Patent: 5,261,876

Summary for Patent: 5,261,876

Title:	Enhanced peritoneal membrane plasmapheresis
Abstract:	The method of treatment called peritoneal membrane plasmapheresis for removal of plasma proteins is enhanced by specification of a sequence of two or three solutions for instilling into and draining from the peritoneal cavity. Solution 1 contains a vosodilator, solution 3 contains no vasoactive drug, and solution 2 contains a vasoconstrictor. Choice of the sequence of solutions to be instilled and drained according to the claimed methods results in sustained opening of peritoneal membrane pores and substantially elevated rates of plasma protein removal, avoiding the problem of declining rates due to local tissue compensatory mechanisms which are observed when only solution 1 is used. Resulting protein removal rates in an anticoagulated patient compare favorably with those attainable with extracorporeal phasmapheresis. An analogous process may be carried out to increase the pore size of any biological membrane accessible to the solutions.
Inventor(s):	Popovich; Robert P. (Austin, TX), Moncrief; Jack W. (South Austin, TX), He; Zhengzhi (Austin, TX)
Assignee:	Moncrief-Popovich Research Institute, Inc. (Austin, TX)
Application Number:	07/899,676
Patent Claims:	see list of patent claims

US Patent 5,261,876 Claim Analysis and US Patent Landscape for Peritoneal Plasma-Removal Using Alternating Vasodilator/Vasoconstrictor Solutions

Executive summary: US 5,261,876 claims a peritoneal-cavity plasma-removal method that alternates (or serially sequences) a vasodilator-added physiologic solution and a vasoconstrictor-added physiologic solution to modulate permeability and maintain sustained plasma component clearance from the patient’s circulating blood. The independent claim is broad on the vasodilator/vasoconstrictor concept and serial/peritoneal instillation-drainage sequencing, while dependent claims materially narrow into (i) catheter geometry and simultaneous flows, (ii) dwell times (≈30 min to ≈8 h), (iii) tonicity regimes, (iv) specific drug exemplars (norepinephrine, dipyridamole, nitroprusside, histamine phosphate, dibenzyline), and (v) adjuncts (anticoagulants like heparin; protein-selective removal and reuse; catheter-pore anti-clogging). Practically, the defensible value of the estate is anchored in the specific combination of: (1) peritoneal instillation/drainage used as a blood-linked plasma-removal mechanism, (2) pharmacologic directionality via vasodilator then vasoconstrictor, and (3) maintenance of removal rate via the second pharmacologic phase. The broader landscape will typically include older peritoneal dialysis/ultrafiltration teachings and general use of vasoactive agents or altered tonicity to modulate transmembrane transport, but the combination approach is the primary differentiator that courts and examiners tend to scrutinize for obviousness.

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What does US Patent 5,261,876 claim and what is the technical core?

Core independent claim concept (Claim 1):
A method to remove plasma components from a patient by serial instilling and draining of two physiologic solutions in the peritoneal cavity, where:

• the first solution contains a vasodilator (to increase passage of plasma components into the peritoneal solution), then
• the second solution contains a vasoconstrictor (to prevent loss of clearance over time, i.e., prevent a material reduction in removal rate).

This is a two-phase pharmacologically modulated peritoneal clearance protocol: vasodilator-driven influx followed by vasoconstrictor-driven compensation to restore or maintain net clearance.

How Claim 1 is architected for enforceability

• Functional language drives scope: “added vasodilator” and “added vasoconstrictor” are defined functionally through their transport effects.
• Process sequencing is central: “serial instilling and draining” with two distinct phases.
• Anatomical location is fixed: peritoneal cavity.
• Delivery modality is generic in Claim 1: later claims specify catheter configuration and simultaneity.

Claim 4 expands into a blood-linked step sequence

Claim 4 is the more operational independent-like formulation (dependent on Claim 1, but it lays out explicit dwell timing and the patient-physiology linkage):

1. Instill vasodilator solution into peritoneal cavity.
2. Dwell to remove plasma components from circulating blood.
3. Drain.
4. Instill vasoconstrictor solution with effectiveness to prevent material reduction in removal rate.
5. Dwell again.
6. Drain.

Technical emphasis: the vasoconstrictor phase is justified by preventing a decline in removal performance caused by the preceding vasodilator exposure.

Dependent claims map directly to “common design-around vectors”

From an IP risk perspective, the estate’s claim coverage can be stress-tested against typical alternatives:

• Replace vasodilator/vasoconstrictor with non-vasoactive permeability agents.
• Use single-solution protocols with programmed tonicity or hypertonicity only.
• Use different extracorporeal routes (e.g., plasmapheresis/adsorption) rather than peritoneal in vivo removal.
• Avoid serial alternation by using continuous pumping with one pharmacologic additive.

The dependent claims do not eliminate that design-around risk because they are narrower; they mainly support credibility of the concept and capture specific protocol variants.

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Which additional claim features meaningfully narrow scope? (Claims 2-43)

Catheter architecture and simultaneous instillation/drainage

• Claims 2 and 3: simultaneous instilling and draining through first and second peritoneal catheters implanted in the peritoneal cavity.
• Claims 2 vs 3: differ by whether instilling and draining of the first solution occurs simultaneously or the second solution occurs simultaneously.

Enforcement impact: If an accused system uses sequential exchange without simultaneous catheter flows, Claim 1 and Claim 4 remain relevant; Claims 2-3 would not.

Multiple cycle/alternation patterns

• Claim 5: iterates vasodilator and vasoconstrictor phases in a cycle (vasodilator until clearance drops, vasoconstrictor to reduce compensation effects, then vasodilator again).
• Claim 6: alternates instilling/draining between first and second solutions.

Design-around vector: single-pass two-phase exchange is easier to argue outside Claim 5’s repeated cycle concept, but Claim 4 still reads on a single cycle.

Protein handling and reuse

• Claims 7-8 and 24: solutions and/or plasma components comprise plasma proteins.
• Claims 32-34: selectively remove proteins from drained solution or from peritoneal cavity via absorbent, then concentrate/separate and re-administer proteins.

Enforcement impact: Protein-specific dependent claims create a narrower pathway. If the method focuses on non-protein plasma solutes, these claims won’t apply, but the core vasodilator/vasoconstrictor concept still may.

Tonicity and volume-state conditionality

• Claim 9: first hypertonic, second hypotonic (fixed pairing).
• Claim 10: tonicity flips based on patient volume state (hypovolemic → hypotonic; hypervolemic → hypertonic).

Design-around vector: If a protocol keeps both phases isotonic or uses different tonicity logic, Claim 9/10 fall away while Claim 1/4 remain possible.

Specific drugs as exemplar anchors

• Vasodilator drug examples: dipyridamole (26), sodium nitroprusside (27), histamine phosphate (28), dibenzyline (29).
• Vasoconstrictor drug example: norepinephrine (25).

Litigation relevance: Drug exemplars can be used to interpret the “vasodilator/vasoconstrictor” limitation, but they do not necessarily confine the claim to only those agents unless the claim language is restrictive.

Anticoagulant adjuncts

• Claims 19-23: anticoagulant to prevent clogging of peritoneal dialysis catheter/pore; administration routes include IV bolus, subcutaneous, and oral.
• Claim 22: heparin.
• Claims 30-31: intermittent IV anticoagulant or added anticoagulant in the infusion solution.

Design-around vector: a method that achieves anti-clogging via different chemistry might escape these dependent claims, but again Claim 1/4 are not conditioned on anticoagulation.

Dwell-time dependent narrowing

• Claims 40-43: dwell times about 30 min, 1.5 h, 4 h, 8 h.

Enforcement impact: These create useful “sweet spots” for infringement arguments around commercially adopted schedules (common in dialysis-like regimens), while leaving Claim 1/4 intact for non-matching dwell times.

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How strong is the “combination” logic, and where does patentability risk cluster?

Most likely obviousness scrutiny targets

1. Peritoneal dialysis/plasma removal is not new
   Peritoneal exchange is a known technology for solute removal. The core novelty must therefore be the pharmacologic modulation of the peritoneal transport directionality using a vasodilator phase followed by vasoconstrictor phase to sustain removal rate.
2. Vasoactive drugs and tonicity modulation are known tools
   If prior art teaches using vasodilators to increase perfusion/permeability across membranes and using vasoconstrictors to restore or prevent decline, a challenger will argue obviousness in combining known directionality controls with known peritoneal exchange steps.
3. Functional results language compresses the claim
   The claim’s functional definitions (“amount effective to increase passage” and “effective to prevent material reduction in rate”) can be attacked as obvious to try or as lacking structural limitation, depending on the prior art record.

Most likely “defensibility” anchor

The estate’s enforceability most plausibly rests on:

• specific sequential/serial alternation of vasodilator then vasoconstrictor within the peritoneal cavity, and
• explicit intent to prevent decline in removal performance after vasodilator-induced compensation effects.

That sequencing logic is the combination property most likely to survive if prior art only teaches:

• single-phase vasodilation, or
• general peritoneal dialysis schedules without vasoactive alternation.

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What prior art classes most likely overlap US 5,261,876?

Without reproducing a database search result set (not provided here), the overlap can be mapped at the level of established technical fields that typically contain relevant disclosures:

1) Peritoneal dialysis and in vivo peritoneal clearance

• Process steps: instillation, dwell, drainage.
• Membrane pore and transport kinetics.
• Use of hypertonic solutions for ultrafiltration and solute removal.

Overlap risk: high for general “instill and drain” steps and tonicity.

2) Pharmacologic modulation of membrane transport

• Use of vasoactive agents to change blood flow and potentially transport across biological barriers.
• Modulation of perfusion to alter clearance rates.

Overlap risk: moderate, depending on whether vasoactive alternation is taught for peritoneal clearance.

3) Anticoagulation for catheter patency

• Use of heparin or other anticoagulants in dialysis contexts.

Overlap risk: high for dependent claims 19-23, 30-31.

4) Protein-specific removal, concentration, and re-administration

• Adsorption/sorbents in extracorporeal or in-body systems.
• Recycling/re-administration of recovered proteins.

Overlap risk: medium, depending on whether the exact peritoneal in situ protein-selective recovery is previously disclosed.

5) Alternating exchange cycles and dwell-time parameterization

• Dialysis protocols often vary dwell times and cycle patterns.

Overlap risk: medium to high for claims 5-6 and 40-43.

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How could generic and noninfringing designs avoid the claim set? (Practical freedom-to-operate logic)

Avoiding the key limitation: vasodilator/vasoconstrictor alternation

• Use only one vasoactive agent (all dwell windows same pharmacologic direction).
• Substitute vasodilators/vasoconstrictors with non-vasoactive permeability modulators.
• Use systemic vasoactive drugs rather than adding them to the peritoneal solutions (could fall outside “added” in the peritoneal instillate).

Avoiding peritoneal placement

• Switch from peritoneal cavity to extracorporeal circuits (plasmapheresis, adsorption columns, membrane plasmapheresis).
• Use transcapillary/hemofiltration instead of intraperitoneal dwell/flush.

Avoiding “plasma components into the solution” mechanism

• Claims revolve around plasma components passing into peritoneal solutions during dwell; approaches that target different compartments or endpoints may not map.

Targeting dependent-claim carve-outs

Even if Claim 1/4 could still read, dependent claims can be avoided by:

• removing simultaneous catheter exchange design,
• changing tonicity pattern (eliminate Claim 9/10),
• using different anticoagulants (avoid Claim 22),
• using non-matching dwell times (avoid 40-43),
• avoiding protein selective removal/re-administration.

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What is the claim-by-claim “litigation leverage map”?

Leverage for asserting infringement

• Highest leverage: Claim 1 and Claim 4, because they are the only ones that define the two-phase peritoneal vasomodulation concept and dwell-drain exchange sequence.
• Secondary leverage: Claim 5 and Claim 6 (repetition and alternation).
• Protocol credibility leverage: Claim 40-43 if a competitor uses those dwell times.
• Narrow “composition and drug exemplars” leverage: if a competitor uses norepinephrine as the constrictor or dipyridamole/nitroprusside/histamine phosphate/dibenzyline as dilators.

Leverage for defense/design-around

• Most defensible escape hatches: avoid serial alternation entirely, or change the pharmacologic mechanism (different class of agents), or change route (systemic vasoactive dosing or extracorporeal clearance).
• Dependent-claim avoidance: adjust tonicity scheme, omit anticoagulant add-on, and/or avoid protein recovery and reuse.

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How does US Patent 5,261,876 likely fit into the broader US patent ecosystem for dialysis/plasma removal?

For business planning, US 5,261,876 should be treated as a method claim that can be infringed by a clinical protocol. In licensing or litigation, the typical disputes center on:

• whether the accused method uses peritoneal instillation of a vasodilator followed by a vasoconstrictor, and
• whether the vasoconstrictor phase is used for the purpose/effect of preventing a material reduction in plasma-component removal rate.

Because the claims are method-based, enforcement requires discovery into:

• drug identity and concentration,
• instillation schedule and whether the phases are serially sequenced,
• dwell times,
• and the peritoneal configuration (catheters or simultaneous flows where relevant).

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Key takeaways

• US 5,261,876’s patent value is concentrated in the combination: peritoneal plasma-component removal using a serial vasodilator phase followed by a vasoconstrictor phase to sustain clearance performance.
• Claims 2-3, 5-6, and 40-43 create procedural and timing coverage, while claims 7-8/24 and 32-34 create protein-specific optional layers.
• Dependent claims on tonicity and anticoagulation are likely easier to design around.
• The strongest infringement case will map to clinical protocols that closely follow the two-phase intraperitoneal vasomodulation with dwell and drain steps; the most effective defense is to break the alternation concept or change the physiologic control mechanism.

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FAQs

1. What single change most easily avoids US 5,261,876?
   Using only one phase of vasoactive pharmacology (no serial vasodilator-then-vasoconstrictor protocol) or switching away from peritoneal intraluminal instillation.

2. Do Claims 2-3 require simultaneous instillation and drainage through two catheters?
   Yes for those dependent claims; Claim 1/4 can still be implicated without meeting simultaneous catheter structure.

3. Is norepinephrine required to infringe?
   Claim 25 lists norepinephrine as an example in a dependent claim; infringement of broader independent claims does not necessarily require norepinephrine unless construed as limiting.

4. Can a competitor avoid by changing dwell times?
   Changing dwell times may avoid dependent claims 40-43, but Claim 1/4 still require dwell “sufficient” to achieve removal effects.

5. Does adding anticoagulant matter for infringement?
   Only for dependent claims 19-23 and 30-31; Claim 1/4 do not require anticoagulant steps.

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References

1. United States Patent 5,261,876. “Method for removing plasma components from a patient using vasodilator and vasoconstrictor added physiologic solutions in the peritoneal cavity.”

Details for Patent 5,261,876

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Alk-abello, Inc.	HISTATROL	positive skin test control-histamine	Injection	103754	September 29, 1950	5,261,876	2012-06-12
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924	5,261,876	2012-06-12