United States Patent 5,654,403: Copper-Ion–Driven IgG1 Degradation with Chelator Rescue

United States Patent (USP) 5,654,403 claims a stabilized IgG1 immunoglobulin formulation in which copper ions are present at a level that would otherwise degrade IgG1, and the formulation is stabilized by adding a copper-ion chelator (with EDTA and citrate as exemplified chelators), including defined chelator concentration ranges and formulation conditions (notably pH). The claims are broad on IgG1 source and target binding (including recombinant, CHO- or myeloma-derived, and tumor-marker or enumerated antigen binding) and narrow primarily on chelator identity (EDTA/citrate), chelator-to-copper functional effect (binding and protection), and selected ranges for EDTA and pH.

What do the claims actually cover?

1) Core inventive concept: “degrading” copper plus “protective” chelator

Claim 1 is the anchor. It defines:

An immunoglobulin composition with IgG1
Copper ions present “in an amount sufficient to degrade the immunoglobulin”
The improvement is addition of a copper chelator
The chelator must be present at an amount “sufficient to bind the copper ions present in the composition and protect the immunoglobulin from degradation by the copper ions,” thereby stabilizing the IgG1.

Claim 16 repeats the core concept in an apparatus-like form (“stabilized immunoglobulin composition comprising an IgG1 and copper ions…” plus chelator protection).

Claim structure consequence: The claims are written around a functional stabilization mechanism in the presence of copper at degrading levels. That is a materially different claim posture than typical “avoid transition metals” stabilization approaches. Here, copper is allowed and even intended to be present at degradation-capable levels, then “tamed” by chelator.

2) IgG1 type and manufacturability scope

Claims 2 to 5 expand the immunoglobulin scope:

Claim 2: immunoglobulin can be recombinant
Claim 3: recombinant may be chimeric or humanized
Claim 4: produced from CHO
Claim 5: produced from myeloma cell (implying non-CHO production routes are also captured)

This yields wide coverage across expression platforms that matter for biologics manufacturing.

3) Antigen binding scope

Claims 6 and 7 broaden the target binding:

Claim 6: IgG1 specifically binds a tumor cell marker antigen
Claim 7: IgG1 specifically binds one of a long antigen list: CD2, CD3, CD4, CD5, CD7, CD8, CD11a, CD11b, CD18, CD19, CD25, CDw52, CD33, CD54

This is a claim expansion strategy: the stabilization chemistry is the same, while the biologic target-binding antigen list provides a practical set of monoclonal antibody targets within scope.

4) Chelators are explicitly limited

Claims 8 to 12 narrow the chelator identity:

Claim 8: chelator is EDTA
Claim 9 and 10: EDTA amounts
- 0.05 mM to 5 mM (Claim 9)
- 0.1 mM to 3 mM (Claim 10)
Claim 11: chelator is citrate ion
Claim 12: citrate is alkali metal citrate

So the claims have two explicit chelator “species” (EDTA, citrate) and a defined concentration window only for EDTA, not for citrate.

5) Formulation constraints

Claim 13 constrains pH:

pH 6 to 7.2

Claims 14 and 15 cover presentation form:

Claim 14: liquid preparation suitable for parenteral administration
Claim 15: lyophilized form for reconstitution into a liquid parenteral preparation

Claim-by-claim critical read: strengths, vulnerabilities, and how courts often view these terms

Claim 1: “Copper ions sufficient to degrade” plus “chelator sufficient to bind and protect”

Strengths for enforceability

The claim is anchored in a clear stabilization mechanism: chelator binds copper ions and prevents copper-driven degradation.
The claim is not limited to a particular antibody sequence, isotype variant beyond IgG1, or manufacturing line. That increases potential commercial coverage.

Enforceability vulnerabilities

“Copper ions in an amount sufficient to degrade” and “chelator… sufficient to… protect” are outcome/functional limitations.
In litigation, such functional language often forces disputes over:
- What test method defines “degrade” (aggregation, fragmentation, loss of potency, chemical modification, etc.)
- What chelator amount qualifies as “sufficient”
- Whether the alleged product meets the functional threshold under relevant conditions (storage time, temperature, light exposure, agitation, oxygen content)

In practice, these terms are usually clarified in the specification and/or prosecution history. The claims as provided do not specify the degradation endpoint or the conditions. That gap can become a factual fight.

Claims 2 to 5: recombinant, chimeric/humanized, CHO, myeloma

These dependent claims do not add a chemistry change; they add coverage gating by biologic type.

If an accused product uses a recombinant humanized antibody made in HEK rather than CHO/myeloma, literal infringement may be avoidable, but the dependent claims do not restrict Claim 1’s base concept of IgG1 stabilization with copper and chelator unless Claim 2 is required for the asserted dependent claim.
If asserted under Claim 1, the manufacturing platform limitation may not apply.

Claims 6 and 7: tumor marker antigen list

This is a classic narrowing strategy by antigen, but it also creates a realistic enforcement handle:

If a drug product binds one of the listed antigens, it becomes an easy mapping step.
If a target is not in the list, the claim could avoid literal infringement, unless other claims cover broader target binding (Claim 6 is broader than Claim 7).

Claims 8 to 12: EDTA and citrate

This is the major tightening in the claims.

If a competitor uses another chelator (e.g., DTPA, EGTA, desferoxamine, NTA, or other copper-binding agents), they may escape the narrower dependent claims.
But under Claim 1, the “chelator of copper ions” is not limited to EDTA or citrate. That means Claim 1 can still capture other chelators, unless the specification defines chelators narrowly or prosecution limited the scope.

Given only the claim text provided, Claim 1 remains potentially broad on chelator identity.

Claims 9 to 10: EDTA concentration windows

These windows can create either:

Clear non-infringement (if a product uses EDTA outside the range and is only alleged under the dependent claims), or
Coverage if a product’s EDTA sits inside the claimed range and the copper is present at “degrading” levels while chelated.

This is where product formulation disclosure and analytical specs matter. If copper is present but chelator is absent or low, chemistry may not meet the “sufficient… to protect” limitation.

Claim 13: pH 6 to 7.2

pH limitations are generally easier to test and harder to dispute. They also matter for:

Copper speciation
chelator binding behavior
antibody stability pathways (deamidation, charge variants, aggregation)

A competitor operating at pH outside 6 to 7.2 can avoid dependent claim 13, but again Claim 1’s base scope may still be asserted depending on the pleading.

Claims 14 and 15: liquid vs lyophilized

This is likely not a major differentiator for infringement because many biologics appear in both forms, but it can still matter for claim mapping if a product is only sold in one presentation.

How this patent likely positions in the broader stabilization landscape

The claim posture is unusual: “don’t remove copper, neutralize it”

Most biologics stabilization doctrines historically focus on excluding or minimizing:

metal catalysis
oxygen-mediated oxidation
trace transition metals that seed aggregation and oxidation

USP 5,654,403 instead claims a formulation where copper is present at levels that would degrade IgG1, then uses chelation to neutralize copper’s deleterious effect.

Business consequence: this can map cleanly to real-world scenarios where manufacturing, container-closure interactions, or raw materials introduce trace copper. It also suggests the patent’s commercial thesis is robustness to copper variability, not copper-free formulation design.

Competitive workaround paths

The claim set points to specific workaround levers:

Chelator change
- Use a different copper-binding agent so dependent claims 8-12 are not met.
- Still requires assessing Claim 1’s breadth if “chelator of copper ions” is construed broadly.
Avoid copper at “degrading” levels
- Reduce free copper or total copper below a degradation-causing threshold.
- This is not necessarily about “no copper,” but about avoiding the “sufficient to degrade” functional element.
Operate outside pH 6 to 7.2
- Escape dependent claim 13.
EDTA concentration outside the claimed windows
- Escape dependent claims 9-10, if asserted separately.

Patent landscape analysis: what can be inferred from the claim pattern (and what cannot)

What the claim text supports

The claims target a narrow chemistry pair (EDTA, citrate) and define:

a functional stabilization mechanism around copper-driven degradation
biologic broad coverage around IgG1 and tumor-antigen specificity
formulation conditions (pH 6 to 7.2) and dosage form (liquid or lyophilized)

This suggests the broader patent family (and prosecution strategy) likely aimed to secure coverage for:

copper chelation in IgG1 formulations
at least some antibody classes defined by target antigen binding

What cannot be completed from the information provided

A comprehensive “patent landscape” normally requires:

identification of the patent’s priority date, assignee, specification details, and prosecution history
family member set and claim correspondence across jurisdictions
citation map (forward and backward), including examiners’ references
colliding claims in active US families (and whether they cover the same functional language or instead cover different chelators/metal handling strategies)
any litigation or post-grant outcomes

The user input provides only the claim text, not bibliographic data, specification, or citations. Without those, any attempt to enumerate landscape competitors or adjudicated scope would be speculative.

Per the operating constraints, no incomplete landscape assertions are included.

Practical claim mapping: what a product would need to match

Minimum elements (Claim 1 / Claim 16)

A product must plausibly have all of the following:

IgG1 immunoglobulin composition
Copper ions present at levels that would degrade IgG1 absent chelation
A copper chelator present at a level sufficient to bind copper and protect IgG1 from copper-driven degradation

Additional elements for stronger dependent coverage

If the product also meets these, it becomes harder to design around:

Recombinant (Claim 2)
Chimeric or humanized (Claim 3)
Made in CHO or myeloma (Claims 4-5)
Binds tumor marker antigens, and potentially one of the enumerated antigens (Claims 6-7)
Chelator is EDTA (Claim 8), preferably with EDTA dose in 0.05-5 mM (Claim 9) or 0.1-3 mM (Claim 10)
Chelator is citrate, specifically alkali metal citrate (Claims 11-12)
pH 6 to 7.2 (Claim 13)
Provided as liquid or lyophilized parenteral preparation (Claims 14-15)

Key Takeaways

USP 5,654,403 claims copper-tolerant IgG1 stabilization by adding a copper chelator at an amount that binds copper and prevents copper-driven degradation.
The independent claim is anchored in functional limitations (“copper… sufficient to degrade” and “chelator… sufficient to… protect”), which can drive evidence disputes over test endpoints and conditions.
Dependent claims materially narrow protection via chelators (EDTA, citrate), EDTA concentration windows, and pH 6 to 7.2, while broadly covering antibody formats and target antigen binding categories.
A competitive design-around is most plausible through eliminating the “degrading copper” condition, using a different chelator approach, or operating outside the pH / EDTA windows tied to dependent claims.

FAQs

1) Is this patent about preventing copper entry into the formulation?

No. It claims formulations where copper ions are present at degrading-capable levels, then uses chelation to prevent degradation.

2) Does the patent limit the antibody to a specific sequence?

No. It is framed around IgG1 and specified target antigen binding, not antibody sequence.

3) Which chelators are explicitly claimed in dependent claims?

EDTA and citrate (including alkali metal citrate).

4) What are the specific EDTA ranges in the claims?

0.05 mM to 5 mM, and a narrower 0.1 mM to 3 mM.

5) What pH range does the patent claim?

pH 6 to 7.2.

References

United States Patent 5,654,403.

Title:	Immunoglobulins stabilized with a chelator of copper ions
Abstract:	A stabilized immunoglobulin composition comprises at least one immunoglobulin together with a stabilizing amount of a chelator of copper ions such as EDTA or citrate. Preferably the immunoglobulin is an antibody, for example, a recombinant CDR-grafted antibody. A process for enhancing the stability of an immunoglobulin comprises subjecting the immunoglobulin to a purification procedure capable of removing copper ions therefrom. Preferably, the immunoglobulin is rendered substantially free from detectable copper ions as determined, for example, by atomic absorption spectroscopy.
Inventor(s):	Smith; Marjorie (Beckenham, GB3), Riveros-Rojas; Valentina (Beckenham, GB3)
Assignee:	Burroughs Wellcome Co. (Research Triangle Park, NC)
Application Number:	08/232,127
Patent Claims:	see list of patent claims
Patent landscape, scope, and claims summary:	United States Patent 5,654,403: Copper-Ion–Driven IgG1 Degradation with Chelator Rescue United States Patent (USP) 5,654,403 claims a stabilized IgG1 immunoglobulin formulation in which copper ions are present at a level that would otherwise degrade IgG1, and the formulation is stabilized by adding a copper-ion chelator (with EDTA and citrate as exemplified chelators), including defined chelator concentration ranges and formulation conditions (notably pH). The claims are broad on IgG1 source and target binding (including recombinant, CHO- or myeloma-derived, and tumor-marker or enumerated antigen binding) and narrow primarily on chelator identity (EDTA/citrate), chelator-to-copper functional effect (binding and protection), and selected ranges for EDTA and pH. What do the claims actually cover? 1) Core inventive concept: “degrading” copper plus “protective” chelator Claim 1 is the anchor. It defines: An immunoglobulin composition with IgG1 Copper ions present “in an amount sufficient to degrade the immunoglobulin” The improvement is addition of a copper chelator The chelator must be present at an amount “sufficient to bind the copper ions present in the composition and protect the immunoglobulin from degradation by the copper ions,” thereby stabilizing the IgG1. Claim 16 repeats the core concept in an apparatus-like form (“stabilized immunoglobulin composition comprising an IgG1 and copper ions…” plus chelator protection). Claim structure consequence: The claims are written around a functional stabilization mechanism in the presence of copper at degrading levels. That is a materially different claim posture than typical “avoid transition metals” stabilization approaches. Here, copper is allowed and even intended to be present at degradation-capable levels, then “tamed” by chelator. 2) IgG1 type and manufacturability scope Claims 2 to 5 expand the immunoglobulin scope: Claim 2: immunoglobulin can be recombinant Claim 3: recombinant may be chimeric or humanized Claim 4: produced from CHO Claim 5: produced from myeloma cell (implying non-CHO production routes are also captured) This yields wide coverage across expression platforms that matter for biologics manufacturing. 3) Antigen binding scope Claims 6 and 7 broaden the target binding: Claim 6: IgG1 specifically binds a tumor cell marker antigen Claim 7: IgG1 specifically binds one of a long antigen list: CD2, CD3, CD4, CD5, CD7, CD8, CD11a, CD11b, CD18, CD19, CD25, CDw52, CD33, CD54 This is a claim expansion strategy: the stabilization chemistry is the same, while the biologic target-binding antigen list provides a practical set of monoclonal antibody targets within scope. 4) Chelators are explicitly limited Claims 8 to 12 narrow the chelator identity: Claim 8: chelator is EDTA Claim 9 and 10: EDTA amounts 0.05 mM to 5 mM (Claim 9) 0.1 mM to 3 mM (Claim 10) Claim 11: chelator is citrate ion Claim 12: citrate is alkali metal citrate So the claims have two explicit chelator “species” (EDTA, citrate) and a defined concentration window only for EDTA, not for citrate. 5) Formulation constraints Claim 13 constrains pH: pH 6 to 7.2 Claims 14 and 15 cover presentation form: Claim 14: liquid preparation suitable for parenteral administration Claim 15: lyophilized form for reconstitution into a liquid parenteral preparation Claim-by-claim critical read: strengths, vulnerabilities, and how courts often view these terms Claim 1: “Copper ions sufficient to degrade” plus “chelator sufficient to bind and protect” Strengths for enforceability The claim is anchored in a clear stabilization mechanism: chelator binds copper ions and prevents copper-driven degradation. The claim is not limited to a particular antibody sequence, isotype variant beyond IgG1, or manufacturing line. That increases potential commercial coverage. Enforceability vulnerabilities “Copper ions in an amount sufficient to degrade” and “chelator… sufficient to… protect” are outcome/functional limitations. In litigation, such functional language often forces disputes over: What test method defines “degrade” (aggregation, fragmentation, loss of potency, chemical modification, etc.) What chelator amount qualifies as “sufficient” Whether the alleged product meets the functional threshold under relevant conditions (storage time, temperature, light exposure, agitation, oxygen content) In practice, these terms are usually clarified in the specification and/or prosecution history. The claims as provided do not specify the degradation endpoint or the conditions. That gap can become a factual fight. Claims 2 to 5: recombinant, chimeric/humanized, CHO, myeloma These dependent claims do not add a chemistry change; they add coverage gating by biologic type. If an accused product uses a recombinant humanized antibody made in HEK rather than CHO/myeloma, literal infringement may be avoidable, but the dependent claims do not restrict Claim 1’s base concept of IgG1 stabilization with copper and chelator unless Claim 2 is required for the asserted dependent claim. If asserted under Claim 1, the manufacturing platform limitation may not apply. Claims 6 and 7: tumor marker antigen list This is a classic narrowing strategy by antigen, but it also creates a realistic enforcement handle: If a drug product binds one of the listed antigens, it becomes an easy mapping step. If a target is not in the list, the claim could avoid literal infringement, unless other claims cover broader target binding (Claim 6 is broader than Claim 7). Claims 8 to 12: EDTA and citrate This is the major tightening in the claims. If a competitor uses another chelator (e.g., DTPA, EGTA, desferoxamine, NTA, or other copper-binding agents), they may escape the narrower dependent claims. But under Claim 1, the “chelator of copper ions” is not limited to EDTA or citrate. That means Claim 1 can still capture other chelators, unless the specification defines chelators narrowly or prosecution limited the scope. Given only the claim text provided, Claim 1 remains potentially broad on chelator identity. Claims 9 to 10: EDTA concentration windows These windows can create either: Clear non-infringement (if a product uses EDTA outside the range and is only alleged under the dependent claims), or Coverage if a product’s EDTA sits inside the claimed range and the copper is present at “degrading” levels while chelated. This is where product formulation disclosure and analytical specs matter. If copper is present but chelator is absent or low, chemistry may not meet the “sufficient… to protect” limitation. Claim 13: pH 6 to 7.2 pH limitations are generally easier to test and harder to dispute. They also matter for: Copper speciation chelator binding behavior antibody stability pathways (deamidation, charge variants, aggregation) A competitor operating at pH outside 6 to 7.2 can avoid dependent claim 13, but again Claim 1’s base scope may still be asserted depending on the pleading. Claims 14 and 15: liquid vs lyophilized This is likely not a major differentiator for infringement because many biologics appear in both forms, but it can still matter for claim mapping if a product is only sold in one presentation. How this patent likely positions in the broader stabilization landscape The claim posture is unusual: “don’t remove copper, neutralize it” Most biologics stabilization doctrines historically focus on excluding or minimizing: metal catalysis oxygen-mediated oxidation trace transition metals that seed aggregation and oxidation USP 5,654,403 instead claims a formulation where copper is present at levels that would degrade IgG1, then uses chelation to neutralize copper’s deleterious effect. Business consequence: this can map cleanly to real-world scenarios where manufacturing, container-closure interactions, or raw materials introduce trace copper. It also suggests the patent’s commercial thesis is robustness to copper variability, not copper-free formulation design. Competitive workaround paths The claim set points to specific workaround levers: Chelator change Use a different copper-binding agent so dependent claims 8-12 are not met. Still requires assessing Claim 1’s breadth if “chelator of copper ions” is construed broadly. Avoid copper at “degrading” levels Reduce free copper or total copper below a degradation-causing threshold. This is not necessarily about “no copper,” but about avoiding the “sufficient to degrade” functional element. Operate outside pH 6 to 7.2 Escape dependent claim 13. EDTA concentration outside the claimed windows Escape dependent claims 9-10, if asserted separately. Patent landscape analysis: what can be inferred from the claim pattern (and what cannot) What the claim text supports The claims target a narrow chemistry pair (EDTA, citrate) and define: a functional stabilization mechanism around copper-driven degradation biologic broad coverage around IgG1 and tumor-antigen specificity formulation conditions (pH 6 to 7.2) and dosage form (liquid or lyophilized) This suggests the broader patent family (and prosecution strategy) likely aimed to secure coverage for: copper chelation in IgG1 formulations at least some antibody classes defined by target antigen binding What cannot be completed from the information provided A comprehensive “patent landscape” normally requires: identification of the patent’s priority date, assignee, specification details, and prosecution history family member set and claim correspondence across jurisdictions citation map (forward and backward), including examiners’ references colliding claims in active US families (and whether they cover the same functional language or instead cover different chelators/metal handling strategies) any litigation or post-grant outcomes The user input provides only the claim text, not bibliographic data, specification, or citations. Without those, any attempt to enumerate landscape competitors or adjudicated scope would be speculative. Per the operating constraints, no incomplete landscape assertions are included. Practical claim mapping: what a product would need to match Minimum elements (Claim 1 / Claim 16) A product must plausibly have all of the following: IgG1 immunoglobulin composition Copper ions present at levels that would degrade IgG1 absent chelation A copper chelator present at a level sufficient to bind copper and protect IgG1 from copper-driven degradation Additional elements for stronger dependent coverage If the product also meets these, it becomes harder to design around: Recombinant (Claim 2) Chimeric or humanized (Claim 3) Made in CHO or myeloma (Claims 4-5) Binds tumor marker antigens, and potentially one of the enumerated antigens (Claims 6-7) Chelator is EDTA (Claim 8), preferably with EDTA dose in 0.05-5 mM (Claim 9) or 0.1-3 mM (Claim 10) Chelator is citrate, specifically alkali metal citrate (Claims 11-12) pH 6 to 7.2 (Claim 13) Provided as liquid or lyophilized parenteral preparation (Claims 14-15) Key Takeaways USP 5,654,403 claims copper-tolerant IgG1 stabilization by adding a copper chelator at an amount that binds copper and prevents copper-driven degradation. The independent claim is anchored in functional limitations (“copper… sufficient to degrade” and “chelator… sufficient to… protect”), which can drive evidence disputes over test endpoints and conditions. Dependent claims materially narrow protection via chelators (EDTA, citrate), EDTA concentration windows, and pH 6 to 7.2, while broadly covering antibody formats and target antigen binding categories. A competitive design-around is most plausible through eliminating the “degrading copper” condition, using a different chelator approach, or operating outside the pH / EDTA windows tied to dependent claims. FAQs 1) Is this patent about preventing copper entry into the formulation? No. It claims formulations where copper ions are present at degrading-capable levels, then uses chelation to prevent degradation. 2) Does the patent limit the antibody to a specific sequence? No. It is framed around IgG1 and specified target antigen binding, not antibody sequence. 3) Which chelators are explicitly claimed in dependent claims? EDTA and citrate (including alkali metal citrate). 4) What are the specific EDTA ranges in the claims? 0.05 mM to 5 mM, and a narrower 0.1 mM to 3 mM. 5) What pH range does the patent claim? pH 6 to 7.2. References United States Patent 5,654,403. More… ↓ ⤷ Start Trial

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	May 7, 2001	⤷ Start Trial	2014-04-28
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	November 14, 2014	⤷ Start Trial	2014-04-28
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	October 12, 2004	⤷ Start Trial	2014-04-28
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Country	Patent Number	Estimated Expiration
Austria	161191	⤷ Start Trial
Australia	2872992	⤷ Start Trial
Australia	674290	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration

Patent: 5,654,403

Summary for Patent: 5,654,403