Patent: 4,534,972

Summary for Patent: 4,534,972

Title:	Protein compositions substantially free from infectious agents
Abstract:	Compositions containing therapeutically or immunologically active proteins are rendered substantially free from infectious agents such as viable viruses and bacteria without substantial loss of therapeutic or immunologic activity by mixing the protein composition with a complex formed from source of transition metal ions, such as copper ions, and an angularly-fused, polynuclear heterocyclic arene having two nitrogen atoms in a \"cis-ortho\" relationship, such as phenanthroline, and a reducing agent such as a thiol in amounts and at a temperature and for a time sufficient to inactivate substantially all of the viruses and bacteria contained therein. Compositions containing therapeutically active proteins substantially free from viral and bacterial infectivity, which have heretofore been unattainable, can be prepared by the method of the invention.
Inventor(s):	Lembach; Kenneth J. (Danville, CA)
Assignee:	Miles Laboratories, Inc. (Elkhart, IN)
Application Number:	06/480,056
Patent Claims:	see list of patent claims

US Patent 4,534,972 landscape and claim-by-claim strength for plasma proteins and vaccines inactivation with copper/phenanthroline and thiols

United States Patent 4,534,972 claims a broadly drafted method for rendering protein compositions “substantially free from infectious agents” while preserving therapeutic or immunologic activity. The core mechanism is the combination of (i) a transition-metal complex of an angularly-fused polynuclear heteroarene arene with two cis-ortho nitrogens and (ii) a thiol/reducing agent, followed by controlled incubation at selected temperature, time, and pH. The claim scope is expansive because it covers multiple protein classes (blood plasma proteins, virus vaccines, bacterial vaccines, non-infectious antigens) and multiple product exemplars, while also specifying concrete parameter windows and a specific embodiment (copper/1,10-phenanthroline plus 3-mercaptopropionic acid).

The patent’s practical value depends on whether competitors’ inactivation processes fall within the same chemical-inactivation regime, including the same copper/phenanthroline-type complex family, comparable thiol/reducing agents, and incubation parameter ranges, and whether the downstream “substantially non-infective” product claims are treated as enforceable product-by-process claims.

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What does US 4,534,972 claim and what exact elements must be present?

Independent claim 1: what has to be mixed, for how long, and under what conditions?

Claim 1 requires all of the following structural steps and functional outcomes:

1. Starting composition

   • A protein composition containing a therapeutically or immunologically active protein selected from:
     • blood plasma proteins,
     • virus vaccines,
     • bacterial vaccines,
     • non-infectious antigens,
   • initially “substantially free from infectious agents selected from viable viruses and bacteria” is the stated target, but the method explicitly inactivates infectious agents by treatment. In practice, claim language requires the method to render the composition substantially non-infective without substantial loss of therapeutic or immunologic activity.

2. Step (a) chemical inactivation system

   • Mix an aqueous solution of the protein composition with:
     • an “effective amount of a complex” formed from:
       • an angularly-fused polynuclear heterocyclic arene having two nitrogen atoms in a cis-ortho relationship, and
       • a source of transition metal ions capable of complexing with the arene,
     • and a thiol in effective amounts to inactivate substantially all infectious agents without substantial loss of therapeutic/immunologic activity.

3. Step (b) incubation

   • Hold the mixture at a time and temperature sufficient to render infectious agents “substantially non-infective” in the protein composition, again without substantial loss of activity.

4. Functional limitation

   • The required end state is “substantially non-infective” plus preserved therapeutic/immunologic activity.

This structure makes claim 1 simultaneously broad (protein type and functional outcome) and constraining (must use a specific metal-complex class plus a thiol system, followed by incubation).

Dependent claims 2–10 narrow the inactivation window and identify preferred reagents

Claim 2 fixes incubation temperature and minimum time:

• ~2–60°C for at least ~0.25 hours

Claim 3 narrows to near room/body temperature:

• ~20–37°C for ~0.5–3 hours

Claim 4 imposes an efficacy metric:

• inactivate at least ~99% of viruses and bacteria

Claim 5–6 add pH compatibility:

• physiologically compatible; and
• pH about 4–10

Claim 7–8 specify concentration ranges:

• complex ~0.001–0.1 mM in ~0.5–2% (w/v) protein solution
• thiol/reducing agent ~0.1–5 mM in ~0.5–2% (w/v) solution

Claim 9 selects a named complex:

• copper/1,10-phenanthroline complex

Claim 10 selects a named thiol:

• 3-mercaptopropionic acid

Dependent claims 11–14 define protein scope via exemplary categories

• Claim 11: component derived from blood plasma
• Claim 12: viral vaccine
• Claim 13: non-infectious antigen
• Claim 14: a long list of plasma proteins/fractions and coagulation factors, including albumin, plasminogen, antihemophilic factor (Factor VIII), Factor IX concentrate (Factors II, VII, IX, X), fibronectin, Factor XIII, immunoglobulins (IgG, IgA, IgD, IgE, IgM), kininogen, antithrombin III, alpha-1-proteinase inhibitor, plasma growth hormone/somatomedin/prealbumin, plasminogen-streptokinase complex, ceruloplasmin, transferrin, haptoglobin, prekallikrein, and mixtures.

Claims 15–18 are product claims tied to method steps

These are downstream “substantially non-infective protein composition produced by the method of claim X”:

• Claim 15: product from claim 12 (viral vaccine)
• Claim 16: product from claim 13 (non-infectious antigen)
• Claim 17: product from claim 14 (specified plasma proteins)
• Claim 18: product from claim 15 (note: as provided, claim 18 refers to claim 15 again, which is either a drafting issue or a transcription anomaly; it still reads as a dependent product claim tethered to a method claim)

Key enforcement implication: product-by-process language can create infringement leverage if an accused product is the same or indistinguishable and is shown to result from the claimed process steps, but challengers can attempt to argue non-identical products or that process limitations do not define product characteristics.

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What is the chemical mechanism claimed, and how does that affect infringement risk?

The metal-heteroarene “complex + thiol” system is the likely infringement trigger

The claim’s chemical system has three moving parts:

1. Heteroarene structure constraint

   • “Angularly-fused, polynuclear heterocyclic arene” with “two nitrogen atoms in cis-ortho relationship.”
   • That language aims to capture specific chelating ligands like phenanthroline-type moieties and potentially other cis-ortho N chelators in the same family.

2. Transition metal complex

   • Requires a metal ion source capable of complexing with the arene.
   • Claim 9 narrows to copper/1,10-phenanthroline.

3. Thiol / reducing agent

   • Required as part of the inactivation system.
   • Claim 10 narrows to 3-mercaptopropionic acid.

Infringement-sensitive design-around options

• Use a different inactivation chemistry (for example, oxidants, detergents, photochemical systems, solvent/detergent methods, heat/low pH, nuclease treatments for different targets, or broad-spectrum sterilization steps) rather than metal-complex + thiol.
• Use a different chelator class not satisfying the cis-ortho N angularly-fused polynuclear heteroarene requirement.
• Avoid including an essential thiol/reducing agent component.

Because claim 1 requires both a qualified complex and a thiol, a competitor that uses only one side of the system (metal complex without thiol; thiol without the specific complex) is positioned for a non-infringement argument.

Why the process windows matter

Claims 2–3 and 5–8 constrain time, temperature, pH, and dosing. If an accused process uses a different range, the case shifts toward claim 1 (broad) rather than the narrower dependent claims.

• If a competitor operates outside the time/temperature/pH ranges but still achieves “substantially non-infective” status without loss of activity, claim 1 remains a potential enforcement path.
• If a competitor operates within narrower ranges but uses different chemistry, then claim 1 itself is vulnerable.

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What patents are likely to be in the same field as US 4,534,972 (plasma protein virus inactivation and vaccine sterilization)?

No jurisdictional patent map can be built from the claim text alone. A complete landscape requires the application publication number, assignee, filing and priority dates, and a full claim-set text for related continuations and divisionals.

Per constraints, only the claim text you provided is used here; no external patent corpus is cited.

Practical overlap areas

Even without a specific citation set, the landscape for virus/bacteria inactivation of protein therapeutics typically clusters around:

• chemical inactivation (oxidation/reduction, chelation-based systems),
• heat and low pH inactivation,
• solvent/detergent and membrane-based approaches for enveloped virus removal,
• ultraviolet/photochemical pathogen reduction systems,
• filtration and downstream purification designed to reduce infectivity,
• ion-exchange/adsorptive chromatography where infectivity reduction is an intended outcome.

Given the claimed metal complex plus thiol approach, the most relevant competitive patents in that ecosystem are those that:

• use transition-metal catalysts/complexes for oxidative or radical generation,
• combine metal complexes with thiols/reductants,
• claim process parameter windows to preserve protein activity.

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When does US 4,534,972 lose exclusivity, and what matters for launch planning?

The exclusivity timeline cannot be calculated from the claim text alone because it depends on:

• priority date(s),
• filing date and whether term adjustment applies,
• any terminal disclaimers,
• whether patents in the family extend coverage via continuations.

Per constraints, this analysis cannot produce an expiration date or exclusivity timetable.

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Is claim 1 broad enough to cover non-copper metal complexes and other cis-ortho N ligands?

Likely breadth: ligand-family coverage

Claim 1 is written to cover:

• any angularly fused polynuclear heterocyclic arene with two cis-ortho nitrogens, and
• any transition metal ion source that forms a complex with that arene.

That is broader than claim 9’s specific copper/1,10-phenanthroline embodiment.

Likely narrowings: functional and safety-preservation limitations

Even with broad chemistry coverage, the method is limited by:

• “effective amounts” that inactivate “substantially all” infectious agents,
• no “substantial loss” of therapeutic or immunologic activity,
• “physiologically compatible” pH appears in dependent claims but claim 1 still requires preservation of activity, which becomes a functional tether.

In litigation, the most contested point often becomes whether an accused composition is “substantially non-infective” and whether activity losses are “substantial.” That turns infringement into an evidentiary exercise anchored in infectivity assays and activity assays.

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How do the product claims (15–18) change enforcement compared with method-only claims?

Claims 15–18 cover “substantially non-infective protein composition produced by the method of claim X.” This is product-by-process.

Commercial significance

• In licensing, product claims can support supply-chain arguments against manufacturers and fillers who distribute the treated composition.
• In litigation, product-by-process claims can be used to target products if the treated product is distinguishable by infectivity level or by residual chemical signature tied to the process.

Design-around

• A competitor could attempt to show that its final product does not meet the “substantially non-infective” threshold, or that it is produced via a different process that produces a different product state.

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What generic entry risks exist for the treated protein therapeutics covered by the claim?

This patent is a process patent, not a composition “active ingredient” patent. Generic risk is mostly indirect:

• For already-approved protein therapeutics, generics/biosimilars face a high bar to prove identity in quality attributes, but process differences (and different pathogen reduction strategies) can change product characteristics.
• If an accused generic/biosimilar uses a different pathogen inactivation approach that avoids the metal-complex + thiol elements, infringement exposure under claim 1 is reduced.
• If it uses the same or functionally equivalent inactivation chemistry and meets the infectivity reduction thresholds, risk rises.

Because the patent covers multiple protein categories (plasma-derived factors, immunoglobulins, and vaccines/non-infectious antigens), the “at-risk” universe is broad at the platform level but narrow at the implementation level: only those products whose manufacturing uses the claimed inactivation chemistry and parameter windows are truly exposed.

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What formulation and manufacturing controls could determine whether an accused process infringes?

Chemical dosing targets

Claims 7–8 specify:

• complex concentration 0.001–0.1 mM in 0.5–2% aqueous solution,
• thiol 0.1–5 mM in 0.5–2% aqueous solution.

Even if a competitor uses the same chemistry, dosing outside these ranges can be argued as avoiding dependent claims while leaving claim 1 as the fallback.

Incubation parameters

Claims 2–4 and 5–6 tie outcome to:

• temperature and time,
• pH 4–10 (dependent),
• ≥99% virus/bacteria reduction (dependent).

Manufacturing records become central evidence: actual temperature profiles, time-at-temperature, measured pH, complex dosing, and assay results for infectivity.

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Key Takeaways

• US 4,534,972 is a platform-style inactivation method patent built on a metal-heteroarene complex + thiol system with controlled incubation to achieve substantially non-infective protein compositions while preserving activity.
• The enforceability anchor is claim 1’s dual chemistry requirement: a cis-ortho N angularly fused polynuclear heteroarene metal complex plus a thiol/reducing agent, followed by incubation.
• Dependent claims 2–10 add enforceable constraints via temperature/time, pH, complex/thiol dosing ranges, a copper/1,10-phenanthroline example, and 3-mercaptopropionic acid.
• Product claims 15–18 are product-by-process and can expand leverage to marketed treated compositions, but infringement hinges on whether the sold product is the result of the claimed method and meets “substantially non-infective” performance.
• Without the patent bibliographic data (assignee, priority, filing, family members), this analysis cannot produce expiration/exclusivity dates, nor a cited competitor patent map.

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FAQs

1. Can an accused process infringe US 4,534,972 if it uses thiol but not a cis-ortho N angularly fused polynuclear heteroarene metal complex?
   Claim 1 requires both the qualified metal complex and a thiol in effective amounts.

2. Does using copper/1,10-phenanthroline alone create infringement risk without 3-mercaptopropionic acid?
   Claim 9 and 10 are dependent; claim 1 can still apply if a different thiol/reducing agent is used that satisfies the “thiol” requirement and achieves the functional inactivation outcome.

3. If a competitor inactivates above 99% but at pH outside 4–10, which claims remain relevant?
   Dependent claim 6 may be avoided, but claim 1 can still be asserted based on the overall preservation and inactivation functional limitations.

4. What role do manufacturing records play in proving infringement for product-by-process claims?
   They support whether the commercial product was produced by the claimed process and whether infectivity and activity outcomes meet the claim thresholds.

5. How can a manufacturer reduce risk under claim 1 during pathogen reduction development?
   Shift away from the metal-complex + thiol chemistry regime or avoid meeting the claim’s structural and functional requirements.

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References (APA)

1. No external sources were cited because this analysis is limited to the claim text provided for US Patent 4,534,972.

Details for Patent 4,534,972

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	PLASMANATE	plasma protein fraction (human)	Injection	101140	October 02, 1958		2003-03-29
Takeda Pharmaceuticals U.s.a., Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	December 21, 1979		2003-03-29
Takeda Pharmaceuticals U.s.a., Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	July 31, 2000		2003-03-29
Takeda Pharmaceuticals U.s.a., Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	August 11, 2005		2003-03-29
Csl Behring Llc	MONOCLATE, MONOCLATE-P	antihemophilic factor (human)	For Injection	103953	May 14, 2003		2003-03-29