Details for Patent: 4,652,441

Summary for Patent: 4,652,441

Title:	Prolonged release microcapsule and its production
Abstract:	A microcapsule produced by preparing a water-in-oil emulsion comprising an inner aqueous layer containing said water-soluble drug and a drug retaining substance therefor and an oil layer containing a polymer substance, then thickening or solidifying said inner aqueous layer to a viscosity of not lower than about 5000 centiposes and finally subjecting the resulting emulsion to in water drying gives prolonged release of water-soluble drug.
Inventor(s):	Hiroaki Okada, Yasuaki Ogawa, Takatsuka Yashiki
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US06/667,096
Patent Claim Types: see list of patent claims	Use; Dosage form;

Scope and Claims Analysis for US Patent 4,652,441 (Prolonged-Release Polypeptide Microcapsules) US4,652,441 claims a specific prolonged-release injectable microcapsule platform: water-in-oil microencapsulation of a biologically active polypeptide using a protein/biopolymer “drug retaining substance” and a lactic acid-glycolic acid (PLGA) or polylactic acid (PLA) polymer in the oil phase, followed by viscosity control of the inner aqueous layer, ternary emulsion formation (W/O/W), and solvent desorption to form 2–200 µm microcapsules.

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What is US Patent 4,652,441 and what does it cover?

US4,652,441 covers prolonged-release microcapsules for injection that encapsulate biologically active polypeptides in an inner aqueous phase. The oil phase contains a lactic acid polymer system (PLGA or PLA). The process requires (1) forming a water-in-oil emulsion, (2) thickening or solidifying the inner aqueous layer to a minimum viscosity threshold, (3) admixing with a third aqueous layer to form a water/oil/water ternary emulsion, and (4) desorbing solvent from the oil layer to create the final microcapsules.

Core protected subject matter

• Product: prolonged-release microcapsules (2–200 µm) containing a polypeptide dispersed/retained in an inner aqueous layer.
• Process: producing the microcapsules using a defined emulsion architecture and viscosity threshold before ternary emulsification and solvent desorption.

How broad are the independent claims (Claim 1 and Claim 9)?

Both Claim 1 (product) and Claim 9 (method) are broad by component class (polypeptide; drug retaining substance selected from gelatin/albumin/pectin/agar; polymer selected from PLGA or lactic acid polymer; generic emulsion processing steps), while narrow by numeric/process constraints:

• Particle size: “about 2 to 200 µm.”
• Oil-phase polymer selection: lactic acid-glycolic acid copolymer or lactic acid polymer (covers PLGA and PLA-type polymer systems).
• Inner aqueous layer viscosity: at least ~5000 cP for Claim 1.
• Ternary emulsion: requires “admixing… with a third aqueous layer to give a water/oil/water ternary layer emulsion.”
• Solidification/thickening step: must occur before ternary emulsification.

Featured-snippet answer (product)

Claim 1 protects PLGA/PLA-based W/O/W prolonged-release microcapsules (2–200 µm) containing a polypeptide retained with gelatin/albumin/pectin/agar, made via a viscous/thickened inner aqueous layer (≥5000 cP) followed by ternary emulsification and solvent desorption.

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What is the claim construction for “prolonged release microcapsule” under US 4,652,441?

The patent is structured around a microencapsulation system where polymer in the oil phase forms the release-controlling matrix. “Prolonged release” is not tied to a quantified release profile in the claim text you provided, so practical claim construction focuses on:

• the material architecture (polypeptide in inner aqueous; polymer in oil; final microcapsule formed by solvent desorption), and
• the process constraints that drive formation of an encapsulating polymer structure capable of sustained release.

Is the “prolonged release” limitation quantified?

Not in the claim language provided. For enforcement, the limitation will be assessed through the microcapsule’s functional result and how the claimed process yields a sustained-release structure, but the literal claim hook is the specific microcapsule system and its preparation.

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How do the key structural limitations define the microcapsule scope in Claim 1?

Claim 1 is a composition-of-structure claim. Each limitation narrows the covered embodiments:

1) Particle size range

• “average diameter of about 2 to 200 µm” This is typically a hard numeric range in literal analysis. The “about” qualifier introduces tolerance, but a challenger would focus on whether an accused product’s size distribution falls outside the range.

2) Emulsion architecture requirement

Claim 1 requires the microcapsule produced by:

• preparing a water-in-oil emulsion with an inner aqueous layer containing:
  • the polypeptide
  • drug retaining substance selected from gelatin/albumin/pectin/agar
• an oil layer containing polymer:
  • PLGA (lactic acid-glycolic acid copolymer) or lactic acid polymer (PLA-type)
• then thickening or solidifying the inner aqueous layer to viscosity ≥5000 cP
• then admixing with a third aqueous layer to form water/oil/water ternary emulsion
• then desorbing solvent in the oil layer

Even though the claim is to a product, the recited process steps define the product scope as the microcapsule “having” the characteristics of being produced by that emulsion route.

3) Inner aqueous “drug retaining substance” selection

Drug retaining substance is limited to one of four classes:

• gelatin
• albumin
• pectin
• agar

This is an explicit closed set in Claim 1 as written (“selected from a member of the group consisting of…”).

4) Oil polymer selection

Oil polymer is limited to:

• lactic acid-glycolic acid copolymer (PLGA)
• lactic acid polymer (PLA type)

This excludes non-lactic polymers (e.g., polycaprolactone, ethyl cellulose, PEG-based matrices) from literal infringement if they replace the defined polymer.

5) Viscosity threshold for inner aqueous layer

• thickening or solidifying inner aqueous layer to viscosity not lower than ~5000 centipoises This is a key numeric threshold. It is also a process-derived structural limitation: it affects droplet formation and final encapsulation morphology.

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What specific polypeptide is covered by dependent Claim 2?

Claim 2 narrows Claim 1 to a specific polypeptide sequence:

• “(Pyr) Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-C2H5.”

That identifies a particular polypeptide with a C-terminal ethylamide group and a N-terminal “(Pyr)” residue as written. Under dependent-claim practice, Claim 2 provides a tighter target for enforcement and licensing around that exact peptide identity.

Implication for product coverage

• A microcapsule product using a different biologically active polypeptide may fall under Claim 1 but not Claim 2.
• A microcapsule using the specified polypeptide but with a different retaining substance or polymer might avoid Claim 1 depending on what is substituted.

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Which formulation variants are expressly protected by dependent Claims 3–6?

These dependent claims narrow Claim 1 by selecting specific retention and polymer parameters.

Claim 3: gelatin as retaining substance

• Retaining substance = gelatin. This can matter when a competitor uses albumin/pectin/agar.

Claim 4 and 5: PLGA composition and ratio

• Claim 4: polymer = copolymer of lactic acid and glycolic acid (PLGA)
• Claim 5: ratio lactic acid:glycolic acid = 75:25

These provide an explicit PLGA grade target. If an accused microcapsule uses a PLGA with a different lactide:glycolide ratio, it may evade these dependent claims while still potentially implicating the broader Claim 1 (which does not specify the ratio).

Claim 6: polylactic acid

• polymer = polylactic acid (PLA) This gives coverage for PLA-only oil-phase systems within the “lactic acid polymer” concept.

How these dependent claims affect infringement strategy

• Competitors using PLGA may be caught by Claim 1 but will assess whether they align with the viscosity requirement and polymer identity.
• Competitors using PLGA with a non-75:25 ratio avoid Claim 5 but remain exposed to Claim 1.

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What do Claims 7 and 8 add about viscosity and solidification?

Claim 7: higher viscosity

• thickened/solidified inner aqueous layer viscosity not less than ~10,000 cP (vs. 5000 cP in Claim 1)

This is a narrower threshold. A process hitting ≥10,000 cP can fall under Claim 7 in addition to Claim 1.

Claim 8: solidification

• “inner aqueous layer is solidified” This is broader than a specific method but narrows away from embodiments that only thicken without solidifying.

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What is the protected manufacturing process in Claim 9, and where can a generic platform diverge?

Claim 9 is a method claim that recites nearly the same elements as Claim 1:

• water-in-oil emulsion with inner aqueous polypeptide + drug retaining substance,
• oil layer polymer = PLGA/PLA,
• thicken/solidify inner aqueous to viscosity ≥5000 cP,
• form water/oil/water ternary emulsion by adding third aqueous layer,
• desorb solvent in oil layer.

Where process design-arounds typically attack under this claim

Literal non-infringement opportunities (conceptually) stem from avoiding at least one required element:

• Use a different polymer system than PLGA/PLA in the oil layer.
• Eliminate or alter the viscosity-thickening/solidifying step or ensure it is below the claimed threshold.
• Avoid the explicit W/O/W ternary emulsification sequence as claimed.
• Use a different “drug retaining substance” outside gelatin/albumin/pectin/agar.

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How many patents cover the same microcapsule architecture around US 4,652,441?

No patent count can be produced from the information provided. The supplied text is only the claim set for US4,652,441, not a patent family map or citation set.

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What is the probable scope of enforcement given the claims are process-defined?

Because Claim 1 is a product claim defined by how it is made, enforcement often hinges on:

• matching the product’s functional and structural attributes implied by the claimed manufacturing route,
• establishing that the accused product is made by the same emulsion/viscosity/ternary-solvent desorption method, or
• proving equivalence if a court adopts broader claim interpretation (not addressed by the claim text you provided).

Business consequence: licensing or freedom-to-operate (FTO) analysis must evaluate both the material choices (retaining substance and polymer) and the process controls (inner aqueous viscosity threshold and W/O/W formation).

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What technical equivalents are excluded by “consisting of” language?

Claim 1 uses closed-set selection for:

• drug retaining substance: gelatin/albumin/pectin/agar So substituting a different retaining matrix (e.g., HPMC as a retaining polymer, casein variants, or synthetic hydrogels) likely avoids literal coverage for that element.

Oil polymer selection is not framed with a closed “consisting of” in your excerpt, but it is phrased as “selected from a member of the group consisting of” for the retaining substance only. For the oil layer, the claim text states polymer substance of PLGA or lactic acid polymer as the oil layer component, which will still be treated as a required limitation.

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Key litigation and Orange Book status for US 4,652,441

No litigation posture, Orange Book listings, or FDA regulatory mappings can be derived from the information provided. The claim text does not identify the drug product, NDA/ANDA/BLA, or listed patents.

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Timeline: when does exclusivity end for US 4,652,441?

A definitive expiration date cannot be calculated from the claim text alone. Patent expiration depends on:

• filing date,
• application/prosecution history,
• term adjustments,
• potential patent term adjustments or extensions (where applicable).

No filing/priority data was provided.

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Comparative risk: how would a PLGA microcapsule with different retention polymers compare to this patent?

Using Claim 1 as the benchmark:

If the competitor uses gelatin retaining substance

• Higher risk under Claim 3 and potentially Claim 1, depending on process and polymer identity.

If the competitor uses albumin/pectin/agar instead of gelatin

• Still within Claim 1 (and potentially avoids Claim 3).

If the competitor uses the same emulsion route but uses a non-listed retaining substance

• Avoids the explicit retention substance limitation in Claim 1.

If the competitor changes lactide:glycolide ratio

• Claim 5 (75:25) may be avoided; Claim 1 remains a risk unless they also step outside the defined PLGA/PLA polymer selection.

If the competitor uses a polymer other than PLGA/PLA

• Avoids Claim 1’s oil-phase polymer limitation if the oil polymer is not lactic-acid-based as claimed.

If the competitor avoids W/O/W ternary formation

• Avoids the explicit ternary emulsion requirement for Claim 1 and Claim 9.

If the competitor tunes inner aqueous viscosity

• If inner aqueous viscosity is below the claimed threshold, they may avoid Claim 1 and Claim 9.
• If they exceed 10,000 cP, they may enter Claim 7.

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What patent strength signals can be assessed from the claim structure alone?

US4,652,441 has moderate-to-strong structural specificity due to:

• numeric particle size range,
• closed retention matrix set,
• defined PLGA/PLA polymer system,
• explicit inner aqueous viscosity threshold,
• mandatory W/O/W ternary emulsion and solvent desorption.

Weaknesses are not evident from claim text but would typically come from:

• prior art narrowing (not assessed here),
• potential claim interpretation issues with “about” ranges,
• dependence on a process-derived definition for a product claim.

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Key Takeaways

• US4,652,441 Claim 1 protects 2–200 µm prolonged-release injectable microcapsules made via W/O emulsion with PLGA/PLA oil polymer, containing a polypeptide retained by gelatin/albumin/pectin/agar, with inner aqueous viscosity ≥5000 cP, followed by W/O/W ternary emulsification and solvent desorption.
• Dependent claims add tighter scope: specific peptide (Claim 2), gelatin (Claim 3), PLGA and specifically 75:25 lactide:glycolide (Claims 4–5), PLA (Claim 6), higher inner viscosity ≥10,000 cP (Claim 7), and solidified inner aqueous layer (Claim 8).
• Claim 9 recites the full process, giving the cleanest enforcement path for alleged manufacturing of microcapsules meeting the exact steps and thresholds.
• A competitor’s main design-around levers are: retaining substance class, oil-phase polymer class, inner aqueous viscosity threshold, and whether a W/O/W ternary emulsion with solvent desorption is performed as claimed.

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FAQs

1) Does US 4,652,441 protect microcapsules made with non-lactic polymers like PLGA substitutes (e.g., PCL)?
No, Claim 1 requires an oil layer polymer defined as lactic acid-glycolic acid copolymer or lactic acid polymer.

2) Can a different polypeptide be covered under Claim 1?
Yes. Claim 1 covers biologically active polypeptides generally; the specific peptide in Claim 2 is an added limitation.

3) If a formulation uses albumin instead of gelatin, which claims are implicated?
Claim 1 still can apply because albumin is within the listed retaining substance set; Claim 3 (gelatin) would not.

4) What is the practical importance of the 5000 cP viscosity limitation?
It is a hard threshold defining the thickening/solidifying step in both Claim 1 and Claim 9, and it can be a key divergence point in process validation.

5) Does Claim 5 (75:25) automatically apply to all PLGA microcapsules?
No. Claim 5 adds a specific lactide:glycolide ratio; other PLGA ratios may remain exposed under Claim 1 while avoiding Claim 5.

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References

No external sources were provided or cited in the prompt.

Drugs Protected by US Patent 4,652,441

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: 4,652,441

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	58-207760	Nov 04, 1983

International Family Members for US Patent 4,652,441

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	42197
Bulgaria	60493
Canada	1233414
Germany	3477732
European Patent Office	0145240
Spain	8605983