UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEUROCRINE BIOSCIENCES, INC.
`Petitioner
`
`v.
`
`SPRUCE BIOSCIENCES, INC.
`Patent Owner
`
`Case PGR2021-00088
`U.S. Patent 10,849,908
`
`DECLARATION OF ROBERT M. CAREY, M.D.
`IN SUPPORT OF PETITION FOR POST GRANT REVIEW OF U.S.
`PATENT NO. 10,849,908
`
`1
`
`NEUROCRINE 1005
`
`

`

`
`
`
`I.
`
`
`I, Robert M. Carey M.D., of Charlottesville, Virginia, declare that:
`
`QUALIFICATIONS AND BACKGROUND INFORMATION
`
`1. My curriculum vitae is attached hereto as Appendix A.
`
`2.
`
`I received my Bachelor of Science degree from the University of
`
`Kentucky with a major in mathematics. I received my Doctor of Medicine degree
`
`from Vanderbilt University School of Medicine. I received my post-doctoral
`
`fellowship training in endocrinology at Vanderbilt University Medical Center. I
`
`received my board certification in Endocrinology and Metabolism from the
`
`American Board of Internal Medicine in 1973.
`
`3.
`
`I am currently a Professor of Medicine in the Division of
`
`Endocrinology and Metabolism at the University of Virginia School of Medicine, a
`
`position I have held since 1980. My responsibilities as a Professor of Medicine
`
`have included clinical care, teaching, research and administration.
`
`4.
`
`I was an Attending Physician at the University of Virginia Medical
`
`Center from 1973 to 2015 and served as the Director of the Division of
`
`Endocrinology and Metabolism in the Department of Medicine from 1978 to 1986.
`
`My responsibilities in these positions included leadership, fostering excellence and
`
`recruiting faculty members and fellows in the field of endocrinology. The Division
`
` 
`
`2
`
`

`

`at the University of Virginia received a ranking of 5th in the United States from US
`
`News.
`
`5.
`
`I served as Dean of the University of Virginia School of Medicine
`
`from 1986 to 2002 and have served as Dean, Emeritus since 2002. As Dean, I was
`
`recognized for transforming academic medicine through building faculty and
`
`student excellence, promoting collaboration with other schools of the University
`
`and creating a professional environment that is welcoming and exciting for all. I
`
`received the Thomas Jefferson Award, the highest award of the University of
`
`Virginia, in 2003 after completion of the deanship.
`
`6.
`
`I have extensive experience in endocrinology and metabolism, with
`
`special expertise in adrenal disorders, including congenital adrenal hyperplasia
`
`(CAH), disorders of aldosterone production and Cushing’s syndrome. I have
`
`focused my clinical interest on cardiovascular endocrinology, adrenal disorders
`
`and hypertension, and my research on the hormonal control of blood pressure and
`
`hypertension. I have maintained a highly productive NIH-funded research
`
`program since 1973. Significant discoveries from my laboratory include
`
`documentation the first case of ectopic corticotropin releasing hormone secretion
`
`as a cause of Cushing’s syndrome, clarifying the mechanisms by which primary
`
`aldoteronism causes high blood pressure, and determining that increased
`
`aldosterone production accounts for a large proportion of patients with primary
`
` 
`
`3
`
`

`

`(essential) hypertension. Additionally, I have lectured on various aspects of
`
`endocrinology around the world.
`
`7.
`
`In 2008-2009, I served as President of the Endocrine Society. As
`
`President, I founded the Endocrinology and Society and the Scientific Statements
`
`programs of the Society.
`
`8.
`
`I currently serve on the editorial board of the Federation of American
`
`Societies for Experimental Biology (FASEB) Journal, Current Opinion in
`
`Endocrinology, Journal of Clinical Hypertension, Physiological Medicine, Current
`
`Hypertension Reports, Current Hypertension Reviews, and Hypertension journals,
`
`and I am an Expert Advisor for the Breakthroughs in Bioscience publication series
`
`with the Federation of American Societies for Experimental Biology.
`
`9. I have authored or co-authored over 400 scientific articles and forty-
`
`four book chapters. I am also the author/editor of four books.
`
`10.
`
`I am an Elected Member of the American Society for Clinical
`
`Investigation, the American Clinical and Climatological Association, the
`
`Association of American Physicians, and the National Academy of Medicine. I am
`
`a Master of the American College of Physicians, a Fellow of the Royal College of
`
`Physicians of London, and a Fellow of the Royal College of Physicians of Ireland.
`
`From 1997 to 2003, I was a member of the Board of Directors of the Hormone
`
`Foundation. I was a Member of the American Board of Internal Medicine,
`
` 
`
`4
`
`

`

`Subspecialty Board of Endocrinology and Metabolism from 1985 to 1990. I have
`
`received both the Distinguished Physician Award and the Outstanding Leadership
`
`in Endocrinology Award from the Endocrine Society.
`
`II.
`
`COMPENSATION
`
`11.
`
`I am being compensated at my customary rate of $1000 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
`
`12.
`
`In writing this Declaration, I have considered the following:
`
`Exhibit
`Number
`1001
`
`1002
`
`1003
`1004
`1006
`
`1007
`
`1008
`
`1009
`
` 
`
`Citation
`
`U.S. Patent No. 10,849,908 to Alexis Howerton, et al. (“the
`‘908 patent”)
`Prosecution History of the ‘908 Patent (“the Prosecution
`History”)
`Application No. PCT/US2018/046760.
`U.S. Provisional Application Serial No. 62/545,406.
`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”).
`
`
`
`
`
`
`
`5
`
`

`

`1010
`
`1011
`
`1012
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`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”)
`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
`
` 
`
`6
`
`

`

`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”).
`“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”).
`
`7
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
` 
`
`

`

`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`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).
`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).
`
`TECHNOLOGY BACKGROUND
`
`
`
`
`A. Congenital Adrenal Hyperplasia
`
`13. Congenital adrenal hyperplasia (“CAH”) is a group of autosomal
`
`
`
`IV.
`
`recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenic
`
`pathway that leads to impaired cortisol biosynthesis. The most common form of
`
`CAH is caused by mutations in CYP21A2, the gene encoding the adrenal steroid
`
`21-hydroxylase enzyme, also referred to as the P-450 c21 hydroxylase enzyme.
`
`EX. 1013 at 4134. 21-hydroxylase enzyme deficiency accounts for over 90% of
`
`CAH diagnoses. Id. at 4134. There is a continuum of 21-hydroxylase enzyme
`
`deficiency, with the more severe forms referred to as “classic CAH” and a milder
`
`form, which is often diagnosed in late childhood or early adulthood, and is referred
`
`to as “non-classical CAH.” EX. 1006 at ¶ [0004]. Classic CAH occurs in between
`
` 
`
`8
`
`

`

`1 in 10,000 to 1 in 20,000 persons. EX. 1024 at 1248. The prevalence of non-
`
`classic CAH ranges from 1 in 200 persons to 1 in 1,000 persons. Id. The
`
`underlying endocrinological mechanism for the classic and non-classic forms of
`
`21-hydroxylase enzyme deficiency are the same. A less frequent form of CAH,
`
`among others, is caused by mutation of the 11β-hydroxylase gene CYP11B1. EX.
`
`1006 at ¶ [0004]; EX. 1015 at 2195.
`
`14.
`
`In persons with normal adrenocortical steroid production, cholesterol
`
`is converted by a number of different enzymes into various adrenocortical steroids,
`
`including aldosterone, cortisol, and androstenedione. EX. 1015 at 2196.
`
`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 and plasma sodium (Na+) and potassium (K+) levels. Cortisol is a
`
`glucocorticoid steroid hormone, which plays an important role in regulating blood
`
`sugar, immune responses, metabolism of fat, protein, and carbohydrates, and
`
`regulation of bone formation. Androstenedione is a common precursor of the
`
`androgen and estrogen sex hormones.
`
`15.
`
`I have included a diagram below showing normal adrenocortical
`
`steroid production, which I created and have used in lectures. In persons without
`
`CAH, the pathway below produces the appropriate (physiologic) amount of
`
` 
`
`9
`
`

`

`androgens, mineralocorticoids, and glucocorticoids necessary for normal growth
`
`and function.
`
`
`
`Adapted from EX. 1015 at 2196-2197, Fig. 2(A).
`
`16.
`
`In persons with 21-hydroxylase enzyme deficiency CAH, the deficient
`
`P-450 c21 hydroxylase enzyme cannot convert progesterone and 17-OH-
`
`progesterone (“17-OHP”) into the precursor hormones for aldosterone and cortisol,
`
`leading to a deficiency in those steroid hormones. EX. 1015 at 2196-2197, Fig.
`
`2(B). The defective cortisol production reduces the normal negative feedback to
`
`the hypothalamus and pituitary gland, resulting in excessive secretion of
`
` 
`
`10
`
`

`

`corticotrophin-releasing hormone from the hypothalamus and, consequently,
`
`adrenocorticotropic hormone (“ACTH”) from the pituitary gland, which signals the
`
`adrenal gland to produce cortisol. EX. 1014 at 1. Because persons with 21-
`
`hydroxylase enzyme deficiency CAH cannot produce an adequate amount of
`
`cortisol, this feedback loop results in ACTH-stimulated overproduction of
`
`precursor hormones, in particular 17-OH progesterone (17-OHP), and excess
`
`androgen production because there is no block in the steroidogenic pathway
`
`synthesizing adrenal androgens. EX. 1015 at 2295-2296. These patients remain
`
`glucocorticoid-deficient, which in turn continues the overproduction of ACTH, and
`
`subsequently the overproduction of 17-OHP and downstream androgens.
`
`17. The diagram below, which I created and have used in lectures, shows
`
`the steroidogenic pathway in patients with 21-hydroxylase enzyme deficiency
`
`CAH. The red line depicts the steroidogenic blockade in the cortisol
`
`(glucocorticoid) and aldosterone (mineralocorticoid) biosynthetic pathways due to
`
`21-hydroxylase deficiency. The red arrows illustrate the overproduction of
`
`pregnenolone from cholesterol, via stimulation by ACTH, and the overproduction
`
`of 17-OHP and downstream androgens as a result of the deficient P-450 c21
`
`hydroxylase enzyme.
`
` 
`
`11
`
`

`

`
`
`Adapted from EX. 1015 at 2196-2197, Fig. 2(B).
`
`18. The treatment of patients with CAH requires correcting both the
`
`glucocorticoid and mineralocorticoid deficiencies, and reducing the elevated
`
`ACTH production from the pituitary gland which drives increased androgen
`
`production. EX. 1001 at 11:1-5; EX. 1014 at 7. Supplemental glucocorticoid
`
`replacement is the current standard of care for adults with CAH, and has been the
`
`standard of care for many decades. EX. 1001 at 11:1-5; EX. 1017 at 4056; EX.
`
`1013 at 4147. However, there is no single standard treatment regimen for all CAH
`
`patients—the types of glucocorticoid or other steroid treatments, and dosing of
`
` 
`
`12
`
`

`

`those treatments, vary according to a patient’s age, symptoms, and severity of
`
`CAH, and the response to hormone replacement therapy. For example, the
`
`Endocrine Society recommends the use of shorter acting hydrocortisone and
`
`recommends against using longer acting glucocorticoid treatment in growing
`
`patients with CAH, but recommends either hydrocortisone or longer acting
`
`glucocorticoids for adult CAH patients. EX. 1017 at 4056; EX. 1013 at 4140,
`
`4147. Mineralocorticoid replacement is also needed in some patients to maintain
`
`blood pressure and electrolyte balance. EX. 1001 at 11:12-15; EX. 1017 at 4056-
`
`57; EX. 1013 at 4147-4148.
`
`19. Glucocorticoid treatment regimens must ensure that sufficient cortisol
`
`is available to support normal human physiology. EX. 1001 at 11:16-19.
`
`However, glucocorticoid dosing that is sufficient to normalize physiologic function
`
`is often insufficient to reduce the early morning surge in ACTH, which is the
`
`principal driver of adrenal androgen overproduction. Id. at 11:41-48; EX. 1014 at
`
`8. The release of ACTH from the pituitary gland follows a circadian pattern, with
`
`the release typically occurring between 1-2 a.m. in most patients, although exact
`
`timing of the release of ACTH can vary somewhat by individual. EX. 1006 at ¶
`
`[0066]. The typical release of ACTH in the early morning hours leads to elevated
`
`ACTH levels throughout the morning in CAH patients. In order address the issue
`
`of excessive ACTH and androgen production, physicians often resort to
`
` 
`
`13
`
`

`

`prescribing supraphysiological (i.e., larger) glucocorticoid doses. EX. 1014 at 8.
`
`However, increased exposure to glucocorticoids can lead to increased
`
`cardiovascular disease risk, glucose intolerance, and bone loss in CAH patients.
`
`Id.; EX. 1001 at 11:45-48. Elevated cortisol levels resulting from excessive
`
`glucocorticoid dosing can also lead to Cushing’s syndrome. EX. 1006 at ¶ [0045].
`
`20.
`
`In addition to the problems associated with overexposure to
`
`glucocorticoids, insufficient cortisol levels in CAH patients can lead to the
`
`development of adrenal insufficiency. EX 1001 at 11:20-21. Treatment that fails
`
`to reduce the elevated ACTH levels observed in CAH patients also results in many
`
`problems associated with overproduction of androgens, including abnormal
`
`puberty and growth, hirsutism (excessive hair growth), virilization and infertility.
`
`EX. 1016 at 2130-2132.
`
`21. The diagram below, which I have used in lectures, summarizes the
`
`difficulties associated with the current glucocorticoid treatment standard for CAH
`
`patients. If a patient receives only sufficient glucocorticoid replacement necessary
`
`to support normal physiology, that patient will be likely to have excessive
`
`androgen levels associated with the overproduction of ACTH and experience the
`
`problems associated with virilization. If a patient receives sufficient glucocorticoid
`
`dosing to suppress elevated ACTH levels at all times, and consequently reduce 17-
`
`OHP and androgen production, the patient will be likely to experience problems
`
` 
`
`14
`
`

`

`associated with excessive cortisol levels and the development of exogenous
`
`Cushing’s syndrome. It is difficult for the treating physician to balance these
`
`competing concerns using the current glucocorticoid treatment recommendations
`
`for CAH patients.
`
`
`
`
`
`
`
`B. The Use of CRF1 Receptor Antagonists to Treat CAH
`
`22. Corticotropin-releasing hormone (“CRH”), also known as
`
`corticotropin-releasing factor (“CRF”), is a polypeptide hormone that activates the
`
`biosynthesis and release of ACTH from the pituitary gland. EX. 1006 at ¶ [0006];
`
` 
`
`15
`
`

`

`Fig. 1. The terms CRH and CRF are used interchangeably, and references to CRH
`
`or CRF in the scientific literature refer to the same hormone. The CRF receptor
`
`has two main subtypes, CRF1 and CRF2. EX. 1018 at 270. By 2002, the literature
`
`had reported CRF as the main regulator of the release of ACTH from the pituitary
`
`gland. EX. 1019 at 333; EX. 1020 at 322.
`
`23.
`
` A CRF1 receptor antagonist is a specific type of antagonist that binds
`
`the CRF receptor and blocks or reduces the actions of CRF. By doing so, CRF1
`
`receptor antagonists can directly inhibit ACTH synthesis and secretion in patients
`
`with CAH, thereby allowing normalization of androgen production while using
`
`lower, more physiologic doses of glucocorticoids, and reducing the treatment-
`
`associated side effects discussed above. EX. 1006 at ¶¶ [0006], [0040].
`
`24. By the early 2000s, the use of CRF1 receptor antagonists as a
`
`potential treatment for CAH had been proposed in the published literature. In a
`
`2001 article entitled New Ideas for Medical Treatment of Congenital Adrenal
`
`Hyperplasia, Drs. Deborah Merke and Gordon Cutler proposed CRF1 receptor
`
`antagonists as a treatment which could dramatically improve the treatment of CAH
`
`by eliminating the need to rely solely on glucocorticoid negative feedback to
`
`prevent excessive adrenal androgen production, and noted that preclinical results
`
`with a CRF1 receptor antagonist were promising. EX. 1021 at 130-131. In a 2002
`
`article published in the Annals of Internal Medicine, Drs. Merke and Bornstein
`
` 
`
`16
`
`

`

`noted that a CRF1 receptor antagonist, in combination with glucocorticoid and
`
`mineralocorticocod therapy, could obviate the need for treatments such as
`
`antiandrogen-aromatase inhibitors or removal of a patient’s adrenal glands, and
`
`reported that early preclinical results with a CRF1 receptor antagonist were
`
`promising. EX. 1022 at 331. These physicians made a similar observation in a
`
`2005 article published in Lancet. EX. 1016 at 2132.
`
`25.
`
`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. EX. 1008. The study found that administration of 300 mg and
`
`600 mg doses of NBI-77860 resulted in meaningful reductions in ACTH and 17-
`
`OHP in six of eight patients. Id. at 1179-1180. Compared to placebo,
`
`administration of 300 mg and 600 mg NBI-77860 reduced ACTH in the 6-10 a.m.
`
`timeframe (referred to as the “morning window” to note the time of peak ACTH
`
`elevation in CAH patients) by a mean of 43% and 41%, respectively. Id. at 1177.
`
`Administration of 600 mg NBI-77860 reduced 17-OHP by a mean of 27%
`
`compared to placebo. Id.
`
`26. Several CAH review articles also cited the Turcu et al. study as
`
`showing that a CRF1 receptor antagonist lowered ACTH and 17-OHP
`
` 
`
`17
`
`

`

`concentrations in patients with 21-hydroxylase deficiency CAH. EX 1015 at 2206;
`
`EX 1014 at 8; EX. 1025 at 6; EX. 1026 at 464.
`
`27. U.S. Patent No. 8,030,304 (the “’304 patent”), entitled “Thiazole
`
`Pyrazolopyrimidines CRF1 Receptor Antagonists” issued on October 4, 2011. EX.
`
`1012. The ’304 patent discloses a class of CRF1 receptor antagonists for the
`
`treatment of various psychiatric and neuroendocrine disorders, neurological
`
`diseases, and metabolic syndrome. Id. at 2:10-62. Tildacerfont, which is currently
`
`being developed by Spruce Biosciences for the treatment of CAH, is included in
`
`the described class of CRF1 receptor antagonists, and is explicitly identified by
`
`chemical name in claim 9 of the ’304 patent. Id. at 44:7-10; EX. 1011. The ’304
`
`patent discloses that the class of CRF1 receptor antagonists described can be used
`
`for treating CAH, among other diseases. EX. 1012 at 2:51-56.
`
`28. Neurocrine Biosciences filed PCT Patent Application No.
`
`PCT/U2015/012315, entitled CRF1 Receptor Antagonists for the Treatment of
`
`Congenital Adrenal Hyperplasia, on January 21, 2015. EX. 1006. The application
`
`published on January 26, 2017 as Publication No. US 2017/0020877. Id. US
`
`2017/0020877 to Grigoriadis (“Grigoriadis”) discloses that “CRF 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
`
` 
`
`18
`
`

`

`side effects.” Id. at Abstract, ¶¶ [0006], [0040]. Grigoriadis discloses a number of
`
`specific CRF1 receptor antagonists as useful for the treatment of CAH, including
`
`NBI-77860 and 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]. Id. at ¶¶ [0051], [0054]. SSR-125543 is also known as
`
`crinecerfont.1 Crinecerfont is currently being developed by Neurocrine
`
`Biosciences for the treatment of CAH. EX. 1027 at 2.
`
`29. Grigoriadis discloses dosing regimens for the CRF1 receptor
`
`antagonists. EX. 1006 at ¶¶ [0063], [0091]. Grigoriadis also describes
`
`pharmaceutical compositions comprising the disclosed CRF1 receptor antagonists.
`
`Id. at ¶¶ [0061], [0073], [0074]. Grigoriadis also discloses the timing of CRF1
`
`receptor antagonist administration, and the administration of glucocorticoids along
`
`with the CRF1 receptor antagonists. Id. at ¶¶ [0066], [0070], [0091]. Grigoriadis
`
`also discloses the Neurocrine clinical study that evaluated NBI-77860 in CAH
`
`patients, and the study results showing consistent and clinically meaningful
`
`reductions from predose levels of both 17-OHP and ACTH observed throughout
`
`the post-dose period following administration of NBI-77860 relative to placebo in
`
`these patients. Id. at ¶¶ [0090]-[0093], Fig. 5. The data presented in Grigoriadis
`
` 
`1 See https://pubchem.ncbi.nlm.nih.gov/compound/5282340.
`19
`
` 
`
`

`

`are from the same study reported by Turcu et al. in their 2016 article in the Journal
`
`of Clinical Endocrinology and Metabolism. Ex. 1008.
`
`V.
`
`THE ’908 PATENT
`
`30.
`
`I have reviewed the ’908 patent and its prosecution history. The ’908
`
`patent issued on December 1, 2020. Spruce Biosciences, Inc. (“Spruce”) is listed
`
`as assignee on the front page of the ’908 patent.
`
`31. The technology described in the ’908 patent relates to the use of a
`
`particular corticotropin releasing factor (“CRF1”) receptor antagonist—4-Chloro-
`
`2-(morpholin-4-yl) thiazol5-yl)-(1-ethylpropyl-2,5-dimethyl pyrazolo(1,5-a)
`
`pyrimidine—to treat CAH. This compound is also known as tildacerfont.2
`
`Tildacerfont is being developed by Spruce as a potential treatment for CAH. Ex.
`
`1011 at 1.
`
`32. All of the disclosure in the ’908 patent relates to the use of
`
`tildacerfont (Compound 1) to treat CAH. For example, the Summary of the
`
`Invention section of the ’908 patent states “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 using
`
` 
`2 The ’908 patent discloses two chemical names that can be referred to as
`“Compound 1.” (Ex. 1001, at 14:15-42.) These two chemical names are
`alternative names for the same compound, tildacerfont. See 
`https://pubchem.ncbi.nlm.nih.gov/compound/Tildacerfont.  
`20
`
` 
`
`

`

`such pharmaceutical compositions for treating congenital adrenal hyperplasia
`
`(CAH).” EX. 1001 at 1:30-38. All of the Examples in the ’908 patent relate to
`
`tildacerfont (Compound 1). Id. at 34:5-47:58. The only clinical data reported in
`
`the ’908 patent are from Phase I and Phase II studies evaluating tildacerfont. Id. at
`
`Tables 5-8, 43:49-44:5. Taken as a whole, I understand the ’908 patent to disclose
`
`the use of tildacerfont for the treatment of CAH. This is consistent with my
`
`understanding that Spruce is developing tildacerfont for the treatment of CAH.
`
`33.
`
`I understand from counsel for Petitioner that the claims of the ’908
`
`patent define the scope of the legal rights of the patent. Unlike the description and
`
`data in the ’908 patent, which disclose only the use of tildacerfont, the ’908 patent
`
`claims recite methods of treating CAH by administering a therapeutically effective
`
`amount of a CRF1 receptor antagonist. EX. 1001 at 48:5-49:15. In my opinion,
`
`this constitutes a significant difference. There is no disclosure of the use of any
`
`CRF1 antagonist other than tildacerfont to treat CAH in the ’908 patent.
`
`VI.
`
`
`
`LEVEL OF KNOWLEDGE OF ONE OF ORDINARY SKILL IN THE
`ART PERTAINING TO THE ’908 PATENT
`
`34. Based on my review of the ‘908 patent specification, the patent
`
`prosecution history, the prior art, and my experience and general knowledge, a
`
`hypothetical person of ordinary skill in the art of the ’908 patent would have a
`
`medical degree or a Ph.D. in a field related to endocrinology, and would have
`
` 
`
`21
`
`

`

`knowledge of hormone regulation and disorders, and knowledge of the treatment
`
`regimens employed to treat such disorders. The hypothetical person of ordinary
`
`skill would also have at least three years of experience conducting research
`
`concerning endocrine disorders, including CAH and other adrenal disorders.     
`
`VII.
`
`INTERPRETATION OF THE ’908 CLAIMS AT ISSUE
`
`35.
`
`I have been informed by counsel for the Petitioner that for purposes of
`
`my analysis, the terms appearing in the ’908 patent claims should be interpreted
`
`according their ordinary and customary meaning as understood by a person of
`
`ordinary skill in this art in view of the patent’s disclosure and prosecution history.
`
`I have been asked to explain how a skilled artisan would understand several terms
`
`in the ’908 patent claims.
`
`A. “Baseline”/ “From Baseline”
`
`36. The term “baseline” appears in ’908 patent independent claims 1 and
`
`11. Claim 1 requires that a human’s ACTH levels are reduced by at least 10%
`
`“from baseline” after administration of a CRF1 receptor antagonist. Claim 11
`
`requires that a human’s 17-OHP levels are reduced by at least 10% “from baseline”
`
`after administration of a CRF1 receptor antagonist.
`
`37.
`
`In my opinion, a skilled artisan would understand the term “baseline”
`
`in the ’908 patent to mean a measurement of a patient’s ACTH or 17-OHP levels
`
`prior to the administration of a CRF1 receptor antagonist. The typical meaning of
`
` 
`
`22
`
`

`

`“baseline” in this field is a measurement prior to the administration of a study drug.
`
`The description in the ’908 patent is consistent with this ordinary meaning.
`
`38. The only clinical data in the ’908 patent relating to ACTH or 17-OHP
`
`levels are present in Example 4 and Figures 2-3. EX. 1001 at 43:49-67; Figs. 2-3.
`
`Example 4 describes a Phase II study in which 10 adult patients with classic CAH
`
`were administered tildacerfont (Compound 1) for up to 6 weeks. Id. at 42:1-11.
`
`The ’908 patent reports that patients had overnight pharmacokinetic and
`
`pharmacodynamic (“PK/PD”) assessments performed “at baseline”, which
`
`included a pre-dose overnight assessment and a post-dose overnight assessment
`
`following administration of the first dose. Id. at 42:12-16. “PD” is an abbreviation
`
`for pharmacodynamic. Pharmacodynamic assessments in the study of CAH
`
`include measurement of ACTH and 17-OHP levels. I understand from this
`
`description in the ’908 patent that ACTH and 17-OHP measurements performed
`
`“at baseline” were taken prior to administration of tildacerfont, the CRF1 receptor
`
`antagonist.
`
`39. Figures 2 and 3 of the ’908 patent present change in the patients’
`
`ACTH and 17-OHP levels “from baseline.” EX. 1001 at Figs. 2-3. The ’908
`
`patent describes Figure 2 as demonstrating “the attenuation of ACTH across
`
`different subjects due to the administration of Compound 1.” Id. at 10:23-24. The
`
`’908 patent describes Figure 3 as demonstrating “the reduction in 17-OHP due to
`
` 
`
`23
`
`

`

`the administration of Compound 1.” Id. at 25-26. This description further
`
`indicates that “baseline” in the ’908 patent refers to the patient’s hormone levels
`
`prior to administration of the CRF1 receptor antagonist, consistent with the typical
`
`use of the term in this field.
`
`40. A CAH patient’s “baseline” for purposes of studying a new treatment
`
`such as a CRF1 receptor antagonist would typically include measurements while
`
`the patient was taking steroid treatment. Steroid (glucocorticoid) treatments, such
`
`hydrocortisone, are the current standard of care for adults with CAH and have been
`
`the standard of care for many decades. EX. 1017 at 4056; EX. 1013 at 4147.
`
`Patients participating in a clinical study would not be withdrawn from their
`
`glucocorticoid or hydrocortisone medications during the course of that study, due
`
`to the high risk of unregulated hormone levels and acute adrenal insufficiency
`
`discussed above. The ’908 patent discloses that in the Phase II stu