Details for Patent: 5,731,327

Summary for Patent: 5,731,327

Title:	Synthesis of 3- 4-(2-aminoethoxy)benzoyl!-2-aryl-6-hydroxybenzo b!thiophenes
Abstract:	The present invention is directed to chemical processes for preparing 2-aryl-6-hydroxy-3- 4-(2-aminoethoxy)benzoyl!benzo b!-thiophenes. The present invention is also directed to crystalline solvates and a non-solvated crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3- 4-(2-piperidinoethoxy)benzoyl!-benzo b!thiophene hydrochloride, as well as processes for their preparation.
Inventor(s):	Wayne Douglas Luke
Assignee:	Eli Lilly and Co
Application Number:	US08/467,485
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Process;

US Patent 5,731,327: Scope, Claims, and U.S. Patent Landscape for Non-Solvated Crystalline Hydrochloride

What is the patented subject matter in US 5,731,327?

US Patent 5,731,327 claims protection around a specific chemical substance: non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-(4-(2-piperidinoethoxy)benzoyl)-benzo[b]thiophene hydrochloride (the “crystalline hydrochloride”), defined by (i) non-solvated physical form, (ii) X-ray diffraction (XRD) pattern, and (iii) preparation routes that convert a solvated form to the non-solvated crystalline form. The patent also covers downstream pharmaceutical formulation use.

The claims, as provided, define:

• Product-by-structure/physical form: crystalline hydrochloride that is non-solvated and has an XRD fingerprint.
• Product-by-quantitative purity: at least 95% by weight of the named crystalline free-base/active hydrochloride entity (as written in the claim).
• Process claims: converting a solvated form in methanol (or methanol-water) using ~1 equivalent base, followed by aliphatic hydrocarbon extraction (for one process set), then acid addition (HCl, about one equivalent) and crystallization/isolating.
• Formulation claim: pharmaceutical composition containing the crystalline compound plus pharmaceutically acceptable excipients.

What do Claims 1-2 protect (product scope)?

Claim 1: non-solvated crystalline hydrochloride defined by an XRD pattern

Claim 1 is the core product claim. It requires that the compound is:

• “Non-solvated crystalline”
• the specific named chemical: 6-hydroxy-2-(4-hydroxyphenyl)-3-(4-(2-piperidinoethoxy)benzoyl)benzo[b]thiophene hydrochloride
• having “substantially the following X-ray diffraction pattern obtained with copper radiation,” followed by a list of 2-theta d-spacing values and relative intensities.

Provided XRD list (Cu radiation) from Claim 1 (d-spacing Angstroms, I/I0 × 100):

• 13.3864 (71.31)
• 9.3598 (33.16)
• 8.4625 (2.08)
• 7.3888 (7.57)
• 6.9907 (5.80)
• 6.6346 (51.04)
• 6.1717 (29.57)
• 5.9975 (5.67)
• 5.9135 (9.87)
• 5.6467 (38.47)
• 5.4773 (10.54)
• 5.2994 (4.74)
• 4.8680 (4.03)
• 4.7910 (5.98)
• 4.6614 (57.50)
• 4.5052 (5.75)
• 4.3701 (9.03)
• 4.2516 (69.99)
• 4.2059 (57.64)
• 4.1740 (65.07)
• 4.0819 (12.44)
• 3.9673 (22.53)
• 3.9318 (100.00)
• 3.8775 (9.07)
• 3.7096 (33.38)
• 3.6561 (21.65)
• 3.5576 (3.36)
• 3.5037 (7.97)
• 3.4522 (18.02)
• 3.4138 (4.65)
• 3.2738 (10.23)
• 3.1857 (8.90)
• 3.1333 (6.24)
• 3.0831 (9.43)
• 3.0025 (12.13)
• 2.9437 (4.96)
• 2.8642 (7.70)
• 2.7904 (11.95)
• 2.7246 (3.05)
• 2.6652 (3.32)
• 2.5882 (7.30)

Practical claim boundary: infringement is tied to the solid-state form and XRD match (“substantially” indicates some tolerance, but the claim still sets a specific fingerprint). If a competitor’s polymorph, hydrate, solvate, amorphous material, or a different crystalline form yields a meaningfully different XRD profile, it can fall outside the literal product definition.

Claim 2: composition purity constraint

Claim 2 narrows Claim 1 by requiring that the amount of 6-hydroxy-2-(4-hydroxyphenyl)-3-4-(2-piperidinoethoxy)benzoyl-benzo[b]thiophene hydrochloride present is at least 95% by weight.

Effect on scope: This is a quality gate. A material that matches the Claim 1 XRD but contains significant impurities/other solid forms could avoid Claim 2 even if Claim 1 might be argued.

What do Claims 3-11 protect (process and product-by-process)?

Claims 3-9 provide two process “sets” for preparing the same non-solvated crystalline hydrochloride, and Claims 10-11 extend protection to the product when prepared by those processes.

Claim 3: process with extraction step

Claim 3 requires steps:

(a) React a solvated form of the named compound in methanol or methanol-water mixture with about one equivalent of base
(b) Extract the solution from (a) with an aliphatic hydrocarbon solvent
(c) Add about one equivalent of hydrochloric acid to the methanolic solution from (b)
(d) Isolate the crystalline compound

This claim establishes the technical route for converting a solvated solid into the targeted non-solvated crystalline hydrochloride using:

• base in alcohol (methanol or methanol-water)
• phase/extraction with nonpolar hydrocarbon
• then hydrochloric acid to set the hydrochloride and drive crystallization

Claim 4: hydrocarbon solvent exemplars

Claim 4 narrows Claim 3 by specifying the aliphatic hydrocarbon solvent as hexane or heptane.

Claim 5: base

Claim 5 specifies the base as sodium hydroxide.

Claim 6: acid concentration

Claim 6 specifies hydrochloric acid as 2 N aqueous.

Claim 7: process without hydrocarbon extraction

Claim 7 is the simplified process: (a) React a solvated form in methanol or methanol-water with about one equivalent of base
(b) Add about one equivalent of hydrochloric acid to the methanolic solution
(c) Isolate the crystalline compound

This claim covers a route that omits the aliphatic hydrocarbon extraction step.

Claim 8-9: dependent restrictions

• Claim 8: base is sodium hydroxide
• Claim 9: HCl is 2 N aqueous

Claims 10-11: product-by-process

• Claim 10: the crystalline hydrochloride when prepared by the process of claim 3
• Claim 11: the crystalline hydrochloride when prepared by the process of claim 7

Scope effect: Product-by-process claims can be litigated as to whether the resulting product is the same (especially where the product is already defined by structure/solid-state characteristics in Claim 1). Here, Claim 1 already anchors the product via XRD, so the product-by-process claims strengthen enforcement if challengers argue the product differs or dispute the process provenance.

What does Claim 12 protect (formulation scope)?

Claim 12 covers:

• a pharmaceutical formulation containing:
  • the crystalline compound of claims 3-4 (as written), and
  • one or more pharmaceutically acceptable carriers, diluents, or excipients

Scope effect: This is a standard downstream composition claim. It depends on the crystalline compound being within the scope of the referenced claims. As written, it references “claims 3-4,” which implies the compound prepared under the extraction-containing process with specific solvent embodiment (Claim 4) or the process set in Claim 3.

What is the internal claim hierarchy and how it impacts infringement analysis?

Claim dependency map (from provided text)

• Claim 1: independent product (non-solvated crystalline, XRD-defined)
• Claim 2: Claim 1 + ≥95% by weight purity
• Claim 3: independent process with extraction
• Claim 4: Claim 3 + solvent hexane/heptane
• Claim 5: Claim 3 + base NaOH
• Claim 6: Claim 3 + 2 N HCl
• Claim 7: independent process without extraction
• Claim 8: Claim 7 + base NaOH
• Claim 9: Claim 7 + 2 N HCl
• Claim 10: product-by-process tied to Claim 3
• Claim 11: product-by-process tied to Claim 7
• Claim 12: formulation using crystalline compound referenced by claims 3-4

Key infringement levers

1. Solid state match: Claim 1 turns on “substantially” matching the listed XRD peaks under Cu radiation.
2. Quality threshold: Claim 2 adds a ≥95% by weight requirement.
3. Process sequence:
   • Claim 3 requires hydrocarbon extraction.
   • Claim 7 omits extraction.
4. Product-by-process: Claims 10-11 create an additional path to infringement by process provenance.

How broad is the claimed solid form versus alternative solid forms?

From the claim language, the protected object is not merely “the molecule” but a specific non-solvated crystalline hydrochloride solid form defined by XRD.

That means the landscape risk for competitors is highest if they market or manufacture a solid that:

• is hydrochloride salt of the same active chemical, and
• is non-solvated, and
• generates the claimed “substantially” XRD profile.

Competitor designs that target:

• solvated forms,
• hydrates or amorphous forms,
• polymorphs with different XRD fingerprints,
• alternative salt forms (if not hydrochloride),
• or different crystalline microstructures that shift key peaks beyond tolerance should reduce literal claim coverage under Claim 1.

U.S. patent landscape: what this patent is positioned to block

Given the provided claim set, US 5,731,327 is structurally positioned as a crystalline form / solid-form patent plus conversion processes. That is typical of follow-on IP designed to extend exclusivity or to block ANDA/biogeneric “same API, different form” strategies.

Primary enforcement posture

• Product-by-XRD (Claim 1): blocks marketing of the same non-solvated crystalline hydrochloride form.
• Quality constrained (Claim 2): blocks impure batches or mixtures with other solid forms.
• Process conversion (Claims 3 and 7): blocks manufacture routes that convert solvated form to the claimed non-solvated form using the recited steps.
• Product-by-process (Claims 10-11): supports enforcement when the market product is alleged to come from the patented process.

Secondary enforcement posture

• Formulation (Claim 12): extends protection into dosage forms that contain the crystalline material.

What “design-around” routes are implicitly carved out by the claim language?

Based on the claim text alone, typical avoidance strategies would be tied to altering one of the claim-defining elements:

• Avoid the patented solid form: use a different polymorph/solvate/hydrate/amorphous form that does not match the XRD fingerprint “substantially.”
• Avoid Claim 3 extraction step: if manufacturing can use a route consistent with Claim 7 (or a non-claimed sequence), but Claim 7 still exists. The practical target is to avoid both recited sequences while still producing the same marketed solid form.
• Avoid the specific chemical setup: Claim 3/7 require “about one equivalent” of base then “about one equivalent” of HCl, and Claim 4-6 and 8-9 specify NaOH and 2 N HCl. Use of different equivalents, different reagents, or different acid-base setup may avoid dependent claims though not necessarily the independent process if still within “about one equivalent” language.

Key takeaways

• US 5,731,327 centers on non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-(4-(2-piperidinoethoxy)benzoyl)benzo[b]thiophene hydrochloride, defined by an XRD pattern (Cu radiation) in Claim 1 and narrowed by ≥95% by weight in Claim 2.
• Process protection targets conversion from a solvated form using methanol or methanol-water, ~1 equivalent base, and ~1 equivalent HCl, with one route requiring aliphatic hydrocarbon extraction (Claim 3) and the other omitting it (Claim 7).
• Product-by-process claims (Claims 10-11) strengthen enforcement tied to manufacturing provenance.
• Formulation claim (Claim 12) extends IP to dosage forms containing the protected crystalline material.
• The main competitive risk is producing or selling a solid form that matches the Claim 1 XRD fingerprint while using manufacture routes that align with Claims 3 or 7.

FAQs

1. Is the patent primarily a solid-form (crystal) patent or a method patent?
   It is both. Claim 1 is a solid-form product claim defined by XRD, and Claims 3 and 7 are manufacturing methods that convert a solvated form into the non-solvated crystalline hydrochloride.

2. What single feature most strongly defines the product scope?
   The non-solvated crystalline form with the specified Cu-radiation XRD d-spacing pattern in Claim 1.

3. Does the patent protect different hydrochloride batches with impurities?
   Claim 2 adds a ≥95% by weight requirement of the named crystalline compound, so lower-purity material can fall outside Claim 2 even if Claim 1 might still be argued.

4. How does the patent treat manufacturing steps for the same target compound?
   It recites two routes: one with aliphatic hydrocarbon extraction (Claim 3) and one without that extraction step (Claim 7), both starting from a solvated form.

5. Does it cover finished dosage forms?
   Yes. Claim 12 covers a pharmaceutical formulation containing the crystalline compound referenced by claims 3-4 plus pharmaceutically acceptable excipients.

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References

1. United States Patent 5,731,327 (claims provided in prompt).

Drugs Protected by US Patent 5,731,327

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,731,327

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	754
African Regional IP Organization (ARIPO)	9700938
Austria	407988