in congenital adrenal hyperplasia,” Nature
`Reviews Endocrinol., 18:337-52 (June 2022) (“Mallappa &
`Merke”).
`Auchus et al., “Crinecerfont Lowers Elevated Hormone Markers
`in Adults With 21-Hydroxylase Deficiency Congenital Adrenal
`Hyperplasia,” J. Clin. Endocrinol. Metabol., 107(3):801-12
`(2022) (“Auchus 2022”).
`Claahsen-van der Grinten et al., “Congenital Adrenal
`Hyperplasia–Current Insights in Pathophysiology, Diagnostics,
`and Management,” Endocrine Reviews, 43(1):91-159 (2022)
`(“Claahsen-van der Grinten”).
`Auchus et al., “Phase 3 Trial of Crinecerfont in Adult
`Congenital Adrenal Hyperplasia,” N. Engl. J. Med., 391(6):504-
`14 (June 2024) (“Auchus 2024”).
`Sarafoglou et al., “Phase 3 Trial of Crinecerfont in Pediatric
`Congenital Adrenal Hyperplasia,” N. Engl. J. Med., 391(6):493-
`503 (June 2024) (“Sarafoglou et al. 2024”).
`“Neurocrine Biosciences Announces FDA Approval of
`CRENESSITY™ (crinecerfont), a First-in-Class Treatment for
`Children and Adults With Classic Congenital Adrenal
`Hyperplasia,” Neurocrine Biosciences (Dec. 13, 2024) (“Dec.
`13, 2024, Neurocrine Press Release”).
`National Center for Biotechnology Information (2025),
`PubChem Compound Summary for CID 134694266,
`Tildacerfont. Retrieved February 4, 2025, from
`https://pubchem.ncbi.nlm.nih.gov/compound/134694266.
`Sertkaya et al., “Key cost drivers of pharmaceutical trials in the
`United States,” Clin. Trials, 13(2):117-26 (2016).
`Spierling S.R. & Zorrilla E.P., “Don’t stress about CRF:
`Assessing the translational failures of CRF1 antagonists,”
`Psychopharmacology (Berl.), 234(9-10):1467-81 (May 2017).
`
`9
`
`

`

`IV.
`
`TECHNOLOGY BACKGROUND
`A. Congenital Adrenal Hyperplasia
`15. Congenital adrenal hyperplasia (CAH) refers to a group of inherited
`
`
`
`autosomal recessive disorders affecting cortisol biosynthesis. EX1049, 93;
`
`EX1053, 2155. Reduced cortisol production disrupts the dynamic equilibrium of
`
`the negative feedback inhibition of both hypothalamic corticotropin-releasing
`
`factor (CRF) and pituitary corticotropin, which results in hyperplasia of the adrenal
`
`cortex. EX1046, 278; EX1053, 494. Approximately 90% to 99% of all CAH cases
`
`are caused by 21-hydroxylase deficiency (21OHD) due to mutations to the
`
`CYP21A2 gene. EX1049, 93. CAH and 21OHD are often used interchangeably.
`
`EX1049, 93. CAH is conventionally separated into “classic” and “non-classic”
`
`forms, based on the severity of enzyme deficiency. EX1049, 93-94; EX1048, 802.
`
`However, current thinking views the different allelic variants of CYP21A2 and
`
`their clinical manifestations as a continuum rather than two separate entities.
`
`EX1049, 93-94; EX1006, ¶ [0004]. Classic CAH occurs in roughly 1-in-10,000 to
`
`1-in-20,000 persons. EX1024, 1248. Non-classic CAH occurs in roughly 1-in-200
`
`to 1-in-1,000 persons. Id. The underlying mechanism for the classic and non-
`
`classic forms of 21OHD are the same. Less common forms of CAH, include a
`
`mutation of the 11β-hydroxylase gene CYP11B1. EX1006, ¶ [0004]; EX1015,
`
`2195; EX1046, 279.
`
`10
`
`

`

`16.
`
`In normal adrenocortical steroid production, all steroids produced in
`
`the adrenal cortex are derived from cholesterol. EX1039, 2155. There, cholesterol
`
`is enzymatically converted into various adrenocortical steroids, including
`
`aldosterone, cortisol, and androstenedione. EX1015, 2196-97. Aldosterone is the
`
`main mineralocorticoid steroid hormone produced by the adrenal gland, and it
`
`plays a central role in the homeostatic regulation of blood pressure, plasma sodium
`
`(Na+) and potassium (K+) levels. Cortisol is a glucocorticoid steroid hormone,
`
`which plays an important role in regulating blood sugar, immune responses, bone
`
`formation, and in the metabolism of fat, protein, and carbohydrates.
`
`Androstenedione is a common precursor in the biosynthesis of androgen and
`
`estrogen sex hormones.
`
`17. The diagram below, taken from Sarafoglou (2023), depicts a
`
`simplified pathway of normal adrenocortical steroid production. In individuals
`
`without CAH, this pathway produces the appropriate amount of androgens,
`
`mineralocorticoids, and glucocorticoids necessary for normal growth and function.
`
`Further, in individuals without CAH, intermediates in this pathway do not
`
`significantly accumulate and the production of theoretical side products is minimal.
`
`EX1039, 2155.
`
`11
`
`

`

`
`
`Adapted from EX1039, 2157, Fig. 3. Cholesterol (blue box) is enzymatically converted
`into various steroids, including aldosterone, cortisol, and androstenedione (red boxes). The
`protein encoded by the CYP21A2 gene (yellow highlighting) is involved in the conversion of
`progesterone into aldosterone and 17-OHP to cortisol.
`
`18.
`
`In persons with the most common type of CAH due to 21-hydroxylase
`
`deficiency, the protein encoded by CYP21A2 cannot properly function and fails to
`
`convert progesterone into the precursor molecule for aldosterone and likewise fails
`
`to convert 17-OH-progestorone (17-OHP) into the precursor molecule for cortisol.
`
`EX1046, 280. As a result, insufficient amounts of cortisol are produced along this
`
`pathway and 17-OHP begins to accumulate both from overproduction due to
`
`ACTH signaling, as well as its inability to be broken down further due to
`
`enzymatic deficiency. EX1039, 2155. The reduction of cortisol in turn reduces
`
`the negative feedback on the hypothalamic-pituitary-adrenal axis and leads to
`
`excess adrenal androgen production, especially 17-OHP. EX1049, 94. The
`
`12
`
`

`

`accumulation of precursor steroids are then shifted to nonaffected androgen
`
`pathways or “backdoor pathway,” specifically through CYP17A1, resulting in the
`
`overproduction of androstenedione, which are then converted to the sex hormones
`
`testosterone and dihydroxytestosterone. EX1046, 280-81; EX1039, 2157.
`
`19. The diagram below, adapted from Turcu & Auchus (2015a), shows
`
`the “backdoor pathway” in patients with 21OHD. The red box labeled “21-
`
`hydroxylase deficiency” disrupts the downstream conversion of 17-OHP and
`
`progesterone into cortisol and aldosterone, respectively. Instead, excess 17-OHP is
`
`converted downstream to androstenedione (“A4”, depicted as “AD” in the diagram
`
`below) and alternative paths (green box) leading to the overproduction of sex
`
`hormones.
`
`13
`
`

`

`
`
`Adapted from EX1046, 280, Fig. 2
`
`20. Treatment of patients with classic CAH aims to reset the multiple
`
`hormonal imbalances by replacing deficient hormones (cortisol and aldosterone)
`
`and controlling adrenal androgen over-production triggered by the accumulation of
`
`precursor steroids and their metabolism by alternative androgenic pathways.
`
`EX1047, 338. Glucocorticoid replacement is the current standard of care for adults
`
`with CAH and has been the standard of care for many decades. EX1047, 338;
`
`EX1026, 456-59; EX1001, 11:27-31. But there is no single standard treatment
`
`regimen for all CAH patients—the steroid treatments used, and the dosing of those
`
`treatments, necessarily vary with a patient’s age, symptoms, severity of CAH, and
`
`14
`
`

`

`response to hormone replacement therapy. For example, hydrocortisone is the
`
`steroid predominately in children with CAH given its short half-life and lessened
`
`growth suppression. EX1047, 338-39. For adult patients with CAH, either
`
`hydrocortisone or longer acting glucocorticoids are used. EX1047, 339; EX1017,
`
`4056; EX1013, 4140, 4147. Mineralocorticoid replacement is also recommended
`
`in patients unable to help maintain normal blood volume to maintain blood
`
`pressure and electrolyte balance. EX1047, 339; EX1001, 11:38-41; EX1017,
`
`4056-57; EX1013, 4147-48.
`
`21. Glucocorticoid treatment regimens must ensure that sufficient cortisol
`
`is available to support normal human physiology. EX1001, 11:42-45. However,
`
`the short to intermediate impact of glucocorticoid is often insufficient to reduce the
`
`early morning surge in adrenocorticotropin (ACTH), which is the principal driver
`
`of downstream androgen overproduction. EX1014, 8; EX1006, ¶ [0066]. The
`
`release of ACTH from the pituitary gland follows normal circadian patterns.
`
`ACTH is typically released between 1:00 and 2:00 a.m. in most patients, although
`
`the exact timing can vary by individual sleep schedules. EX1006, ¶ [0066]. The
`
`typical release of ACTH in the early morning hours leads to elevated ACTH levels
`
`throughout the morning in CAH patients. In attempts to counteract the excessive
`
`androgen production that follows due to inappropriately high ACTH, physicians
`
`often prescribe supraphysiological (i.e., larger) glucocorticoid doses. EX1014, 8.
`
`15
`
`

`

`However, this increased exposure to glucocorticoids may lead to debilitating side
`
`effects including increased cardiovascular disease risk, glucose intolerance, and
`
`bone density loss in CAH patients. EX1014, 8; EX1001, 12:4-7. Elevated cortisol
`
`levels resulting from excessive glucocorticoid dosing can also lead to Cushing’s
`
`syndrome. EX1006, ¶ [0045].
`
`22. Beyond the problems associated with overexposure to glucocorticoids,
`
`insufficient cortisol levels in CAH patients can lead to the development of adrenal
`
`insufficiency. EX1001, 11:46-47. Failure to reduce the ACTH levels in CAH
`
`patients can result in problems associated with the overproduction of androgens,
`
`including abnormal puberty, abnormal linear growth, excessive hair growth,
`
`virilization, and infertility. EX1016, 2130-32. Balancing the risks between
`
`excessive cortisol or excessive androgens in CAH patients is difficult for
`
`physicians and patients alike.
`
`B.
`The Use of CRF1 Receptor Antagonists to Treat CAH
`23. Corticotropin-release hormone (CRH), interchangeably referred to as
`
`corticotropin-releasing factor (CRF), is a polypeptide hormone secreted by the
`
`hypothalamus that increases ACTH secretion by the pituitary gland. EX1049, 102.
`
`In turn, CRF may act directly on adrenocortical cells to increase cortisol secretion
`
`and expression of CYP21A2. EX1049, 102. CRF receptors include two main
`
`subtypes, CRF1 and CRF2. EX1018, 270. It has been understood in the field
`
`16
`
`

`

`since at least 2002 that CRF is the main regulator of the release of ACTH from the
`
`pituitary gland. EX1019, 333; EX1020, 322.
`
`24. CRF1 receptor antagonists specifically bind to CRF1, thus blocking
`
`the ability of the agonist to bind to the receptor, therefore directly reducing ACTH
`
`secretion. There are large variety of CRF1 receptor antagonists with different
`
`structural properties and different binding affinities for the receptor. In patients
`
`with CAH this could in turn decrease the downstream production of androgens and
`
`reduce symptoms of hyperandrogenism, while also potentially allowing for the
`
`administration of glucocorticoids at physiological doses. EX1048, 802. This
`
`normalization of androgen production coupled with lower doses of glucocorticoids
`
`has the potential to reduce some of the treatment-associated side effects discussed
`
`above.
`
`25. Scientific thought on CRF1 receptor antagonists as a treatment for
`
`CAH is well documented. The use of CRF1 receptor antagonists as a potential
`
`treatment for CAH has been discussed in the field since the early 2000s. For
`
`example, in a 2001 article entitled “New Ideas for Medical Treatment of
`
`Congenital Adrenal Hyperplasia,” Drs. Deborah Merke and Gordon Cutler
`
`proposed the use of CRF1 receptor antagonists to treat CAH and eliminate the need
`
`to rely solely on glucocorticoid negative feedback to prevent excessive adrenal
`
`androgen production. EX1021, 130-31. Then, in a 2002 article published in the
`
`17
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`

`

`Annals of Internal Medicine, Drs. Merke and Bornstein noted that a CRF1 receptor
`
`antagonist, in combination with glucocorticoid and mineralocorticoid therapy,
`
`could potentially obviate the need for treatments such as antiandrogen-aromatase
`
`inhibitors or removal of a patient’s adrenal glands. EX1022, 331. These
`
`observations were published again in Lancet in 2005. EX1016, 2132.
`
`26. Then in 2016, Turcu et al. published the results of a Phase I clinical
`
`study evaluating the safety and efficacy of a CRF1 receptor antagonist developed
`
`by Neurocrine Biosciences, NBI-77860, in adult patients with 21-hydroxylase
`
`enzyme deficiency CAH. EX1008. Turcu and colleagues found that
`
`administration of 300 mg and 600 mg doses of NBI-77860 resulted in meaningful
`
`reductions in ACTH and 17-OHP in 6 of 8 patients. EX1008, 1179-80. The
`
`clinical report also detailed that the administration of 300 mg and 600 mg doses of
`
`NBI-77860 reduced androstenedione levels in 6 of 8 patients. EX1008, Table 3.
`
`Compared to placebo, administration of 300 mg and 600 mg NBI-77860 reduced
`
`androstenedione in the 6:00 to 10:00 a.m. timeframe (referred to as the “morning
`
`window” to note the time of peak ACTH elevation in CAH patients) in 6 of 8
`
`patients, including one patient who achieved 57.9% reduction in androstenedione
`
`levels after a 600 mg dose and another patient who achieved a 27.9% reduction in
`
`androstenedione levels after a 300 mg dose. EX1008, Table 3.
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`18
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`

`27. Subsequently, several CAH review articles also cited the Turcu 2016
`
`study as showing that a CRF1 receptor antagonist lowered ACTH and 17-OHP
`
`concentrations in patients with 21-hydroxylase deficiency CAH. EX1015, 2205;
`
`EX1014, 8; EX1025, 6; EX1049, 123.
`
`28.
`
`In January 2015, Neurocrine Biosciences filed PCT Patent
`
`Application No. PCT/U2015/012315, entitled CRF1 Receptor Antagonists for the
`
`Treatment of Congenital Adrenal Hyperplasia. EX1006. The application published
`
`on January 26, 2017, as Publication No. US 2017/0020877. EX1006. US
`
`2017/0020877 to Grigoriadis (“Grigoriadis”) discloses that “CRF1 receptor
`
`antagonists have the potential to directly inhibit ACTH release in patients with
`
`CAH and thereby allow normalization of androgen production while using lower,
`
`more physiologic doses of hydrocortisone, and thus reducing treatment-associated
`
`side effects.” EX1006, Abstract, ¶¶ [0006], [0040]. Grigoriadis discloses a
`
`number of specific CRF1 receptor antagonists as useful for the treatment of CAH
`
`based on their dissociation half-life, including SSR-125543 [4-(2-chloro-4-
`
`methoxy-5-methylphenyl)-N-(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)
`
`ethyl-5-methyl-N-(2-propyn-1-yl)-2- thiazolamine]. EX1006, ¶¶ [0051], [0054],
`
`[0077]-[0083]. SSR-125543 is also known as crinecerfont. See EX1033.
`
`Crinecerfont was developed by Neurocrine Biosciences for the treatment of CAH
`
`(EX1027, 2) and is now FDA approved, as of December 13, 2024. EX1058.
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`19
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`

`

`29. Neurocrine has studied crinecerfont as a treatment for CAH. On
`
`October 15, 2021, Neurocrine published the results of a Phase II clinical study
`
`evaluating crinecerfont for the treatment of CAH. EX1009. The Phase II study was
`
`an open-label, multiple-dose study to access the safety, tolerability,
`
`pharmacokinetics, and pharmacodynamics of crinecerfont in adult subjects with a
`
`documented medical diagnosis of classic 21-hydroxlase deficiency CAH. Id., 2-4.
`
`The study reported that the administration of crinecerfont to CAH patients resulted
`
`in reduction of ACTH, 17-OHP and A4 levels, compared to those patients’
`
`baseline hormone levels. Id., 3-11, Tables 2-3, Figs. 2-4.
`
`30. Neurocrine also studied crinecerfont for the treatment of CAH in adult
`
`and pediatric Phase III clinical studies. EX1052; EX1053. The Phase III studies
`
`were multi-dose studies to evaluate the efficacy, safety, and tolerability of
`
`crinecerfont versus placebo administered for 28 weeks in pediatric subjects, and 24
`
`weeks in adult subjects with classic CAH due to 21-hydroxylase deficiency.
`
`EX1052; 1053. The adult Phase III study found the use of crinecerfont resulted in a
`
`greater decrease from baseline in the mean daily glucocorticoid dose, including a
`
`reduction to the physiologic range, than placebo following evaluation of adrenal
`
`androgen levels. EX1052, Abstract. The pediatric study found crinecerfont was
`
`superior to placebo in reducing elevated A4 levels in pediatric participants with
`
`CAH and was also associated with a decrease in the glucocorticoid dose from
`
`20
`
`

`

`supraphysiologic to physiologic levels while A4 control was maintained. EX1053,
`
`Abstract. Both of these Phase III studies were published in the New England
`
`Journal of Medicine. Crinecerfont was approved by the FDA on December 13,
`
`2024, as an adjunctive treatment to glucocorticoid replacement to control
`
`androgens in adults and pediatric patients 4 years of age and older with classic
`
`CAH. EX1058.
`
`31. Spruce Biosciences, Inc. (“Spruce”) has studied tildacerfont as a
`
`potential treatment for CAH. In March 2024, Spruce announced results from a
`
`Phase IIb clinical study evaluating tildacerfont for the treatment of CAH. EX1044.
`
`Tildacerfont did not meet its primary efficacy endpoint in this study. Id. On
`
`December 10, 2024, Spruce announced results from a second Phase IIb clinical
`
`study evaluating the safety and efficacy of tildacerfont in reducing
`
`supraphysiologic glucocorticoid usage in 100 adults with classic CAH. EX1045.
`
`Tildacerfont also did not meet its primary efficacy endpoint in the Phase IIb study.
`
`Id.
`
`V.
`
`THE ’166 PATENT
`32.
`I have reviewed the ’166 patent and its prosecution history. The ’166
`
`patent issued on October 15, 2024. Spruce is listed as assignee on the front page of
`
`the ’166 patent. The ’166 patent claims priority to provisional application no.
`
`62/545,406, filed on August 14, 2017. EX1001.
`
`21
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`

`

`33. The technology described in the ’166 patent relates to relates to the
`
`use of a single CRF1 receptor antagonist, Compound 1, to treat CAH. Compound 1
`
`is defined in the ’166 patent as 3- (4-Chloro-2-(morpholin-4-yl)(thiazol5-yl)-7-(1-
`
`ethylpropyl)-2,5-dimethylpyrazolo(1,5-a) pyrimidine (or alternatively 4-(4-chloro-
`
`5-(2,5 dimethyl-7-pentan-3-yl) pyrazolo[1,5-a] pyrimidin-3-yl) thiazol-2-yl)
`
`morpholine). EX1001, 1:40-44, 14:40-67. I understand that this compound is also
`
`known as tildacerfont. See EX1059.
`
`34. All the disclosure in the ’166 patent relates to the use of Compound 1
`
`(tildacerfont) to treat CAH. For example, the Summary of the Invention section
`
`states, “[t]he 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 using such pharmaceutical
`
`compositions for treating congenital adrenal hyperplasia (CAH).” EX1001, 1:40-
`
`44. When discussing methods of treating CAH that further comprise administering
`
`a glucocorticoid, the specification states “[i]n some embodiments, the amount of
`
`glucocorticoid administered is reduced as compared to a method not comprising
`
`administering Compound 1, or a pharmaceutically acceptable salt or solvate
`
`thereof.” Id., 7:50-54; see also id., 32:22-29.
`
`35. The ’166 patent specification also defines stability as the stability of
`
`Compound 1. EX1001, 25:22-28 (“Stable as used herein refers to pharmaceutical
`
`22
`
`

`

`compositions having about 95% or greater of the initial Compound 1 amount and
`
`about 5% w/w or less total impurities or related substances at the end of a given
`
`storage period. The percentage of impurities is calculated from the amount of
`
`impurities relative to the amount of Compound 1.”). All of the stability data in the
`
`’166 patent relates to pharmaceutical compositions containing Compound 1 as the
`
`active ingredient. EX1001, 34:57-36:57 (Example 2).
`
`36. All of the Examples in the ’166 patent relate to Compound 1
`
`(tildacerfont). EX1001, 33:35-47:49. The only clinical data reported in the ’166
`
`patent specification is from Phase I and Phase II studies evaluating Compound 1.
`
`Id., Tables 5-8, 44:43-67. As discussed in further detail belo