Details for Patent: 12,582,634

Which drugs does patent 12,582,634 protect, and when does it expire?

Patent 12,582,634 protects CRENESSITY and is included in two NDAs.

This patent has sixty-four patent family members in twenty-six countries.

Summary for Patent: 12,582,634

Title:	Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine
Abstract:	The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).
Inventor(s):	Andrew Becker, Scott Stirn, Joel Radisson, Christina Marie COSTA
Assignee:	Sanofi SA , Neurocrine Biosciences Inc
Application Number:	US17/782,617
Patent Claim Types: see list of patent claims	Composition; Compound; Process;

United States Patent 12,582,634 Scope and Claims: process-by-alkylation, crystalline Form I/tosylate, and impurity-controlled drug substance and drug product

United States Patent 12,582,634 is a US-composition and process patent that concentrates on (1) a specific alkylation step that converts a thiazol-2-amine precursor (Compound 9A) to the final “Compound 1” (free base), (2) downstream intermediate synthesis (Compounds 6A, Ig, Ie, 3A), (3) isolation and formulation, and (4) tight solid-state and quality-attribute constraints, including an anhydrous crystalline XRPD-defined free-base Form I and tosylate salt, plus impurity and residual solvent limits for a defined impurity set (Compounds IIa/IIb/IIc/9A and ethanol/propargyl bromide).

---

What is the invention in US 12,582,634 and what does it claim to protect?

Core protection targets

1. A process for preparing Compound 1 (final API) via phase-transfer-catalyzed alkylation of Compound 9A with a Formula (Ii) alkylating agent (where LG is a leaving group).
2. Process-by-sequence coverage for building blocks and intermediates used to reach Compound 1:
   • cyclization to make Compound 9A
   • deprotection and reduction steps to make Compound 6A and Compound Ig
   • condensation to make Compound Ie, and Grignard-type chemistry to make Compound 3A
3. Solid-state forms:
   • an anhydrous crystalline free base Form I defined by XRPD peak list
   • a crystalline tosylate salt defined by XRPD peak list
4. Drug product compositions and impurity-residual controls:
   • defined maximum levels of specific related compounds (IIa, IIb, IIc, and in some claims Compound 9A)
   • limits on ethanol (down to ≤1000 ppm in dependent claims; ≤3000/≤5000 ppm in others)
   • limits on residual propargyl bromide (down to ≤30 ppm)
   • definitions of a crystalline form (anhydrous) in the final composition context

Claim-structure map (what claim families exist)

Claim group	Claim numbers (from provided text)	Protection style	Key technical axis
Final alkylation process (Compound 9A → Compound 1)	1–40	Method of preparing API	phase-transfer alkylation, solvent/base/catalyst, temperature windows, leaving group and alkylating agent identity
Alkylating agent identity and leaving groups	26–29	Method/agent-limited	LG scope, specific propargyl derivatives
Sequential intermediate prep	31–35	Method of preparing intermediates used for API	cyclization, deprotection, reduction, condensation, organomagnesium step
Crystalline solid form(s)	46–47	Polymorph/form protection	XRPD peak lists for anhydrous free base and tosylate salt
Drug compositions (quality and impurity controls)	48–65, 67–105 (as present in provided text) and 98–101	Composition and composition-process	impurity ceilings, ethanol/propargyl bromide residual limits, inclusion of crystalline forms
Composition with specific impurity set	50, 67, 98	Composition with quantitative related-compound specs	Compounds IIa/IIb (and later IIc, 9A, IIc, propargyl bromide), ethanol ppm

---

What is the main US 12,582,634 claim 1 and how broad is its alkylation process?

Claim 1 is the broadest “process for preparing Compound 1” anchor. It covers:

• Starting material: Compound 9A (S-configuration specific in its use as the alkylation substrate)
• Alkylation reagent: “Compound of Formula (Ii)” where LG is a leaving group
• Reaction conditions: presence of:
  • an alkylating-step solvent
  • a phase-transfer catalyst
  • an alkylating-step base
  • water
• Outcome: Compound 1 (or pharmaceutically acceptable salt)

How does the claim define the alkylation reagent scope?

Claim 1 is intentionally broad with respect to the alkylating agent framework (Formula (Ii) with LG as leaving group). It then narrows in dependent claims 26–29.

• Claim 26 (LG general scope): LG includes:
  • C1–C4 alkylsulphonyloxy
  • C6–C10 arylsulphonyloxy
  • halogen
  • hydroxy
    with optional substitutions allowed on sulphonyloxy aryl group (C1–C4 alkyl, C1–C4 alkoxy, halogen, C1–C4 haloalkyl, C1–C4 haloalkoxy, nitro).
• Claim 27: “LG is halogen.”
• Claim 28 (specific reagents): Formula (Ii) includes propargyl halide and propargyl sulfonates:
  • propargyl bromide
  • propargyl methanesulfonate
  • propargyl trifluoromethanesulfonate
  • propargyl benzenesulfonate
  • propargyl p-toluenesulfonate
• Claim 29: Formula (Ii) is propargyl bromide.

Implication for scope: Claim 1 can be practiced with any Formula (Ii) consistent with LG categories, but commercial/competitive “design around” often targets the specific propargyl leaving group identity (bromide vs mesylate/tosylate vs triflate) and/or avoids the phase-transfer pattern altogether.

What are the key process limitation axes in claim 1’s dependent claims?

1) Stoichiometry

• Claim 2–3: Formula (Ii) present in molar excess; dependent says about 20% molar excess
• These create a typical process-operating window that can matter in infringement if a generic producer uses materially different stoichiometry.

2) Catalyst ratio and base loading

• Claim 4–5: Compound 9A : phase-transfer catalyst ratio ranges
• Claim 6–7: Compound 9A : phase-transfer catalyst : alkylating-step base ratio ranges
• These dependent claims are structured to capture variations in catalyst and base equivalents while maintaining the same core reaction concept.

3) Solvent identity

• Claim 8–10: solvent class and then explicit list
  • Broad list includes halogenated solvents, ethers, aprotic solvents, and many common organics (e.g., dichloromethane, toluene, DME, CPME, 2-MeTHF, 1,4-dioxane, MTBE, etc.)
  • Claim 10 narrows solvent to MTBE/toluene/mixtures

4) Phase-transfer catalyst identity

• Claim 11–13: quaternary ammonium salts; explicit list; dependent narrows to TBAB (tetra-n-butylammonium bromide)

5) Base identity

• Claim 14–15: alkali metal hydroxide; dependent specifies potassium hydroxide

6) Temperature and addition pattern

• Claim 16: defines a two-stage mixing approach:
  • form first-alkylating mixture containing solvent, catalyst, Compound 9A at first temperature
  • add base (in water) and Formula (Ii) at second-alkylating temperature, maintaining biphasic conditions
• Claim 17: heat to ~55–65 °C then cool back to first temperature
• Claim 18–19: base added as aqueous solution; w/w concentration ~52–53%
• Claim 20–21: Formula (Ii) added as solution in the organic solvent; w/w concentration ~75–85%
• Claim 22–23: concurrent vs serial addition, rate-controlled to maintain temperature
• Claim 24–25: temperature windows:
  • first-alkylating temperature about −5 to 7 °C
  • second-alkylating temperature about 0 to 10 °C

Implication for scope: While claim 1 is not limited to a single solvent, catalyst, or temperature, dependent claims strongly anchor common manufacturing conditions. These dependent claims are often the “workhorse” infringement hooks in litigation because accused processes tend to reuse the same equivalents and operational ranges.

---

How are intermediates covered, and how much of the synthetic route is claimed?

The patent does not stop at the API alkylation. It claims multiple upstream synthesis steps and their intermediates, creating a “route coverage” pathway that can capture partial process modifications.

What intermediate synthesis steps are explicitly claimed?

Cyclization to Compound 9A

• Claim 31: preparation of Compound 9A by cyclizing:
  • Compound 6A with Compound 8A (1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one)
  • in presence of cyclizing-step solvent

Deprotection to Compound 6A

• Claim 32: deprotect a Compound of Formula (Ig) with hydrogen and deprotecting catalyst in deprotecting-step solvent

Reduction to Compound Ig

• Claim 33: reduce Compound of Formula (Ie) with hydrogen and reducing catalyst

Condensation to Compound Ie

• Claim 34–35: condense 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) with Compound Ic (not fully expanded here) under condensing-step acid and solvent to form Compound Ie

Preparation of Compound 3A

• Claim 35: react 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in reacting-step solvent

Implication for enforcement: If a competitor sources any intermediate externally but still uses the same downstream alkylation and crystallization/formulating, infringement can still occur. Conversely, if a competitor redesigns the route upstream to avoid intermediate forms or key reagents, the route claims are positioned to block that alternative.

---

What crystalline solid-state claims exist (XRPD Form I and tosylate), and what do they cover?

Anhydrous crystalline free base: Claim 46

Claim 46 protects:

• Compound 1 free base
• as an anhydrous crystalline form
• defined by an XRPD pattern with at least three peaks, each peak specified within ±0.2° 2θ at selected values including:
  • 6.0, 11.9, 13.9, 14.3, 16.8, 17.9, 19.7, 20.2, 20.9, 21.8, 22.3, 23.2, 23.9, 24.2, 25.7, 26.8, 28.7, 29.6, 36.1, 43.5 (degrees 2θ)

This is a “form as characterized by diffraction peaks” claim. It does not require a specific method of making the solid form, so it can be infringed by sale/manufacture of the solid meeting the XRPD pattern.

Crystalline tosylate salt: Claim 47

Claim 47 protects:

• Compound 1 tosylate
• an anhydrous crystalline form defined by XRPD peaks with at least three peaks selected from:
  • 9.1, 10.5, 11.3, 13.2, 16.3, 19.0, 19.3, 20.4, 21.1, 22.8, 23.3, 23.8, 28.5 (degrees 2θ)

Implication for solid-state design-around: A competitor can attempt to use different polymorphs or solvates, but the claim language is tied to an XRPD peak set. If the accused form matches the defined peak list sufficiently, the claim becomes a strong barrier.

---

How do the drug substance and drug product composition claims control impurities and residuals?

The patent uses composition claims to lock down quality attributes: related compounds ceilings and residual solvents/reactants.

What impurity set is defined?

Across claims 50 and 67 and 98, the patent references multiple impurities/related compounds:

• Compound IIa: (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine
• Compound IIb: (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine
• Compound IIc: appears in claim 83–86 and claim 98 description as another specified impurity variant (4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine)
• Compound 9A: precursor impurity appears in claim 75–78 and claim 98/99 (as Compound 9A in mixture)

What are the quantified limits?

Key quantitative ceilings from the provided claim set:

Related compound thresholds (Claim 50 basis)

• no more than 0.8% Compound IIa
• no more than 0.15% Compound IIb
• and 500 ppm ethanol cap

Dependent variations adjust these ceilings:

• IIa ≤0.7% (claim 58), ≤0.6% (claim 59)
• IIb ≤0.1% (claim 60), ≤0.05% (claim 61)

Ethanol residual

• ethanol ≤3000 ppm (claim 62/63)
• ethanol ≤1000 ppm (claim 63)
• later composition claim 98 adds ethanol ≤5000 ppm (and then ≤3000 ppm? present in dependent chain; claim 88/89/90 specify ≤5000/≤3000/≤1000 ppm)

Propargyl bromide residual

• in claim 91–94: propargyl bromide ≤200 ppm, ≤100 ppm, ≤30 ppm
• claim 98 sets propargyl bromide ≤30 ppm as part of a broader impurity/spec grid

Additional impurity ceilings (claim 98)

• IIa ≤0.8%
• 9A ≤0.2%
• IIb ≤0.15%
• IIc ≤0.2%
• ethanol ≤5000 ppm
• propargyl bromide ≤30 ppm (dependent claim 99–101 then tie these compositions to free-base/an anhydrous crystalline form and excipient availability)

Implication for infringement landscape: Many Paragraph IV “generic process” disputes turn into “are you making the same impurity profile” or “are you within the claimed specification” style disputes. Here, the patent is built to create a measurable acceptance window.

---

What is the likely litigation-relevant separation between process claims and composition/form claims?

Even without the remaining patent metadata, the claim architecture implies two distinct infringement theories:

1. Process infringement (manufacturing step):

   • phase-transfer alkylation of Compound 9A with Formula (Ii) under specified solvent/catalyst/base/water conditions
   • temperature windows and aqueous/organic concentration ranges
   • addition patterns (concurrent vs serial)

2. Product/form infringement (what is sold or made):

   • anhydrous XRPD-defined crystalline Form I free base
   • XRPD-defined crystalline tosylate
   • composition impurity/residual constraints tied to specific related compounds

This bifurcation means a competitor could theoretically change the process but still fall into the crystalline form or composition-spec claims, or change the product/spec but still run into the manufacturing process claim.

---

How strong is the patent estate for generic entry risk based on claim breadth?

Strength drivers in this patent text

• Multiple independent claim targets: process, intermediates, crystalline forms, and compositions.
• Specificity on operative chemistry: phase-transfer catalyst class with explicit examples (including TBAB) and base class with explicit example (KOH).
• Specificity on XRPD-defined solids: free base and tosylate each have defined peak sets.
• High-resolution quality specs: quantified thresholds for multiple impurities plus residual ethanol/propargyl bromide.

Strength drivers for enforcement

• Solid-state claims can be asserted even if the accused process differs, as long as the sold/present API matches the XRPD-defined form.
• Composition specs create a direct analytical testing pathway.

Key “attack surfaces” for a defendant

• Use alternative alkylating agents outside the LG/propargyl set or avoid phase-transfer with water biphasic conditions (if claim 1’s broad elements are avoided).
• Avoid XRPD peak matching by making a different polymorph/solvate or using a form outside the defined peak set for either free base or tosylate.
• Maintain impurity/residual profile outside the claimed ranges (but this is more difficult because impurities and solvents are often difficult to drive below tight ppm/0.05% thresholds).

---

What comparisons matter versus adjacent patent families (what to look for in competitors’ estates)?

Because only the claims text was provided, only the general comparison framework can be stated. For a competitor, the most relevant comparison is whether their process and solids match any of the following “signature” features embedded in this patent:

• phase-transfer alkylation of Compound 9A with propargyl derivatives
• use of TBAB (or other quaternary ammonium salts) with KOH
• MTBE or toluene as solvent with defined concentration windows
• two-step temperature protocol (heat/cool into sub-10 °C range)
• crystallization to an anhydrous XRPD Form I with the specified peak list
• impurity envelope: IIa/IIb/IIc and precursor 9A, plus ethanol and propargyl bromide residual limits

---

Key Takeaways

• US 12,582,634 is built around a phase-transfer alkylation process converting Compound 9A to Compound 1, with dependent claims locking in propargyl reagent types, quaternary ammonium catalysts, KOH, solvent lists (including MTBE/toluene), and temperature/addition/concentration windows.
• The patent claims additional upstream intermediates (Compound 6A, Ig, Ie, and 3A), creating broader route coverage.
• It adds solid-state protection for:
  • anhydrous crystalline Compound 1 free base (XRPD Form I) defined by a specified peak set (Claim 46)
  • crystalline tosylate defined by a different peak set (Claim 47)
• It adds composition claims with tight impurity and residual limits, including quantified ceilings for Compounds IIa/IIb/IIc/9A, plus ethanol (down to ≤1000 ppm) and propargyl bromide (down to ≤30 ppm).

---

FAQs

1) Can a competitor avoid US 12,582,634 by changing the alkylating agent from propargyl bromide to another propargyl sulfonate?
The alkylating agent scope is LG-based in claim 1 and then explicitly covers multiple propargyl derivatives in dependent claims, so switching within the covered LG categories may not avoid the process claims.

2) Do the XRPD crystalline claims require a specific manufacturing step?
No. Claim 46/47 define the solid forms by XRPD peak sets and anhydrous characterization, so infringement can hinge on the form used/sold rather than the exact crystallization method.

3) If a generic maker avoids the phase-transfer catalyst, are they still exposed?
They can still be exposed through the crystalline form and composition impurity/residual claims if the resulting API and finished material meet the claimed XRPD and quantitative specifications.

4) How do the impurity limits affect practical product release testing?
The claims require specific maximums (e.g., IIa/IIb/IIc percentages; ethanol ppm; propargyl bromide ppm), so batch testing and controls must demonstrate compliance with the claimed acceptance ranges.

5) What part of the patent is most likely to be litigated: process or formulation specs?
This patent supports both theories; the highest-information dispute typically occurs where analytical results can be mapped to the claimed impurity/residual grids and XRPD form definitions, alongside comparisons to the phase-transfer alkylation conditions.

---

References

No sources were provided in the prompt beyond the claims text itself, and no bibliographic identifiers (publication number, filing date, priority date, assignees, prosecution history, or prosecution citations) were included.

Drugs Protected by US Patent 12,582,634

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Neurocrine	CRENESSITY	crinecerfont	CAPSULE;ORAL	218808-001	Dec 13, 2024		RX	Yes	No	12,582,634			Y
Neurocrine	CRENESSITY	crinecerfont	CAPSULE;ORAL	218808-002	Dec 13, 2024		RX	Yes	No	12,582,634			Y
Neurocrine	CRENESSITY	crinecerfont	CAPSULE;ORAL	218808-003	Dec 13, 2024		RX	Yes	Yes	12,582,634			Y
Neurocrine	CRENESSITY	crinecerfont	SOLUTION;ORAL	218820-001	Dec 13, 2024		RX	Yes	Yes	12,582,634			Y

International Family Members for US Patent 12,582,634

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2019393256
Australia	2021289538
Australia	2025205083
Brazil	112021010847
Canada	3121920