Patent: 8,420,081

Summary for Patent: 8,420,081

Title:	Antibody formulations and methods of making same
Abstract:	The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductivity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.
Inventor(s):	Fraunhofer; Wolfgang (Shrewsbury, MA), Bartl; Annika (Ludwigshafen, DE), Krause; Hans-juergen (Grunstadt, DE), Tschoepe; Markus (Hessheim, DE), Kaleta; Katharina (Ludwigshafen, DE)
Assignee:	AbbVie, Inc. (North Chicago, IL)
Application Number:	12/325,049
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,420,081
Patent Claims:	see list of patent claims

United States Patent 8,420,081 (Formulation/Process Claims) Critical Analysis: Scope, Claim Strength, Design-Around Paths, and Potential Infringement Risk

Bottom line: US 8,420,081 claims a narrow but commercially meaningful platform for high-concentration antibody solutions in low-conductivity, low-osmolality, reduced hydrodynamic size formats, with multiple fallback claim ladders that are tightened around specific physical-property thresholds and (in later claims) defined antibody variable-region sequences. The estate is strongest against competitors attempting to market similar “water-based, low-ion conductivity, sub-aggregating” liquids using the same antibody types (especially adalimumab) and similar formulation/processing routes (notably diafiltration using water). It is weaker against products that preserve antibody monomer size via different excipient systems, use higher conductivity/osmolality, or avoid the claimed molecular-weight/diameter/sequence-specific constraints.

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What is US Patent 8,420,081 about and what do the claims actually cover?

Core inventive concept (from claim language): an aqueous formulation (water as the principal medium) containing an antibody (or antigen-binding fragment) at high concentration and meeting low conductivity (and in some claims low osmolality) and showing smaller hydrodynamic diameter relative to the same antibody in a buffer at the same concentration. The claims also cover a manufacturing process using diafiltration with water and include device/article-of-manufacture dependents.

Claim architecture (high level)

• Independent claim set around physical-property limits
  • Claim 1: aqueous antibody at ≥20 mg/mL, conductivity <2.5 mS/cm, antibody MW >47 kDa.
  • Claim 13: adds osmolality ≤30 mOsmol/kg.
  • Claim 17: adds hydrodynamic diameter (Dₕ) at least 50% less than in buffered solution at same concentration.
  • Claim 28: Dₕ <4 nm.
• Concentration ladders
  • Claims 9–12: ≥100, ≥150, ≥200 mg/mL, and >200 mg/mL.
• Conductivity ladders
  • Claims 6–8: <2, <1, <0.5 mS/cm.
• MW ladders
  • Claims 2–5: MW >57, >100, >150, >250 kDa.
• Antibody scope
  • Broad antibody class lists (Claim 26) and narrower functional targets:
    • Anti-TNF-α / anti-IL-12 (Claim 22)
    • Specifics include ustekinumab (Claim 23) and infliximab/golimumab/certolizumab pegol as options (Claim 24), plus adalimumab (Claims 25 and 27).
• Sequence-specific embodiments (major scope tightening)
  • Claims 57, 68, 84 and their dependencies recite:
    • LCVR/HCVR CDR1/CDR2/CDR3 amino acid sequences via SEQ ID NOs with defined single-alanine substitutions at specified CDR positions.
• Excipient-specific variants
  • Claims 34–37 and 60–65, 74–81, 80–83, 100–105, 106–111:
    • “Further comprising a non-ionizable excipient”
    • specific non-ionizable excipients: polyols (mannitol/sorbitol) and sucrose/trehalose/raffinose/maltose and non-ionic surfactants (polysorbate 20/40/60/80), including specific combination claims (mannitol + polysorbate 80; sucrose + polysorbate 80).
• Processing / preparation claims
  • Claims 44: diafiltration with water “until at least a five-fold volume exchange”.
  • Claims 120–125 and 121–127: diafiltration using water with “at least five-fold volume exchange”, with follow-on concentrating; various optional refinements (centrifugation, 6–7 fold exchange, excipient reduction relative to first solution).
• Device/article-of-manufacture
  • Claims 42, 55, 56, 98, 99, 118, 119 map product embodiments into downstream infringement hooks.

Featured snippet answer

US 8,420,081 is a formulation-and-process patent claiming high-concentration aqueous antibody solutions with low electrical conductivity and (in some embodiments) low osmolality plus reduced hydrodynamic diameter, achieved or enabled by water-only diafiltration, and in later claims anchored to adalimumab-like CDR sequence embodiments via SEQ ID NO-defined variable-region domains.

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Which claims are the real “money claims” for enforcement?

Highest infringement leverage: Claim 1 / Claim 13 / Claim 17 / Claim 28

These are the backbone constraints that most directly define a product:

• Claim 1: aqueous antibody formulation, ≥20 mg/mL, conductivity <2.5 mS/cm, MW >47 kDa.
• Claim 13: Claim 1 plus osmolality ≤30 mOsmol/kg.
• Claim 17: Claim 1 plus Dₕ ≥50% reduction vs buffered solution at same concentration.
• Claim 28: Claim 1 plus Dₕ <4 nm.

From an infringement standpoint, these claims require plaintiffs to show not just composition but measured physical properties (conductivity/osmolality and Dₕ under defined comparison conditions). That shifts enforcement into test-method and benchmark comparability territory.

Strength amplification: numeric ladders (conductivity and concentration)

Even within the same broad framework, the patent includes multiple dependent thresholds:

• Conductivity: <2.0, <1.0, <0.5 mS/cm (Claims 6–8)
• Concentration: ≥100, ≥150, ≥200 mg/mL (Claims 9–12)
• MW: >57, >100, >150, >250 kDa (Claims 2–5)
• Osmolality tightening: ≤15 mOsmol/kg (Claim 14)

These provide “lanes” if a competitor’s product misses one threshold but hits another.

Enforcement anchor by sequence: Claim 57 / Claim 68 / Claim 84

These dependents materially narrow the antibody species and create a second enforcement axis:

• Defined antibody variable regions by CDR amino acid sequences (LCVR and HCVR CDR1/CDR2/CDR3), with single-alanine substitution at enumerated positions.
• Claim 57 also explicitly ties these sequence-defined variable regions to a conductivity <2.5 mS/cm formulation at ≥50 mg/mL with the same physical-property framing.
• Claim 68 and 84 repeat the sequence anchor combined with Dₕ reduction and Dₕ limits.

If an accused product uses adalimumab (or an equivalent with identical/covered CDRs), these claims become the most direct.

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How broad is claim scope across antibodies and formats?

Broadest antibody coverage

• Claim 21: chimeric/human/humanized/dAb (domain antibody).
• Claim 26: a long enumerated list covering many therapeutic antibodies (e.g., alemtuzumab, cetuximab, trastuzumab, rituximab, ustekinumab, bevacizumab, etc.).
• Claim 32: similar list for the Dₕ <4 nm family.

This means the patent is not limited to TNF-α only. However, physical-property requirements remain the real gate.

Functional narrowing: TNF-α and IL-12

• Claim 22 confines to anti-TNF-α or anti-IL-12 antibodies.
• Claim 23: ustekinumab.
• Claim 24: infliximab, golimumab, certolizumab pegol.
• Claim 25: adalimumab.
• Claim 31: anti-TNF-α or anti-IL-12.

Most commercially salient: adalimumab

• Multiple claims explicitly name adalimumab (Claims 25, 27, 33, 67, 73, 87, 105, 111, 116).
• Sequence-specific claims (57, 68, 84) also map to the adalimumab CDR framework via SEQ ID NOs.

Net effect: the patent likely has its strongest practical litigation and licensing value where competitors attempt adalimumab liquid concentrates meeting the conductivity and Dₕ constraints.

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What does “hydrodynamic diameter reduced vs buffered solution” mean for infringement and design-around?

Key technical requirement

Claim 17 requires:

• Aqueous formulation (water-based)
• ≥20 mg/mL
• Dₕ at least 50% less than Dₕ of the same antibody at the same concentration in a buffered solution
• MW >47 kDa

Claim 18–20 scale that reduction to 60% and 70% vs PBS at same concentration.

Claim 28 instead uses a direct absolute threshold:

• Dₕ <4 nm
• with MW >47 kDa

Claim 45 and later Dₕ claims integrate similar frameworks and can include excipient variants.

Why this is both strong and litigable

• Strong: if accused formulations demonstrably produce smaller effective hydrodynamic size (e.g., via reduced aggregation, altered hydration shell behavior, or measurement methodology).
• Litigable: infringement depends on comparative measurement against a buffered comparator “at the same concentration,” and on the measurement protocol for Dₕ. Even if a competitor avoids the exact numeric thresholds, they may still be caught if their data under the claimed comparison conditions shows qualifying Dₕ.

Design-around levers

• Increase conductivity or osmolality above claimed cutoffs (miss Claim 1 or 13).
• Use excipient systems that preserve standard Dₕ behavior so that the “reduced vs buffered solution” criterion is not met (miss Claim 17/18/20 and Claim 28 if Dₕ not driven below 4 nm).
• Formulate at concentrations below the ladder thresholds if the independent claim is not met (though Claim 1 minimum is 20 mg/mL, so the window is narrow for high-concentration liquids).
• If sequence-specific claims are asserted, ensure the antibody variable regions fall outside the SEQ ID NO-defined CDRs and the allowed single-alanine substitutions.

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What is the patent’s manufacturing/process coverage, and does it create additional infringement pathways?

Diafiltration with water

Claim 44 and Claims 120–124 cover preparation by:

• providing antibody in a first solution
• diafiltration using water as diafiltration medium
• achieving at least five-fold volume exchange (or optional 6–7 fold)
• then concentrating (for methods)
• in some dependent claims, using water-only diafiltration and reducing excipient levels substantially (Claims 125, 126)

Why process claims matter

Competitors can avoid product infringement by changing formulation parameters, but process claims create potential exposure if manufacturing steps mirror:

• water-only diafiltration
• to specified volume exchange levels
• with the final product meeting MW and concentration criteria

In litigation, process evidence can be less transparent; however, if a competitor licenses a known platform or uses process documentation similar to the claimed steps, discovery can bridge the gap.

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How does the excipient sub-scope change the risk profile?

“Non-ionizable excipient” as a carve-in

Claims 34–37 and 60–65 and others allow non-ionizable excipients, including:

• polyols: mannitol, sorbitol
• non-ionic surfactants: polysorbate 20/40/60/80
• sugars: sucrose, trehalose, raffinose, maltose

But the independent claim structure already requires low conductivity and (in some claims) low osmolality and Dₕ behavior. Therefore, excipient inclusion does not broaden into high-salt systems unless the physical properties remain within the cutoffs.

Specific combinations

Claims 80–83 (sucrose + polysorbate 80), and 94–97 (mannitol + polysorbate 80) tighten the formulation identity, which can be used as a “fallback” if a competitor’s actual formulation includes those combinations.

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How many patents cover this space? What is the broader landscape?

No complete landscape assessment is possible from claim text alone. A meaningful “how many patents” and “which assignees” analysis requires:

• US 8,420,081 bibliographic data (assignee, filing date, priority chain)
• full citation graph and family members
• Orange Book/biologics reference linkages
• litigation/settlement docket identification

Per the constraints, an analysis without those data cannot be completed accurately.

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Timeline: when does exclusivity expire for this patent?

Not computable from the claim text provided. Expiration depends on:

• filing date / earliest priority
• PTA/PTE
• term adjustments and terminal disclaimers
• continuation/divisional status in the family

No exact expiration can be stated without patent bibliographic data.

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What Orange Book status applies and is there likely biosimilar/Paragraph IV relevance?

Not determinable from the provided claim set. For biologics and antibody drugs, relevance typically depends on:

• which reference product is implicated (adalimumab suggests a likely FDA biologics license context)
• which formulation is approved and listed
• whether the patent is in the relevant FDA patent list

Claim text alone cannot establish Orange Book status or listing mechanics.

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How strong is the claim set for litigation (validity, indefiniteness, and enablement risk)?

Strength: objective property limits create a clear infringement matrix

Conductivity thresholds, osmolality caps, Dₕ ratios vs comparator, and Dₕ absolute cutoffs provide measurable criteria. The sequence-specific claims add molecular specificity.

Potential validity pressure points created by the claim drafting style

• Physical-property dependence on measurement methodology: Dₕ and conductivity can vary with instrumentation, sample preparation, temperature, and comparator buffer preparation. Defense strategies often focus on whether the patent’s description supports consistent measurement leading to reproducible infringement determinations.
• Comparator requirement: Claims tied to “same concentration in buffered solution” can be contested if the accused product’s comparator differs in buffer composition, pH, or ionic strength. The claims themselves state “buffered solution” and “in PBS” in specific dependents, which may reduce ambiguity but still invites protocol fights.
• Broad antibody lists plus specific thresholds: A broad roster paired with strict physical limits can trigger an argument that the patent does not enable all embodiments across that roster to meet the thresholds. This is a classic enablement/utility attack surface in formulation patents.

Those issues are litigation-relevant but cannot be scored without the specification details and prosecution history.

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Commercial exposure: which marketed antibody liquids are most at risk?

From the claim text, products that match:

• adalimumab (high-likelihood commercial focus due to explicit naming and sequence-specific CDR claims)
• antibody at ≥20 mg/mL
• conductivity below 2.5 mS/cm
• and for stronger match: osmolality ≤30 mOsmol/kg and/or Dₕ reduced vs buffered solutions or Dₕ <4 nm

are the principal candidates for exposure. However, mapping to actual marketed formulations requires FDA product composition data and testing results, which are not provided.

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Key Takeaways

• US 8,420,081 is structured around measurable formulation physics for antibody solutions: conductivity, osmolality, and hydrodynamic diameter behavior vs buffered references.
• The claims form enforcement “ladders” through dependent numeric cutoffs on concentration, conductivity, MW, and osmolality.
• The strongest specificity is in sequence-defined variable region embodiments (SEQ ID NO-defined CDRs with limited substitutions), which are the most credible to assert against adalimumab-type antibodies.
• The manufacturing claims add an IP pathway at process level for water-only diafiltration with at least five-fold volume exchange.
• Practical validity and infringement disputes likely concentrate on measurement methodology and comparator conditions for Dₕ and conductivity.

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FAQs

1. Can a competitor avoid infringement by using a different buffer instead of water-only diafiltration?
   Avoiding “diafiltration using water as diafiltration medium” targets the process claims, but product claims may still apply if the final formulation meets the conductivity/osmolality/Dₕ thresholds.

2. If a product misses the Dₕ ratio requirement, can it still infringe under the conductivity-only claims?
   Yes. Claim 1 can be met without satisfying the Dₕ reduction requirements, depending on measured conductivity and concentration.

3. Are the conductivity and osmolality thresholds likely to be treated as objective metrics in court?
   Yes, because they are explicit numeric limits, but measurement protocol and sample conditioning remain likely dispute points.

4. Do the sequence-specific claims cover only exact adalimumab, or also variants with the allowed alanine substitutions?
   They cover the CDR amino acid sequences as defined by the SEQ ID NOs, plus variants with single alanine substitutions at the enumerated positions.

5. Do the excipient claims broaden coverage to typical formulation salts?
   The excipient language is limited to “non-ionizable excipient” classes; coverage still depends on meeting the conductivity/osmolality thresholds.

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References

1. United States Patent 8,420,081. (Claim text provided by user).

Details for Patent 8,420,081

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Centocor Ortho Biotech Products, L.p.	ORTHOCLONE OKT3	muromanab-cd3	Injection	103463	September 14, 1992		2028-11-28
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	December 22, 1994		2028-11-28
Aytu Bioscience, Inc.	PROSTASCINT	capromab pendetide	Injection	103608	October 28, 1996		2028-11-28
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2028-11-28
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	February 19, 2002		2028-11-28
Hoffmann-la Roche Inc.	ZENAPAX	daclizumab	Injection	103749	December 10, 1997		2028-11-28

International Patent Family for US Patent 8,420,081

Country	Patent Number	Estimated Expiration
Australia	2008334099
Australia	2013204044
Australia	2013204165
Australia	2017203012
Brazil	PI0819714
Canada	2707483