Patent: 5,914,111

Summary for Patent: 5,914,111

Title:	CD2-binding domain of lymphocyte function associated antigen-3
Abstract:	Polypeptides and proteins comprising the CD2-binding domain of LFA-3 are disclosed. DNA sequences that code on expression for those polypeptides and proteins, methods of producing and using those polypeptides and proteins, and therapeutic and diagnostic compositions are also disclosed. Deletion mutants unable to bind CD2 and methods for their use are also disclosed. In addition, fusion proteins which comprise the CD2-binding domain of LFA-3 and a portion of a protein other than LFA-3, DNA sequences encoding those fusion proteins, methods for producing those fusion proteins, and uses of those fusion proteins are disclosed.
Inventor(s):	Wallner; Barbara P. (Cambridge, MA), Miller; Glenn T. (Haverhill, MA), Rosa; Margaret D. (Winchester, MA)
Assignee:	Biogen Inc. (Cambridge, MA)
Application Number:	08/459,657
Patent Claims:	see list of patent claims

United States Patent 5,914,111 (LFA-3/Ig Fc Chimeric Polypeptides): Claims, Scope, and US Patent Landscape Impact

US 5,914,111 is directed to inhibiting T-cell activation by administering engineered LFA-3 polypeptides fused to immunoglobulin-derived Fc region elements (including hinge/constant domains and IgG1 Fc with protein A recognition). The independent concept centers on LFA-3 amino-terminal residues 1-92 joined to immunoglobulin constant domain portions (hinge, CH2, CH3) or an Fc region capable of protein A binding, with dependent claim sets specifying hinge disulfide bond formation and sequence-window fusions (including constructs encoded by a specific plasmid and fusions using a defined SEQ ID NO.:43 residue range).

This matters for freedom-to-operate (FTO) and invalidity strategy because the patent’s enforceable reach is likely anchored to:

1. Specific LFA-3 residue windows and fusion architecture (LFA-3 1–92 and/or LFA-3 residues 29–120, plus SEQ ID NO.:43-based constructs), and
2. Immunoglobulin Fc functional constraints (protein A recognition and hinge disulfide linkage capability).

What do the independent claims of US 5,914,111 cover and how broad are they?

Claim 1: LFA-3(1-92) joined to immunoglobulin hinge + CH2 + CH3 (non-LFA-3 polypeptide)

Claim 1 recites a method: administering a chimeric polypeptide to inhibit T-cell activation, where the polypeptide contains:

• LFA-3 amino terminal amino acids 1–92, fused to
• a protein/polypeptide other than LFA-3 comprising a portion of an immunoglobulin that includes:
  • hinge
  • C_H2
  • C_H3 constant domains

Practical claim scope

• The claim is architecture-driven: it requires LFA-3 1–92 plus specific immunoglobulin region content (hinge and CH2/CH3).
• It is not limited to full-length IgG; it allows “a portion” of constant domains.
• It does not require explicit species of immunoglobulin beyond being “an immunoglobulin” portion, but hinge/CH2/CH3 are typically associated with IgG-type Fc scaffolds, and hinge disulfides and Fc receptor binding are likely expected features.

Key strength point

• Limiting to LFA-3 residues 1–92 narrows prior art space relative to claims that would cover the entire extracellular domain or any LFA-3-Fc fusion.

Key vulnerability

• Prior art is often strongest when a reference has an LFA-3 extracellular fragment fused to an Fc (or a functional Fc equivalent). If a prior art reference uses LFA-3 residue windows overlapping 1–92 and uses IgG CH2/CH3 (with or without hinge), claim 1 may be vulnerable to obviousness or anticipation-by-equivalents arguments depending on how the original prosecution treated structural versus functional limitations.

Claim 2: LFA-3(1-92) + Fc region recognized by protein A

Claim 2 narrows claim 1 by specifying:

• the fusion includes LFA-3 amino terminal 1–92, and
• a portion of an Fc region of human IgG1 sufficient to be recognized by protein A.

Practical claim scope

• It introduces a functional binding criterion tied to protein A recognition.
• It also restricts the Fc type to human IgG1 (at least for the relevant Fc region “portion”).

Key strength point

• “Sufficient to be recognized by protein A” is a functional limitation that can exclude Fc variants that fold or present residues outside the protein A-binding site.

Key vulnerability

• Protein A recognition can be satisfied by many engineered Fc sequences that retain the classic protein A-binding face. If prior art uses IgG1 Fc (even truncated for CH2/CH3), claim 2 can be attacked if the protein A-binding residues are preserved.

Claims 3: hinge capable of forming intermolecular disulfide bonds

Claim 3 depends from claim 2, requiring:

• hinge region “capable of forming intermolecular disulfide bonds.”

Practical claim scope

• This is an additional structural/functional restriction: the hinge must enable dimer stabilization via intermolecular disulfides (consistent with IgG hinge behavior).
• It can exclude Fc formats that disrupt hinge disulfides or adopt non-covalent dimerization.

Key strength point

• Strengthens the ability to distinguish from Fc formats lacking disulfide-linked dimerization.

Key vulnerability

• Many classical IgG1 Fc fragments and hinge-containing Fc fusions have exactly this property. If prior art includes standard IgG1 Fc or conventional hinge designs, claim 3 may not add meaningful differentiation.

Claim 4: plasmid pSAB152 ATCC 68720 encoded polypeptide

Claim 4 recites:

• a polypeptide encoded by a DNA sequence contained in plasmid pSAB152, ATCC Accession 68720.

Practical claim scope

• This can be both broad and fragile:
  • Broad because “encoded by” may cover expression products even if sequences differ slightly, as long as they fall within what the plasmid encodes.
  • Fragile because enforceability depends on the actual nucleotide sequence and resulting polypeptide(s) encoded by that specific plasmid deposit.

Key strength point

• Uses a specific deposit identifier to anchor the sequence disclosure.

Key vulnerability

• If the plasmid encodes multiple products or if the critical “encoded polypeptide” differs from commercial products, there can be disputes over whether accused products meet the definition.

Claim 5 and 6: LFA fragment using SEQ ID NO.:43 residues 29–120 fused to Fc; claim 6 specifies Fc comprises residues 121–347

Claims 5 and 6 refine the construct using a sequence definition framework:

• Claim 5: polypeptide comprising amino acid residues 29–120 of SEQ ID NO.:43 linked to an Fc portion of IgG.
• Claim 6: Fc portion comprises amino acids 121–347 of SEQ ID NO.:43.

Practical claim scope

• These claims are effectively vector-mapped: they define the boundaries in the context of the defined sequence set out in the patent’s SEQ ID NO.:43.
• Such claims often capture specific embodiments where the inventors engineered a particular domain order and residue connectivity.

Key strength point

• High specificity reduces the range of non-infringing designs.

Key vulnerability

• If competitors use the same functional concept but differ in junction placement, hinge choice, or exact domain boundaries relative to SEQ ID NO.:43, they may avoid literal infringement.

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What is the likely novelty center of US 5,914,111 (and what prior art vectors matter most)?

Based on the claim language alone, the novelty center appears to sit at the intersection of:

• LFA-3 extracellular fragment choice (notably 1–92 and also 29–120 via SEQ ID NO.:43),
• IgG Fc constant-region architecture (hinge + CH2 + CH3; IgG1 Fc; protein A recognition),
• and dimerization/disulfide capability for hinge.

Prior art vectors that most directly threaten the claims

1. Other LFA-3-Ig or LFA-3-Fc fusions using residue fragments overlapping 1–92 or covering the functional interaction surface for T-cell activation.
2. Standard IgG1 Fc architectures that are protein A-binding and hinge-disulfide-capable.
3. Engineered Fc fusions where the hinge/CH2/CH3 boundaries are conventional, making “portion of hinge, CH2, CH3” easy to satisfy.
4. Sequence-defined equivalents: if competitors use a construct that functionally corresponds to SEQ ID NO.:43 boundaries, claim 5/6 risk rises.

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How strong is the patent estate for LFA-3/Fc T-cell inhibition around 1998–2001 competitive timing?

US 5,914,111 (published as issued patent) likely belongs to a late-1990s patent generation for immunomodulatory fusion proteins. Strength typically correlates with:

• whether the patent’s SEQUENCE-SPECIFIC claims are supported by robust written description and enablement,
• and whether the deposit-anchored plasmid claim is supported with clear sequence identity in the specification.

Where the estate is strongest for enforcement is when claim scope is locked to:

• exact LFA-3 residue windows (1–92 and/or 29–120 in SEQ ID NO.:43),
• and exact Fc region elements that preserve protein A binding and hinge disulfide bonding.

Where the estate is weaker is when competitors can substitute:

• a different LFA-3 fragment boundary (outside 1–92 and 29–120),
• a different Fc subclass/scaffold that does not satisfy protein A recognition,
• or a non-disulfide hinge design.

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Which claim elements create the biggest design-around opportunities?

LFA-3 residue window switching

If a competitor uses an LFA-3 fragment that is:

• missing residues within the patent-defined ranges, or
• shifts the N-terminus or C-terminus such that the polypeptide no longer contains amino terminal amino acids 1–92, infringement of claims 1–3 may be avoided.

Fc scaffold changes that defeat protein A recognition

Claim 2’s “recognized by protein A” limitation can be designed around by:

• using Fc variants that retain Fc functionality but alter the protein A-binding surface.

Hinge disulfide disruption

Claim 3’s hinge-disulfide capability can be designed around with:

• hinge designs that prevent intermolecular disulfide formation,
• or formats that avoid disulfide-stabilized dimerization.

Sequence-defined boundary avoidance (SEQ ID NO.:43)

Claims 5–6 are the most design-sensitive because they fix residue boundaries in SEQ ID NO.:43.

• Competitors can attempt to use the same overall concept (LFA-3 extracellular linked to Fc) but with different linkers/junctions so that the boundaries no longer map to residues 29–120 and 121–347 as defined.

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How do these claims map to litigation-style infringement analysis?

Claim 1/2/3 infringement requires meeting both halves

Infringement analysis for method-of-inhibiting T-cell activation claims is typically split:

• Whether the administered polypeptide includes the required LFA-3 residues; and
• whether it includes the required Fc portion identity/function (hinge+CH2/CH3; protein A recognition; disulfide-enabled hinge).

Because these are structural elements described partly by functional tests (protein A recognition; disulfide-forming hinge), the evidentiary battle often turns on:

• protein sequence/construct mapping,
• and experimental Fc-binding properties.

Claim 4 infringement is sequence-anchored to a plasmid deposit

If an accused polypeptide is not identical to what pSAB152 encodes, non-infringement arguments become stronger.

Claims 5/6 depend on residues in SEQ ID NO.:43

Infringement typically becomes a “numbered-residue mapping” issue:

• accused sequence alignment to SEQ ID NO.:43,
• and domain boundary identification.

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What formulations or delivery systems are covered (and are they relevant to infringement)?

The claims are written as methods of inhibiting T-cell activation by administering a polypeptide. They do not specify:

• route of administration,
• dosage form (injectable, infusion, etc.),
• excipients,
• or manufacturing format.

As a result, formulation and route generally should not limit literal infringement, so long as the administered active polypeptide matches the structural claim limitations.

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What Orange Book status matters here?

US 5,914,111 is a biologic/protein patent profile, and the Orange Book primarily tracks small-molecule NDA products and certain biologic equivalents under Hatch-Waxman with the FDA Orange Book listing. Protein biologics and many fusion proteins instead track in the BLA/Biosimilar regulatory framework rather than classic generic Orange Book pathways.

Without product identification from within this patent analysis, Orange Book status cannot be reliably stated for US 5,914,111 itself. The relevant practical point for business risk is that exclusivity and follow-on competition would likely be driven by:

• patent expiry timing for the specific biologic product,
• and any separate pediatric exclusivity or data exclusivity tied to the first approval.

No product/NDA/BLA mapping is provided in the claim text, so status cannot be accurately derived.

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Key takeaways for patent strength, FTO, and design-around

1. The enforceable heart is LFA-3 extracellular fragment fused to IgG Fc elements with explicit structural windows (notably LFA-3 1–92 and SEQ ID NO.:43 residue boundaries).
2. Claims 2–3 add Fc functional constraints: human IgG1 protein A recognition and hinge disulfide intermolecular bonding capability. These features can be used for infringement testing but are also common engineering targets for design-around.
3. Claims 5–6 are the most construct-specific and likely define a relatively narrow set of sequences that map to SEQ ID NO.:43 boundaries.
4. Claim 4 anchors to a specific plasmid deposit; infringement is tied to what that plasmid encodes. If a competitor changes the coding sequence while preserving function, claim 4 is easier to contest.

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FAQs

1) Does US 5,914,111 require full IgG (Fc region) or only a portion?

The claims require an Fc-related portion with specified content, including hinge and CH2/CH3 elements in claim 1, and a portion of human IgG1 Fc sufficient for protein A recognition in claim 2.

2) Can a competitor avoid infringement by using a different IgG subclass for the Fc?

Claim 2 ties the relevant Fc portion to human IgG1 and protein A recognition. Changing to a different subclass or engineering to disrupt protein A recognition can reduce literal fit.

3) Are hinge disulfide characteristics required for all claims?

No. Disulfide-forming hinge is required only in claim 3, which depends on claim 2.

4) Is the method claim limited to any particular delivery route?

No. The method-of-inhibiting T-cell activation claims specify administering the polypeptide but do not restrict route or formulation.

5) What is the most likely design-around path against claims 5–6?

Use an LFA-3-Fc construct that does not align to the SEQ ID NO.:43 residue boundary mapping (29–120 for the LFA portion and 121–347 for the Fc portion).

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References

(No external sources were cited because the provided prompt contains only the claim text for US 5,914,111 and does not include any bibliographic identifiers, prosecution history, assignees, priority data, or product mapping needed for accurate landscape citations.)

Details for Patent 5,914,111

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Astellas Pharma Us, Inc.	AMEVIVE	alefacept	For Injection	125036	January 30, 2003	5,914,111	2015-06-02

International Patent Family for US Patent 5,914,111

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	9216622
United States of America	5928643
United States of America	5728677
United States of America	5547853
Singapore	47766
Portugal	503648
Mexico	9203138