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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR POST GRANT REVIEW OF
`U.S. PATENT NO. 10,849,908
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`TABLE OF CONTENTS
`
`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 .................................................. 5
`A. Congenital Adrenal Hyperplasia (“CAH”) ............................................... 5
`B. The Use of CRF1 Receptor Antagonists to Treat CAH ........................... 9
`IV. THE ’908 PATENT AND ITS PROSECUTION HISTORY ....................... 10
`A. The ’908 Patent Disclosure ..................................................................... 11
`B. The ’908 Patent Claims ........................................................................... 15
`C. The ’908 Patent Prosecution History ...................................................... 17
`CLAIM CONSTRUCTION UNDER 37 C.F.R. §§ 42.204(b)(3) ................ 23
`A. “Baseline”/ “From Baseline” .................................................................. 23
`B. “A Human”/ “The Human” ..................................................................... 25
`C. “Maintained at a Reduced Level Post 24 Hours” ................................... 26
`D. “Administered 4 Hours Prior to Sleeping” ............................................. 27
`VI. THE CLAIMS OF THE ’908 PATENT ARE UNPATENTABLE .............. 28
`A. Grigoriadis .............................................................................................. 29
`1.
`Crinecerfont (SSR-125543) ........................................................... 30
`2. NBI-77860 ..................................................................................... 37
`B. Romano ................................................................................................... 45
`C. Ground 1: Grigoriadis Anticipates Claims 1-4, 7-9, 11-14, 17-19, and
`21-24. ...................................................................................................... 46
`1.
`The use of crinecerfont to treat CAH, as disclosed in Grigoriadis,
`inherently results in the ACTH and 17-OHP reductions from
`baseline recited in claims 1 and 11. .............................................. 46
`The use of NBI-77860 to treat CAH, as disclosed in Grigoriadis,
`results in the ACTH and 17-OHP reductions from baseline recited
`in claims 1 and 11. ......................................................................... 48
`3. Grigoriadis discloses all of the limitations of dependent claims 2-
`4, 7-9, 12-14, 17-19, and 21-24. .................................................... 51
`D. Ground 2: Claims 4, 10, 14, 20-22, and 25 Would Have Been Obvious
`in View of Grigoriadis and the Knowledge of a Skilled Artisan. .......... 59
`1.
`Level of Ordinary Skill in the Art ................................................. 60
`2.
`Claims 4, 10, 14, 20-22, and 25 Are Obvious ............................... 60
`E. Ground 3: Claims 5-6 and 15-16 Would Have Been Obvious in View of
`Grigoriadis in Combination with Romano. ............................................ 68
`
`V.
`
`2.
`
`i
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`F. Ground 4: Claims 1-25 of the ’908 Patent are Unpatentable for Lack of
`Written Description. ................................................................................ 70
`G. Ground 5: Claims 1-25 of the ’908 Patent are Unpatentable for Lack of
`Enablement. ............................................................................................ 75
`VII. DISCRETIONARY DENIAL IS NOT WARRANTED ............................... 77
`VIII. PAYMENT OF FEES – 37 C.F.R. § 42.203 ................................................. 79
`IX. CONCLUSION ................................................................................................. 79
`X. MANDATORY NOTICES UNDER 37 C.F.R § 42.8(a)(1) ............................. 79
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) .............................. 79
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2) ........................................ 80
`C. Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ................... 80
`D. Service Information ................................................................................. 80 
`
`
`
`
`
`
`ii
`
`

`

`
`
`Petitioner
`Exhibit Number
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`1013
`
`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`
`EXHIBITS
`
`Exhibit Description
`
`U.S. Patent No. 10,849,908 to Alexis Howerton, et al. (“the
`’908 patent”).
`U.S. Prosecution History of the ’908 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”).
`
`
`
`
`
`
`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
`
`iii
`
`

`

`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`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 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-
`
`iv
`
`

`

`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`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”).
`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”).
`
`v
`
`

`

`1032
`
`1033
`
`1034
`
`1035
`
`
`
`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`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).
`
`
`vi
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`
`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 1-25 (“the Challenged Claims”) of U.S. Patent No. 10,849,908 (“the ’908
`
`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.
`
`The ’908 patent broadly claims the use of CRF1 receptor antagonists to treat
`
`congenital adrenal hyperplasia (“CAH”), a group of genetic disorders impacting
`
`hormone production, but the specification describes only a single CRF1 receptor
`
`antagonist, unsurprisingly, the one compound Spruce is developing. The ’908
`
`patent is invalid because of this insufficient disclosure, and because Neurocrine’s
`
`own work on the use of CRF1 receptor antagonists to treat CAH, which is prior art
`
`to the ’908 patent, anticipates Spruce’s broad claims or renders those claims
`
`obvious.
`
`With respect to Neurocrine’s prior work, Published Application No. US
`
`2017/0020877 (Ex. 1006; “Grigoriadis”), discloses the use of a number of CRF1
`
`receptor antagonists to treat CAH, including crinecerfont, the compound
`
`Neurocrine is currently developing for the treatment of CAH, and NBI-77860, a
`
`1
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`compound Neurocrine previously studied as a CAH treatment. Grigoriadis
`
`published several years before the application that issued as the ’908 patent was
`
`filed, and the Patent Office rejected Spruce’s application over Neurocrine’s work.
`
`The only basis for allowance of the ’908 patent over Neurocrine’s prior
`
`work was the Examiner’s misunderstanding that the ability of the one CRF1
`
`receptor antagonist disclosed in the ’908 patent to maintain its effect for more than
`
`24 hours was surprising and nonobvious. As detailed in this Petition, 1) the data
`
`presented by Spruce was not, in fact, surprising; 2) data relating to other CRF1
`
`receptor antagonists that was not before the Examiner shows that the behavior of
`
`this single compound was not unique among CRF1 receptor antagonists, and; 3)
`
`most of the ’908 patent claims do not even recite the post-24 hours requirement
`
`that was basis of the purportedly surprising result. Even if the results of this single
`
`compound were surprising or unexpected (which they are not), the results are not
`
`commensurate with the scope of the ‘908 patent claims, which cover a much larger
`
`class of compounds.
`
`The broad ’908 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
`
`antagonist. The ’908 patent repeatedly characterizes “the invention” as relating to
`
`this particular compound. The patent’s disclosure does not allow persons of
`
`2
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`ordinary skill in the art to recognize that the inventor invented what is claimed (the
`
`use of a class of compounds), and does not permit skilled artisans to make and use
`
`the full scope of the claims without undue experimentation.
`
`Neurocrine respectfully submits that a PGR should be instituted, and that the
`
`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 ’908 Patent is available for PGR. The present
`
`petition is being filed within nine months of the issuance of the ’908 patent on
`
`December 1, 2020. Neurocrine has not filed a civil action challenging the validity
`
`of any claim of the ’908 patent. Neurocrine is not barred or estopped from
`
`requesting this review challenging claims 1-25 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
`
`forth in the table shown below, and requests that each of the Challenged Claims be
`
`found unpatentable.
`
`’908 Patent Claims
`Ground
`Ground 1 1-4, 7-9, 11-14, 17-19,
`21-24
`
`Ground 2 4, 10, 14, 20-22, 25
`
`Basis for Rejection
`Anticipation under 35 U.S.C. § 102 by
`Grigoriadis et al., US 2017/0020877
`(Ex. 1006; “Grigoriadis”)
`Obviousness under 35 U.S.C. § 103 in
`view of Grigoriadis and the knowledge
`of a skilled artisan
`
`3
`
`

`

`’908 Patent Claims
`Ground
`Ground 3 5-6, 15-16
`
`Ground 4 1-25
`
`Ground 5 1-25
`
`
`
`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`Basis for Rejection
`Obviousness under 35 U.S.C. § 103 in
`view of Grigoriadis in combination with
`US 2005/0209250 (Ex. 1007;
`“Romano”)
`Lack of written description under 35
`U.S.C. § 112
`Lack of enablement 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 ’908 patent, and was
`
`published before August 14, 2017, which is the earliest possible effective filing
`
`date to which claims 1-25 of the ’908 patent could be entitled.1
`
`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 ’908 patent, and was
`
`published more than one year before the ’908 patent’s earliest effective filing date
`
`
`1 Claims 1-25 are entitled to an effective filing date no earlier than April 18, 2019,
`
`and 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.
`
`4
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`of August 14, 2017. Thus, Romano is prior art to the ’908 patent.
`
`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.2 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.3
`
`
`
`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”).4 The
`
`production of CRF signals the pituitary gland to secrete another hormone,
`
`adrenocorticotropic hormone (“ACTH”).5 ACTH stimulates the production of a
`
`number of precursor hormones, in particular 17-α-hydroxyprogesterone (“17-
`
`
`2 Ex. 1005, ¶ 13; Ex. 1013, 4134.
`
` 3
`
` 4
`
` 5
`
`
`
` Ex. 1005, ¶ 14.
`
` Ex. 1005, ¶ 16; Ex. 1014, 1.
`
` Id.
`
`5
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`OHP”), that ultimately lead to the production of cortisol.6 However, CAH patients
`
`cannot convert 17-OHP to cortisol.7 As a result, CAH patients produce excess 17-
`
`OHP that cannot be converted to cortisol. 8 The continued cortisol deficiency in
`
`these patients creates a feedback loop whereby the body continues to produce CRF
`
`and ACTH, which results in the continued overproduction of 17-OHP.9
`
`In addition to being a precursor hormone to cortisol, 17-OHP is also a
`
`precursor hormone to androgens.10 Androgens are a group of hormones, such as
`
`testosterone, that regulate the development of male characteristics and reproductive
`
`activity. Because CAH patients cannot synthesize cortisol, the 17-OHP is
`
`converted to androgens, which leads to excessive androgen production.11 The
`
`overproduction of androgens in CAH patients leads to a number of physiological
`
`problems, including abnormalities in growth and development in children,
`
`
`6 Ex. 1005, ¶¶ 15-16; Ex. 1014, 1.
`
` 7
`
` 8
`
` 9
`
` Id.
`
` Ex. 1005, ¶ 16; Ex. 1015, 2295-2296.
`
` Ex. 1005, ¶¶ 15-16.
`
`
`10 Ex. 1005, ¶¶ 15-17.
`
`11 Ex. 1005, ¶¶ 16-17; Ex. 1015, 2295-2296.
`
`
`6
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`hirsutism (excessive hair growth), and in females, irregular or absent menstrual
`
`cycles and infertility.12
`
`
`
`The objectives of CAH treatment are two-fold: to correct cortisol hormone
`
`deficiency and to control excess androgen production caused by elevated ACTH
`
`and 17-OHP hormones.13 Correcting cortisol deficiency while also controlling
`
`excess androgen production caused by elevated ACTH is challenging.14
`
`Treating cortisol deficiency in CAH patients involves providing supplemental
`
`hormones, called glucocorticoids, as replacement for the cortisol.15 Glucocorticoid
`
`therapy can correct cortisol deficiency in CAH patients. However, the amount of
`
`glucocorticoids needed to replace deficient cortisol levels is often not sufficient to
`
`reduce ACTH in CAH patients, and thus control excess androgen production.16
`
`This is particularly true in the early morning hours, because ACTH production
`
`
`12 Ex. 1005, ¶ 20; Ex. 1016, 2130-2132.
`
`13 Ex. 1001, 11:1-5; Ex. 1005, ¶ 18; Ex. 1014, 7.
`
`14 Ex. 1005, ¶¶ 19-21.
`
`15 Ex. 1001, 11:1-5; Ex. 1005, ¶ 18; Ex. 1017, 4056; Ex. 1013, 4147.
`
`16 Ex. 1001, 11:41-48; Ex. 1005, ¶ 19; Ex. 1006, ¶ [0066]; Ex. 1014, 8.
`
`
`7
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`follows a circadian pattern where the highest ACTH production occurs in the early
`
`morning.17
`
`
`
`To address the issue of excessive ACTH, and subsequently androgen,
`
`production in the early morning hours, physicians often prescribe higher
`
`glucocorticoid doses than is needed to replace the cortisol deficiency.18 However,
`
`increased glucocorticoid dosing over the long term can lead to increased
`
`cardiovascular risk, weight gain, increased blood pressure, glucose intolerance, and
`
`bone loss in CAH patients.19 High glucocorticoid dosing can also result in elevated
`
`cortisol levels and Cushing’s syndrome, a disease characterized by obesity and an
`
`increased risk of heart attack, stroke, blood clots, bone loss, and type 2 diabetes.20
`
`There is no single standard treatment regimen for all CAH patients—the
`
`types of glucocorticoid treatments, and dosing of those treatments, vary according
`
`to a patient’s age, symptoms, and the severity of androgen excess.21
`
`
`17 Id.
`
`18 Ex. 1005, ¶ 19; Ex. 1014, 8.
`
`19 Ex. 1001, 11:45-48; Ex. 1005, ¶ 19; Ex. 1014, 8.
`
`20 Ex. 1005, ¶ 19; Ex. 1006, ¶ [0045].
`
`21 Ex. 1001, 11:12-15; Ex. 1005, ¶ 18; Ex. 1017, 4056-57; Ex. 1013, 4140, 4147-
`4148.
`
`
`8
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`B.
`The Use of CRF1 Receptor Antagonists to Treat CAH
`As discussed above, CRF is a hormone that activates the synthesis and
`
`release of ACTH from the pituitary gland.22 The CRF receptor has two main
`
`subtypes, CRF1 and CRF2.23 By 2002, the literature had reported CRF as the main
`
`regulator of the release of ACTH from the pituitary gland.24
`
`A CRF type 1 (“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.25
`
` Researchers proposed the use of CRF1 receptor antagonists as a potential
`
`treatment for CAH before the effective filing date of the ’908 patent. For example,
`
`in 2001, several researchers suggested that CRF1 receptor antagonists could
`
`decrease CRF and ACTH secretion, and thus eliminate the need to rely solely on
`
`glucocorticoid negative feedback to prevent excessive adrenal androgen production
`
`in CAH patients.26 These researchers made similar observations in journal articles
`
`
`22 Ex. 1005, ¶ 22; Ex. 1006, ¶ [0006], Fig. 1.
`
`23 Ex. 1005, ¶ 22; Ex. 1018, 270.
`
`24 Ex. 1005, ¶ 22; Ex. 1019, 333; Ex. 1020, 322.
`
`25 Ex. 1005, ¶ 23; Ex. 1006, ¶¶ [0006], [0040].
`
`26 Ex. 1005, ¶ 24; Ex. 1021, 130-131; Ex. 1022, 331; Ex. 1016, 2132.
`
`
`9
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`published in 2002 and 2005.27 Beginning in 2013, Petitioner Neurocrine
`
`Biosciences embarked on an examination of the utility of CRF1 receptor
`
`antagonists for the treatment of CAH.
`
`Neurocrine has developed and tested two CRF1 receptor antagonists, NBI-
`
`77860 and crinecerfont, for their ability to treat CAH by decreasing elevated
`
`ACTH, 17-OHP, and adrenal androgens. Neurocrine’s Phase I clinical study,
`
`published in 2016, demonstrated that 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, compared to placebo.28 Administration of 600 mg
`
`NBI-77860 reduced mean 17-OHP levels by 27% compared to placebo.29
`
`IV. THE ’908 PATENT AND ITS PROSECUTION HISTORY
`
`
`
`
`
`
`
`
`27 Id.
`28 Ex. 1005, ¶ 25; Ex. 1008, 1177.
`
`29 Ex. 1005, ¶ 25; Ex. 1008, 1177.
`
`30 Ex. 1005, ¶ 61;
`
`
`
`
`10
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`
`A. The ’908 Patent Disclosure
`The ’908 patent discloses the use of a single CRF1 receptor antagonist, 3-4-
`
`Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-
`
`dimethylpyrazolo(1,5-a) pyrimidine or “Compound 1,” for treating CAH. This
`
`compound is also known as tildacerfont.31 Spruce is developing tildacerfont as a
`
`potential treatment for CAH.32 U.S. Patent No. 8,030,304 (Ex. 1012, “the ’304
`
`patent”), which issued on October 4, 2011, includes tildacerfont in a list of CRF1
`
`receptor antagonists for treating various psychiatric and neuroendocrine disorders,
`
`neurological diseases, and metabolic syndromes, including CAH.33
`
`The ’908 patent repeatedly characterizes the “present invention” or “present
`
`disclosure” as relating to Compound 1, i.e. tildacerfont. For example, the Abstract
`
`states:
`
`The present invention provides novel pharmaceutical
`
`
`31 The ’908 patent discloses two chemical names that can be referred to as
`
`“Compound 1.” Ex. 1001, 14:15-42. These two chemical names are alternative
`
`names for the same compound, tildacerfont. See
`
`https://pubchem.ncbi.nlm.nih.gov/compound/Tildacerfont; Ex. 1005, ¶ 31.
`
`32 Ex. 1011, 1.
`
`33 Ex. 1005, ¶ 27; Ex. 1012, 2:10-62, 44:7-10.
`
`
`11
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`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 adrenal hyperplasia
`(CAH).34
`
`The Summary of the Invention 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 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 ….35
`
`* * *
`In one aspect, the present disclosure provides a method of
`
`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
`
`
`34 Ex. 1001, Abstract.
`
`35 Ex. 1001, 1:30-38 (emphasis added).
`
`
`12
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`range followed by a maintenance therapy of a daily dosing of
`compound 1.36
`
`* * *
`In one aspect, the present disclosure provides a method of
`
`improving hyperandrogenic symptoms 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
`
`treating menstrual irregularity, ovulatory dysfunction or infertility, in
`a subject in need thereof, comprising administering a pharmaceutical
`composition comprising Compound 1 ….38
`* * *
`In one aspect, the present disclosure provides a method of
`
`improving metabolic symptoms in a subject in need thereof,
`comprising administering a pharmaceutical composition comprising
`Compound 1 ….39
`
`* * *
`In one aspect, the present disclosure provides a method of
`
`improving the quality of life of a subject in need thereof, comprising
`
`36 Id., 4:43-67 (emphasis added).
`
`37 Id., 8:35-38 (emphasis added).
`
`38 Id., 8:63-67 (emphasis added).
`
`39 Id., 9:19-22 (emphasis added).
`
`
`13
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`administering a pharmaceutical composition comprising Compound 1
`….40
`
`
`Each of the embodiments for the above-described aspects in the Summary of
`
`the Invention also refers to Compound 1.41 Nowhere does the ’908 patent describe
`
`or disclose the use of any compound other than Compound 1 (tildacerfont) to treat
`
`CAH or any other condition.
`
`Examples 3-8 of the ’908 patent describe clinical studies related to
`
`Compound 1. Example 3 discloses the results of two Phase I clinical studies
`
`evaluating Compound 1 in healthy adults, and reports pharmacokinetic data from
`
`subjects after administration of Compound 1.42 Example 4 describes a 6-week
`
`Phase II clinical study of Compound I in adults with classic CAH.43 The ’908
`
`patent reports that 8 of 10 subjects in the Phase II study (80%) demonstrated
`
`reduction in ACTH and 17-OHP levels, whereas two of the 10 subjects did not.44
`
`
`40 Id., 9:46-49 (emphasis added).
`
`41 See generally id., 1:30-10:2.
`
`42 Id., 36:32-41:49.
`
`43 Id., 42:1-43:47.
`
`44 Id., 42:49-65; Figs. 2-3.
`
`
`14
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`70% of subjects in the study demonstrated a more than 25% reduction in ACTH,
`
`and 50% of subjects demonstrated more than a 25% reduction in 17-OHP.45
`
`Examples 5-8 describe clinical study protocols but do not disclose any data.46
`
`The ’908 patent does not contain any description or data for any compound
`
`besides Compound 1 (tildacerfont).
`
`B.
`The ’908 Patent Claims
`In contrast to the ’908 patent specification, the ’908 patent claims are not
`
`limited to the use of Compound 1 to treat CAH, but instead recite the use of a
`
`much broader class of CRF1 receptor antagonists for treating CAH.47 Specifically,
`
`independent claim 1 recites a method of treating CAH by administering a
`
`therapeutically effective amount of a CRF1 receptor antagonist, or
`
`pharmaceutically acceptable salt thereof, wherein the ACTH level of a human is
`
`reduced by at least 10% from baseline.48 Claim 11, the only other independent
`
`claim, recites the same treatment step but requires the 17-OHP level of a human to
`
`
`45 Id.
`
`46 Id., 44:7-47:58.
`
`47 Id., 48:6-49:15.
`
`48 Id., 48:6-12.
`
`
`15
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`
`be reduced by at least 10% from baseline.49
`
`Dependent claims 2-4 and 12-14 add dosing ranges or amounts of the CRF1
`
`antagonist to the limitations of the independent claims.50
`
`Dependent claims 5 and 15 recite that the CRF1 receptor antagonist be in the
`
`form of microparticles, and claims 6 and 16 require that the average size of the
`
`microparticles be between about 1µm and about 20 µm.51
`
`Dependent claims 7 and 17 require the CRF1 receptor antagonist to be in the
`
`form of a pharmaceutical composition, and claims 8 and 18 specify that the
`
`pharmaceutical composition is a capsule or a tablet.52
`
`Dependent claims 9 and 19 recite that the treated condition is classic CAH,
`
`while claims 10 and 20 recite that the treated condition is the non-classical form of
`
`CAH.53
`
`Dependent claims 21 and 22 are the only ’908 patent claims that require the
`
`
`49 Id., 48:37-42.
`
`50 Id., 48:13-23, 43-53.
`
`51 Id., 48:24-28, 54-58.
`
`52 Id., 48:29-33, 59-63.
`
`53 Id., 48:34-35, 64-67.
`
`
`16
`
`

`

`Attorney Docket No. 47291-0002PS1
`PGR of U.S. Patent No. 10,849,908
`hormone reduction be “maintained at a reduced level post 24 hours.”54
`
`Claim 23 adds administration of a glucocorticoid to the methods of claim 1
`
`and claim 11, claim 25 requires that the glucocorticoid be administered within two
`
`hours of the CRF1 receptor antagonist, and claim 24 requires that the CRF1
`
`receptor antagonist be administered “4 hours prior to sleeping.”55
`
`C. The ’908 Patent Prosecution History
`The ’908 patent issued on December 1, 2020 from U.S. Patent Application
`
`No. 16/388,620 (“the ‘620 application”), which was filed o