IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`Howerton et al.
`In re Patent of:
`Attorney Docket No. 47291-0007PS1
`12,115,166
`
`U.S. Patent No.:
`
`October 15, 2024
`Issue Date:
`
`Appl. Serial No.: 18/307,718
`
`Filing Date:
`April 26, 2023
`Title:
`CORTICOTROPIN RELEASING FACTOR RECEPTOR
`ANTAGONISTS
`
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`PETITION FOR POST GRANT REVIEW OF
`UNITED STATES PATENT NO. 12,115,166
`
`
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`REQUIREMENTS FOR PGR ......................................................................... 5
`A. Grounds for Standing ................................................................................ 5
`B. Identification of Challenge ....................................................................... 5
`C. The ’166 Patent Is Eligible for PGR ......................................................... 6
`
`III. THE BOARD PREVIOUSLY DETERMINED THAT THE SAME
`SPECIFICATION DOES NOT SUPPORT CLAIMS RECITING A GENUS
`OF CRF1 RECEPTOR ANTAGONISTS ....................................................... 6
`
`IV. THE ’166 PATENT ......................................................................................... 8
`A. The ’166 Patent Disclosure ....................................................................... 8
`B. The ’166 Patent Claims ...........................................................................11
`C. The ’166 Patent Prosecution History ......................................................12
`
`V.
`
`LEVEL OF ORDINARY SKILL ..................................................................15
`
`VI. CLAIM CONSTRUCTION ..........................................................................16
`
`2.
`
`3.
`
`VII. DETAILED EXPLANATION OF GROUNDS ............................................16
`A. Ground 1: Claims 1-10, 12-21 are unpatentable for lack of written
`description ...............................................................................................16
`1.
`The ’166 Patent Specification Does Not Disclose a Representative
`Number of Species or Common Structural Features of the Claimed
`Genus .............................................................................................18
`The ’166 Patent Disclosure Does Not Convey to a POSA that the
`Inventor Possessed the Claimed Subject Matter ...........................20
`There is No Written Description Support for the Challenged
`Claims’ Stability Limitation ..........................................................25
`B. Ground 2: Claims 1-10, 12-21 are unpatentable for lack of enablement ...
`
` .......................................................................................................27
`1.
`The broad scope of the claims weighs against enablement (Factor
`8) ....................................................................................................30
`The ’166 patent’s lack of guidance for making and using the
`claimed genus (Factor 2) and examples limited to Compound 1
`(Factor 3) weigh against enablement ............................................31
`The undue amount of experimentation necessary to identify CFR1
`receptor antagonists that achieve the recited results (Factor 1) and
`
`2.
`
`3.
`
`i
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`the lack of any structure-function relationship for CFR1 receptor
`antagonists in the art (Factor 5) weigh against enablement ..........34
`The complex nature of treating CAH patients (Factor 4) and
`unpredictability in the art (Factor 7) weigh against enablement ...38
`The relatively high level of skill is does not support enablement
`(Factor 6) .......................................................................................40
`Summary .......................................................................................41
`
`4.
`
`5.
`
`6.
`
`VIII. NO BASIS EXISTS FOR DISCRETIONARY DENIAL ............................42
`A. §324(a) ....................................................................................................42
`B. §325(d) ....................................................................................................42
`
`IX. PAYMENT OF FEES – 37 C.F.R. § 42.203 .................................................46
`
`X. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1) ........................46
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)..............................46
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2) .......................................46
`C. Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ...................46
`D. Service Information ................................................................................46
`
`XI. CONCLUSION ..............................................................................................47
`
`
`
`
`
`
`
`
`
`ii
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`LIST OF EXHIBITS
`
`Exhibit No.
`
`Exhibit Description
`
`1001
`
`1002
`
`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, 2496-3119
`
`1003
`
`Declaration of Maya Lodish, M.D.
`
`1004
`
`Declaration of David E. Bugay, Ph.D.
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`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”).
`
`Director Decision, Paper 16, Neurocrine Biosciences, Inc. v.
`Spruce Biosciences, Inc., No. PGR2021-00088 (Aug. 4, 2023).
`
`iii
`
`

`

`Exhibit No.
`
`Exhibit Description
`
`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Director Decisions, Paper 15, Neurocrine Biosciences, Inc. v.
`Spruce Biosciences, Inc., No. PGR2022-00025 (Aug. 4, 2023).
`
`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):4133-60 (2010)
`(“Speiser”).
`
`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
`390:2194-210 (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):4043-88 (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): 270-81 (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
`
`iv
`
`

`

`Exhibit No.
`
`Exhibit Description
`
`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`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”).
`
`Trapp et al., “Congenital adrenal hyperplasia: an update in
`children,” Curr. Opin. Endocrinol. Diabetes Obes., 18(3):166-70
`(2011) (“Trapp”).
`
`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 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”).
`
`Nella et al., “A Phase 2 Study of Continuous Subcutaneous
`Hydrocortisone Infusion in Adults With Congenital Adrenal
`Hyperplasia,” J. Clin. Endocrinol. Metabol., 101(12):4690-98
`(December 2016) (“Nella”)
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`v
`
`

`

`Exhibit No.
`
`Exhibit Description
`
`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`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.
`
`Reserved
`
`U.S. Provisional Application Serial No. 62/545,406.
`
`U.S. Patent No. 10,849,908 to Alexis Howerton, et al. (“the ’908
`patent”).
`
`U.S. Patent No. 11,007,201 B2 to Alexis Howerton, et al. (“the
`’201 patent”).
`
`Yamaguchi et al., “Approval success rates of drug candidates
`based on target, action, modality, application, and their
`combinations,” Clin. Transl. Sci. 14:1113-22 (2021)
`(“Yamaguchi”).
`
`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”).
`
`1040
`
`Reserved
`
`vi
`
`

`

`Exhibit No.
`
`Exhibit Description
`
`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`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”).
`Reserved
`
`“Spruce Biosciences Achieves Proof of Concept in Phase 2 Study
`in Tildacerfont in Congenital Adrenal Hyperplasia,” Spruce
`Biosciences (March 25, 2019) (“Spruce March 25, 2019, Press
`Release”).
`“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 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 Review, 43(1):91-159 (2022)
`(“Claahsen-van der Grinten”).
`“Guidance for Industry, Q1A(R2) Stability Testing of New Drug
`Substances and Products,” U.S. Department of Health and Human
`Services, Food and Drug Administration (November 2003).
`
`vii
`
`

`

`Exhibit No.
`
`Exhibit Description
`
`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`“Guidance for Industry, Q1E Evaluation of Stability Data,” U.S.
`Department of Health and Human Services, Food and Drug
`Administration (June 2004).
`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”).
`Product Quality Review: CRENESSITY™ (Crinecerfont), Center
`for Drug Evaluation and Research, Food & Drug Administration
`(Nov. 4, 2022) (“FDA Product Quality Review”).
`Reserved
`
`
`Reserved
`
`“Neurocrine Biosciences Announces U.S. FDA Accepts New
`Drug Applications and Grants Priority Review for Crinecerfont for
`Pediatric and Adult Patients with CAH,” Neurocrine Biosciences
`(July 1, 2024) (“Neurocrine July 1, 2024, Press Release”).
`“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.
`Reserved
`
`Petition for Post Grant Review of U.S. Patent No. 10,849,908,
`Paper 2, Neurocrine Biosciences, Inc. v. Spruce Biosciences, Inc.,
`No. PGR2021-00088 (May 28, 2021).
`Petitioner’s Reply to Patent Owner’s Response, Paper 32,
`Neurocrine Biosciences, Inc. v. Spruce Biosciences, Inc., No.
`PGR2021-00088 (June 20, 2024).
`
`viii
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`Exhibit No.
`
`Exhibit Description
`
`1063
`
`1064
`
`1065
`
`1066
`
`Petition for Post Grant Review of U.S. Patent No. 11,007,201,
`Paper 2, Neurocrine Biosciences, Inc. v. Spruce Biosciences, Inc.,
`No. PGR2022-00025 (Feb. 18, 2022).
`Petitioner’s Reply to Patent Owner’s Response, Paper 30,
`Neurocrine Biosciences, Inc. v. Spruce Biosciences, Inc., No.
`PGR2022-00025 (June 20, 2024).
`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).
`
`ix
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`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 1-10 and 12-21 (the “Challenged Claims”) of U.S. Patent No. 12,115,166
`
`(the “’166 patent;” EX1001) assigned to Spruce Biosciences, Inc. (“Patent Owner”
`
`or “Spruce”).
`
`I.
`
`INTRODUCTION
`
`The ’166 patent is Spruce’s latest attempt to lay claim to work it did not do
`
`in an effort to cover the groundbreaking work of its competitor, Neurocrine. The
`
`’166 patent issued on October 15, 2024, approximately six weeks before the Board
`
`issued Final Written Decisions determining all claims of two other Spruce patents
`
`in this family—U.S. Patent Nos. 10,849,908 (“the ’908 patent”) and 11,007,201
`
`(“the ’201 patent”)—unpatentable for lack of written description. The ’166 patent
`
`shares the same defective specification as those patents and, like Spruce’s other
`
`patents, impermissibly claims a sweeping genus of CRF1 receptor antagonists for
`
`treating congenital adrenal hyperplasia (“CAH”). Spruce’s third shot at patent
`
`overreach must also fail for violating the requirements of 35 U.S.C. §112(a).
`
`While Neurocrine and Spruce each studied CRF1 receptor antagonists for
`
`the treatment of CAH, Neurocrine led the way. See EX1003, ¶¶23-31.
`
`Neurocrine’s pioneering work on CRF1 receptor antagonists spans over 30 years.
`
`Neurocrine launched a clinical program studying CRF1 receptor antagonists to
`
`1
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`treat CAH in 2012 and was the first company to investigate CRF1 receptor
`
`antagonists for the treatment of CAH. By January 2016, Neurocrine had completed
`
`and published the first clinical study of a CRF1 receptor antagonist to treat CAH.
`
`EX1008. Neurocrine went on to develop a second CRF1 receptor antagonist,
`
`crinecerfont, which was highly effective in treating CAH in clinical studies.
`
`EX1054; EX1009. In 2016, Neurocrine filed an Investigational New Drug
`
`application seeking authorization from the FDA to study crinecerfont in humans
`
`with CAH. In January 2017, Neurocrine’s published patent application disclosed
`
`the utility of crinecerfont as a CAH treatment. EX1006, [0054]. Spruce, by
`
`contrast, was not formed until 2014—two decades after Neurocrine first began
`
`work on CRF1 receptor antagonists, and two years after Neurocrine launched its
`
`CAH clinical program. Spruce did not report results of its first clinical study until
`
`March 2019. EX1043.
`
`Neurocrine’s work on crinecerfont for treating CAH is groundbreaking.
`
`Crinecerfont is the first new CAH treatment to be approved by the FDA in 70
`
`years, and is the first and only CRF1 receptor antagonist approved as a CAH
`
`therapy. The FDA granted Neurocrine “Fast Track,” “Breakthrough Therapy,”
`
`“Priority Review,” and “Orphan Drug” designations for crinecerfont as a first-in-
`
`class therapy that meets a long-felt and unmet medical need to reduce
`
`glucocorticoid dosing in CAH patients. EX1057. The FDA approved two
`
`2
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`formulations of crinecerfont (capsule and oral solution) for treating CAH in
`
`December 2024, and both are now available to patients under the trade name
`
`CRENESSITY™. EX1058. In stark contrast, the only compound disclosed in
`
`Spruce’s patents, tildacerfont, has been an abject failure. Tildacerfont failed to
`
`meet its primary efficacy endpoint in its last two clinical trials, and Spruce has
`
`announced it is no longer pursuing tildacerfont as a CAH treatment. EX1044;
`
`EX1045.
`
`Having lost on the science, Spruce’s ’166 patent represents its latest attempt
`
`to capture Neurocrine’s innovation by improperly expanding its patent claims to a
`
`scope it neither described nor enabled. Unsurprisingly, the entire disclosure of the
`
`’166 patent relates to tildacerfont, the only CRF1 receptor antagonist Spruce
`
`studied. The Challenged Claims, however, recite the use of an entire genus of
`
`CRF1 receptor antagonists to treat CAH and achieve specific clinical results. The
`
`specification does not disclose a representative number of species within the scope
`
`of that genus—it discloses only one, tildacerfont. The specification likewise fails to
`
`disclose common structural features of the claimed genus. Thus, the Challenged
`
`Claims are unpatentable under §112(a) for lack of written description.
`
`As noted above, the Board already addressed this exact issue in Neurocrine’s
`
`challenges to Spruce’s other patents in this family: PGR2021-00088 (determining
`
`all claims of the ’908 patent unpatentable) and PGR2022-00025 (determining all
`
`3
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`claims of the ’201 patent unpatentable). Like the ’166 patent, both of those patents
`
`broadly claimed the use of an entire genus of CRF1 receptor antagonists to treat
`
`CAH, but, like the ’166 patent here, only disclosed a single species, tildacerfont.
`
`Both patents share the same specification as the ’166 patent. In its Final Written
`
`Decisions, the Board determined that all claims of Spruce’s patents were
`
`unpatentable under §112(a) for lack of written description. EX1005, 42-59;
`
`EX1007, 40-57. Given that the ’166 patent has the same disclosure as Spruce’s
`
`other patents, the Board should also find the Challenged Claims of the ’166 patent
`
`unpatentable for lack of written description.
`
`Spruce’s overbroad genus claims are also unpatentable under §112(a) for
`
`lack of enablement because the ’166 patent’s disclosure does not enable a person
`
`of ordinary skill in the art (“POSA”) to make and use the full scope of the claims
`
`without undue experimentation. The Challenged Claims recite an entire genus of
`
`CRF1 receptor antagonists by their function—treating CAH and achieving specific
`
`clinical results—but the specification does not provide a sufficiently predictable
`
`way for a POSA to identify CRF1 receptor antagonists useful for the claimed
`
`methods. The POSA is, instead, left with a trial-and-error approach for determining
`
`which CRF1 receptor antagonists fall within the scope of the broad claims. Trial-
`
`and-error is insufficient to satisfy the enablement requirement for the reasons the
`
`Supreme Court articulated in Amgen Inc. v. Sanofi, 598 U.S. 594, 610 (2023).
`
`4
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`Disclosure of a single failed species (tildacerfont) does not show possession
`
`of the use of an entire class of CRF1 receptor antagonists to treat CAH. Trial-and-
`
`error is not enablement. Neurocrine respectfully requests that the Board institute
`
`this PGR and cancel the Challenged Claims as unpatentable.
`
`II. REQUIREMENTS FOR PGR
`
`A. Grounds for Standing
`
`Pursuant to 37 C.F.R. §42.204(a), Neurocrine certifies that the ’166 patent is
`
`available for PGR and that Neurocrine is not barred or estopped from requesting
`
`PGR challenging claims 1-10 and 12-21 on the below-identified grounds of
`
`unpatentability. This Petition is being filed within nine months of the issuance of
`
`the ’166 patent on October 15, 2024.
`
`B.
`
`Identification of Challenge
`
`Pursuant to 37 C.F.R. §42.204(b), Neurocrine requests PGR of the
`
`Challenged Claims on the grounds set forth below, and requests that the Board
`
`cancel each of the Challenged Claims.
`
`Ground
`
`Claims
`Challenged
`
`35 U.S.C. §
`
`Reference(s)/Basis
`
`1
`
`2
`
`
`
`1-10, 12-21
`
`112(a)
`
`Lack of Written
`Description
`
`1-10, 12-21
`
`112(a)
`
`Lack of Enablement
`
`
`
`5
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`C. The ’166 Patent Is Eligible for PGR
`
`The ’166 Patent claims an earliest-possible filing date of August 14, 2017.
`
`EX1001, code [60]. Accordingly, the ’166 patent is an AIA “first-to-file” patent
`
`filed on or after March 16, 2013.
`
`III. THE BOARD PREVIOUSLY DETERMINED THAT THE
`SAME SPECIFICATION DOES NOT SUPPORT CLAIMS
`RECITING A GENUS OF CRF1 RECEPTOR ANTAGONISTS
`
`Neurocrine previously challenged two other Spruce patents in PGR
`
`proceedings: PGR2021-00088 (challenging all claims of the ’908 patent) and
`
`PGR2022-00025 (challenging all claims of the ’201 patent). Both the ’908 and
`
`’201 patents are in the same family as the ’166 patent. And, except for cross-
`
`reference information, all three patents share the same specification.
`
`Like the Challenged Claims, the ’908 and ’201 patent claims recite the use
`
`of an entire class of CRF1 receptor antagonists to treat a CAH patient and achieve
`
`specific clinical effects (e.g., reduction in adrenal hormones). EX1036, 48:5-49:15;
`
`EX1037, 47:50-48:51. Neurocrine asserted that all claims of both patents were
`
`invalid for lacking written description, because the disclosure does not show that
`
`Spruce possessed an entire class of CRF1 receptor antagonists to treat CAH.
`
`EX1061, 70-75; EX1062, 4-12; EX1063, 75-79; EX1064, 4-11.
`
`In detailed Final Written Decisions, the Board held that all claims of the
`
`’908 and ’201 patents were unpatentable for lack of written description support.
`
`6
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`EX1005, 42-59; EX1007, 40-57. The Board noted the undisputed fact that the
`
`shared specification discloses only a single CRF1 receptor antagonist, Compound 1
`
`(tildacerfont). See, e.g., EX1005, 43. The Board found that “[g]iven the large
`
`number of CRF1 receptor antagonists with varying structures and effectiveness,”
`
`the disclosure of a single species, Compound 1, “fails on its face to meet Ariad’s
`
`requirement that the Specification disclose ‘a representative number of species
`
`falling within the scope of genus or structural features common to the members of
`
`the genus so that one of skill in the art can ‘visualize or recognize’ the members of
`
`the genus.” Id., 44-45 (citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336,
`
`1350 (Fed. Cir. 2010) (en banc). The Board also found that the prior art of record
`
`“indicate a very considerable structural diversity of molecules that can act as CRF1
`
`receptor antagonists” and rejected Spruce’s characterization of these antagonists as
`
`a “well-known, well-characterized, and discrete class.” Id., 55-57.
`
`The Board concluded that a skilled artisan “would not have recognized,
`
`either from the express disclosures of the [] Specification or from the knowledge of
`
`the prior art, the ‘structure, formula, chemical name, physical properties, or other
`
`properties, of species falling within the genus’ of claimed CRF1 receptor
`
`antagonists” and held all claims unpatentable. Id., 59. These findings were
`
`consistent with former Director Vidal’s decisions in PGR2021-00088 and
`
`7
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`PGR2022-00025. EX1010, 10-14; EX1011, 3.1
`
`Because the Board held all claims of the ’908 and ’201 patents unpatentable
`
`for lack of written description, the Board did not reach Neurocrine’s other grounds
`
`of unpatentability based on lack of enablement, anticipation, and obviousness.
`
`EX1005, 59; EX1007, 57.
`
`IV. THE ’166 PATENT
`
`A. The ’166 Patent Disclosure
`
`The ’166 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.2 Spruce developed tildacerfont as a
`
`treatment for CAH. However, tildacerfont failed to meet its primary efficacy
`
`endpoint in two Phase II(b) clinical trials, and in December 2024, Spruce
`
`announced that it is no longer pursuing tildacerfont as a CAH treatment. EX1044;
`
`
`1 Spruce has requested Director Review of the Final Written Decisions. PGR2021-
`00088, Paper 65; PGR2022-00025, Paper 63. Those requests are pending.
`Neurocrine believes Spruce’s requests are meritless, and has requested an
`opportunity to respond to address the new arguments and numerous misstatements
`in Spruce’s requests.
`
` 2
`
` The ’166 patent discloses two chemical names that can be referred to as
`“Compound 1.” EX1001, 14:40–67. These two chemical names are alternative
`names for the same compound, tildacerfont. See EX1059, 4, 6; EX1003, ¶33.
`
`
`8
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`EX1045.
`
`The ’166 patent repeatedly characterizes the “present invention” or “present
`
`disclosure” as Compound 1, i.e., tildacerfont. For example, the Abstract 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 of
`using the same for the treatment of Congenital adrenal hyperplasia
`(CAH).
`
`EX1001, Abstract (emphasis added). 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 . . . .
`
`Id., 1:40-48 (emphasis added).
`
`The methods described in the specification are likewise limited to the use of
`
`Compound 1, or salts or solvates of Compound 1:
`
`Disclosed herein is a method of treating congenital adrenal hyperplasia
`(CAH) in a subject in need thereof, comprising administering a
`pharmaceutical composition comprising Compound 1, or a
`pharmaceutically acceptable salt or solvate thereof.
`
`Id., 26:50-55 (emphasis added).
`
`
`
`
`
`9
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`Nowhere does the ’166 patent describe or disclose the use of any compound
`
`other than Compound 1 (tildacerfont) to treat CAH or any other condition. The
`
`only stability data provided for an CRF1 receptor antagonist is for Compound 1.
`
`EX1001, 25:20-29, 34:58-36:57. The only disclosure of reducing the amount of
`
`glucocorticoid needed in a patient is in reference to administering Compound 1,
`
`not any other CRF1 receptor antagonist. Id., 32:22-29.
`
`The same is true as to the specification’s disclosure of clinical data.
`
`Examples 3-8 of the ’166 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. Id., 36:58-42:32. Example 4 describes a 6-
`
`week Phase II clinical study of Compound I in adults with classic CAH. Id., 42:36-
`
`44:67. The ’166 patent reports that the subjects in the Phase II study demonstrated
`
`reduction in ACTH, 17-OHP, and A4 levels after six weeks of receiving
`
`Compound 1. Id., 44:42-67; Figs. 2-4. Examples 5-8 describe prophetic clinical
`
`study protocols (all using only tildacerfont) but do not disclose any data. Id., 45:1-
`
`48:61.
`
`The ’166 patent does not contain any description or data for any compound
`
`besides Compound 1 (tildacerfont). EX1003, ¶¶32-38.
`
`
`
`
`
`10
`
`

`

`Attorney Docket No. 47291-0007PS1
`PGR of U.S. Patent No. 12,115,166
`
`
`B.
`
`The ’166 Patent Claims
`
`In contrast to the specification, the ’166 patent claims are not limited to the
`
`use of Compound 1 to treat CAH, but instead recite the use of a much broader
`
`genus of CRF1 receptor antagonists for treating CAH. Specifically, claim 1, the
`
`only independent claim, recites a method for treating CAH as follows:
`
`1. A method for treating congenital adrenal hyperplasia (CAH)
`in a hum