Details for Patent: 4,931,288

Summary for Patent: 4,931,288

Title:	Controlled release compositions (II)
Abstract:	A controlled release composition comprising a prostaglandin and a polymeric carrier therefor comprising residues having a ratio of number average molecular weight to functionality greater than 1,000 which comprise polyethylene oxide and are cross-linked through urethane groups.
Inventor(s):	Mostyn Embrey, Neil B. Graham
Assignee:	BTG International Ltd
Application Number:	US07/188,674
Patent Claim Types: see list of patent claims	Use; Composition; Compound;

Scope, Claims, and US Patent Landscape for Drug US 4,931,288

US Patent 4,931,288 claims a controlled release composition in which a prostaglandin is dispersed in a specific cross-linked polymeric carrier made from polyethylene oxide (PEO) residues, cross-linked through urethane groups (or analogues), with strict limits on molecular architecture (PEO functionality vs number-average molecular weight ratio), cross-link density, and PEO content, plus material-performance constraints (crystalline regions in the dry state at 20°C and syneresis in the wet state). Claims then broaden by allowing additional drugs, alternative prostaglandins/synthetic analogues, and multiple dosage forms and use indications.

This is a platform-style composition claim with device and therapeutic-use hooks layered on top.

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What is the core claim scope?

What does claim 1 actually require? (independent claim architecture)

Claim 1 recites a controlled release composition with these mandatory components and properties:

1. Actives

   • At least one prostaglandin (broadly stated at claim 1 level).

2. Polymeric carrier identity

   • A polymeric carrier “comprising residues”:
     • cross-linked through urethane groups (or analogues).
     • comprising polyethylene oxide (PEO).

3. PEO molecular architecture constraint

   • Ratio of number-average molecular weight (Mn) to functionality of the PEO must be > 1,500.
   • Functionality is tied to the number of reactive sites in the PEO building block (implied by the later dependent claim defining “reaction product of a mixture” with di-, tri-, or tetra-substituted compounds reacted with ethylene oxide).

4. Cross-link density constraint

   • There must be at least:
     • 1 cross-linking point per 10 PEO residues (at minimum).
   • The degree of cross-linking must be balanced so that PEO still dominates by mass:
     • “but such that the proportion of the said polyethylene oxide is greater than 50% by weight of the polymeric carrier.”

5. Material state and performance constraints

   • When prostanglandin-free, the carrier:
     • is a hydrogel in the dry form at 20°C,
     • contains crystalline regions,
     • exhibits syneresis in the wet form.

Claim 2 repeats nearly all of the above but phrases the hydrogel state “in the presence of said prostaglandin.”

Legal effect: The carrier must satisfy a set of physicochemical constraints (crystallinity and syneresis) that can be used as non-obvious, measurable limitations for infringement analysis and validity challenges.

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What are the claim-by-claim expansion points?

How do dependent claims narrow or broaden the scope?

Below is a structured mapping of what each dependent claim adds.

Additional drug stacking

• Claim 3/4: Adds “an additional drug other than a prostaglandin.”
  • Claim 3 ties to claim 1 carrier condition (prostanglandin-free hydrogel parameters).
  • Claim 4 ties to claim 2 language (carrier performance “in the presence of said prostaglandin”).

Scope impact: Enables combination products while keeping the same carrier architecture.

PEO Mn/functionality threshold strengthening

• Claim 5: Mn/functionality > 2,000 (higher threshold than claim 1).

Scope impact: A narrower subset of claim 1 where PEO chain architecture is more extended relative to functionality.

PEO precursor definition (synthesis route for PEO)

• Claim 6: PEO is “the reaction product of a mixture comprising”

  • (i) an aliphatic/aromatic compound di-, tri-, or tetra-substituted by hydroxyl/carboxyl/amino/mercapto groups,
  • (ii) ethylene oxide.

• Claim 7: component (i) comprises a di- or tri-hydroxyl-substituted aliphatic compound.

Scope impact: This is a specific process/formulation definition. For infringement, it gives a path to argue PEO composition is limited to PEO built from certain polyfunctional initiators.

Cross-link density tightening

• Claim 8: at least 1 cross-linking point per 5 residues of PEO.
• Claim 9: at least 1 cross-linking point per residue of PEO.

Scope impact: Highest density is claim 9; it does not remove the general claim 1 requirement that PEO remains >50 wt%, but it pushes toward higher cross-linking.

PEO content tightening

• Claim 10: PEO proportion > 70 wt%.
• Claim 11: PEO proportion > 80 wt%.

Scope impact: These carve out higher PEO loading formulations.

Allowance for other polyalkylene oxide

• Claim 12: carrier can include up to 20 wt% of an “additional polyalkylene oxide.”

• Claim 13: up to 20 wt% additional PEO with Mn/functionality not greater than 1000.

Scope impact: This is an internal heterogeneity permission: the carrier can include lower-Mn/functionality PEO fraction while still meeting the claim 1 overall PEO Mn/functionality ratio limitation (though the independent claim sets the condition on “polyethylene oxide having a ratio … > 1,500,” so interpretation hinges on whether “polyethylene oxide” refers to the main PEO fraction or any PEO present).

Water-extractable fraction constraint

• Claim 14: up to 30 wt% water-extractable fraction.
• Claim 15: reduced to no more than 5 wt%.

Scope impact: Defines extractables and indirectly stability and network completeness.

Prostaglandin subgroup limitations

• Claim 16: naturally occurring prostaglandins of E and Fα groups.
• Claim 17: PGE2 or PGF2α.
• Claim 18-19: synthetic analogues, listing multiple named analogues including:
  • 15-methyl-PGF2α
  • 16,16-dimethyl-PGE2
  • 16,16-dimethyl-PGE2 parabenzaldehyde semicarbazone ester
  • 16-phenoxy-17,18,19,20-tetranor-PGE2
  • 16,16-dimethyl-trans Δ2-PGE1 and its methyl ester
  • 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF2α

Scope impact: Broad at claim 1; narrower at claims 16-19, but those narrower claims can still be strong enforcement targets where those prostaglandins are used.

Dosage form limitations

• Claim 20: cylinder, film, or slab.
• Claim 21: cylinder can be hollow; film/slab can have holes/hollows to modify release.

Scope impact: Not just chemistry; this covers practical implant-like or vaginal insert-like formats.

Therapeutic and use claims

• Claim 22: use as an abortifacient.
• Claim 23: use in induction of labor.
• Claim 24: use as a contraceptive.
• Claim 25: use in treatment of schizophrenia.
• Claim 26: use in treatment of cervical incompetence in livestock.

Scope impact: The therapeutic-use spread is broad and includes both human and veterinary applications, including indications that are mechanistically distinct (contraception/abortion/labor induction vs schizophrenia). If enforced, this increases the number of infringement theories depending on regulatory labels and intended use.

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How does the claim language shape infringement risk?

What technical features are most likely to determine infringement?

Given the claim set, infringement analysis would typically hinge on four technical axes:

1. Cross-link chemistry

   • Must be urethane-cross-linked residues (or analogues).
   • Alternative cross-linkers likely avoid literal coverage unless they qualify as “analogues.”

2. PEO molecular ratio

   • Mn/functionality > 1,500 (independent claim).
   • If the product PEO does not meet this ratio, it fails a hard limitation.

3. Network density

   • Cross-link density at least 1 per 10 PEO residues.
   • If the network is too lightly cross-linked, it may fail.

4. Material behavior

   • Crystalline regions in the dry, prostaglandin-free hydrogel at 20°C.
   • Syneresis in the wet form.

These are performance-based limitations that can be measured. They also reduce over-breadth compared with purely structural hydrogel claims.

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What is the US patent landscape around this composition?

What else is in the landscape? (high-level map of relevant IP themes)

US 4,931,288 sits at the intersection of:

• Controlled release prostaglandin delivery systems
• Hydrogel matrices with high PEO content
• Urethane cross-linked polymer networks (or functional equivalents)
• Embodied dosage forms (cylinders, films, slabs with holes)

This landscape usually includes:

• patents on prostaglandin depots (vaginal inserts, intrauterine systems, cervical/labor induction devices),
• patents on hydrogel controlled release (including PEO-containing networks),
• patents that tune release rate with cross-link density and extractables,
• and patents that tie specific prostaglandins to specific delivery architectures.

Where are likely competitors positioned relative to this patent?

In practice, competitive designs typically shift one or more of:

• cross-link chemistry (avoid urethane cross-links or argue “analogues” not met),
• PEO molecular architecture (fail Mn/functionality threshold),
• PEO wt% dominance (keep PEO below thresholds like 70%/80% and argue independent claim “>50%” not met),
• network behavior (reduce crystallinity or syneresis characteristics),
• dosage form embodiment (still controlled release but use different geometry, or different matrix chemistry).

The claim language makes “close variants” contestable based on measurable attributes like crystallinity and syneresis.

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Claims breadth vs. enforceability profile

How broad is the independent claim relative to dependent claims?

• Claim 1 is broad in:
  • prostaglandin type (any prostaglandin),
  • dosage forms (only claim 20-21 specify form),
  • carrier composition up to the PEO/urethane/network constraints.
• Claim 1 is narrow in that it requires:
  • PEO Mn/functionality ratio above a numeric threshold,
  • specific minimum cross-linking density,
  • PEO content above 50 wt%,
  • and specific physical behavior (crystalline regions; syneresis).

This blend often yields a patent that is chemically and physically defined rather than merely “prostaglandin + hydrogel.”

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Practical competitive takeaways from the claim set

What design-around vectors exist within the claim language?

Potential design-around moves, based on the claim’s hard limitations:

• Reduce PEO content to ≤50 wt% of the polymeric carrier (aims at failing the independent “greater than 50% by weight” constraint).
• Use a polymer network that is not urethane cross-linked residues (or deny it is an “analogue”).
• Use PEO with Mn/functionality ≤ 1,500 for the relevant fraction.
• Reduce cross-link density to below 1 per 10 residues.
• Engineer the matrix to eliminate crystalline regions at 20°C (dry, prostaglandin-free).
• Engineer to avoid syneresis in wet state (key performance limitation).

These do not require changing the prostaglandin; they target the matrix definition that controls infringement.

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Key Takeaways

• US 4,931,288 claims a controlled release prostaglandin composition using a urethane-cross-linked PEO hydrogel defined by numeric constraints on PEO Mn/functionality (>1,500), cross-link density (≥1 per 10 PEO residues), and PEO loading (>50 wt%), plus physicochemical performance (crystalline regions dry at 20°C and syneresis wet).
• The dependent claims add narrower bands (>2,000 Mn/functionality; >70% or >80% PEO), allow defined mixture PEO synthesis origins (polyfunctional initiator + ethylene oxide), allow blends with other polyalkylene oxides (≤20 wt%), control extractables (≤30 wt% or ≤5 wt%), and cover prostaglandin species down to named synthetic analogues.
• Use claims span abortifacient, labor induction, contraception, schizophrenia, and cervical incompetence in livestock, creating multiple potential enforcement hooks tied to product labeling and intended use.
• The most infringement-determinative elements are the urethane cross-linking, the PEO molecular ratio, the cross-link density, and the dry crystallinity/syneresis behavior.

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FAQs

1) Does claim 1 require prostaglandin-free testing results?

Yes. Claim 1 requires that when prostaglandin-free, the carrier at 20°C is a hydrogel in the dry form, has crystalline regions, and exhibits syneresis in the wet form.

2) What are the numeric thresholds that most constrain product scope?

Key constraints in claim 1 are: PEO Mn/functionality > 1,500, ≥1 cross-link point per 10 PEO residues, and PEO wt% > 50%.

3) Can the composition include additional drugs?

Yes. Claim 3/4 add “an additional drug other than a prostaglandin.”

4) Does the patent cover specific prostaglandins like PGE2 and PGF2α?

Yes. Claim 17 specifies PGE2 or PGF2α; claim 19 lists multiple synthetic analogues.

5) What dosage forms are explicitly claimed?

Claim 20 limits to cylinder, film, or slab, and claim 21 adds hollow or hole features to modify release properties.

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References

[1] US Patent 4,931,288, “Controlled release composition comprising prostaglandin and urethane cross-linked polyethylene oxide hydrogel,” claims as provided in the prompt.

Drugs Protected by US Patent 4,931,288

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

Foreign Priority and PCT Information for Patent: 4,931,288

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	7909853	Mar 21, 1979

International Family Members for US Patent 4,931,288

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	14979
Austria	15444
Australia	537740
Australia	537741