Patent: 6,316,408

Summary for Patent: 6,316,408

Title:	Methods of use for osetoprotegerin binding protein receptors
Abstract:	A novel polypeptide, osteoprotegerin binding protein, involved in osteolcast maturation has been identified based upon its affinity for osteoprotegerin. Nucleic acid sequences encoding the polypeptide, or a fragment, analog or derivative thereof, vectors and host cells for production, methods of preparing osteoprotegerin binding protein, and binding assays are also described. Compositions and methods for the treatment of bone diseases such as osteoporosis, bone loss due to arthritis or metastasis, hypercalcemia, and Paget\'s disease are also provided. Receptors for osteoprotegerin binding proteins are also described. The receptors, and agonists and antagonists thereof, may be used to treat bone diseases.
Inventor(s):	Boyle; William J. (Moorpark, CA)
Assignee:	Amgen Inc. (Thousand Oaks, CA)
Application Number:	09/052,521
Patent Claims:	see list of patent claims

Executive summary US Patent 6,316,408 claims a treatment/prevention method for bone diseases in mammals by administering a therapeutically effective amount of a soluble form of an osteoclast differentiation and activation receptor (ODAR), including soluble human ODAR, with limitations around lacking a functional transmembrane region, extracellular-domain binding capability to OPG, and fusion constructs such as Fc. The patent’s enforceable value hinges on whether the specification supports (i) the exact structural definitions of “soluble ODAR” and (ii) the “capable of binding to OPG” functional constraint, plus whether later competing agents in the U.S. market practice the same clinical mechanism (OC differentiation/activation receptor signaling blockade via soluble decoy formats). The claim set is broad on indication and dosing concept, but narrow on the molecular construct: soluble ODAR (human), optionally extracellular-domain-only, optionally Fc-fused, and OPG-binding competent.

Patent scope at a glance (core limitations that control infringement)

• Act (method claim): administer a therapeutically effective amount to prevent or treat bone disease in a mammal.
• Drug substance: “a soluble form of an ODAR.”
• ODAR identity: at least in dependent claims, “soluble form of human ODAR.”
• Structural constraint (dependent): “lacking a functional transmembrane region.”
• Functional constraint (dependent): extracellular domain “capable of binding to OPG binding protein.”
• Construct scope (dependent): soluble human ODAR fused to a heterologous amino acid sequence, including human IgG Fc.
• Population (dependent): mammal is human.
• Indication (dependent): a long list including osteoporosis, osteomyelitis, hypercalcemia of malignancy, Paget’s disease, osteonecrosis, rheumatoid arthritis-related bone loss, periodontal bone loss, immobilization, prosthetic loosening, and osteolytic metastasis.
• Combination (dependent): allows co-administration with multiple bone biology agents and regulators (BMP, TGF-β family, FGF, IL-1 inhibitor, TNF-α inhibitor, PTH, prostaglandins, bisphosphonates, estrogen/SERM, mineral).

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How strong is the patent estate for US 6,316,408 ODAR soluble receptor decoy claims

Quick answer: The patent’s strength is driven by claim construction around “soluble ODAR” and, in dependent claims, the structural and binding constraints. The broad indication language increases reach of method coverage, but infringement turns on the administered molecule’s construct features (soluble human ODAR, lack of transmembrane domain, extracellular OPG-binding competence, and Fc fusion when that dependent claim is invoked).

What the independent claim 1 covers in legal terms

Claim 1 covers a method that uses a therapeutically effective amount of soluble ODAR to prevent or treat bone disease in a mammal with reduced bone density or susceptible to it.

Key claim construction pressure points:

• “soluble form of an ODAR”: This is the central novelty handle. Courts typically require that “soluble form” be supported as a specific, reproducible molecular entity. If the term is treated broadly, the claim becomes more vulnerable to prior art and indefiniteness arguments; if construed narrowly to constructs disclosed in the specification, enforceability is higher for those exact formats.
• “ODAR” identity: ODAR in osteoclast biology maps functionally to a receptor that regulates osteoclast differentiation and activation. The claim language is “osteoclast differentiation and activation receptor (ODAR).” If ODAR is used as a defined receptor name in the specification, then the scope is anchored to that receptor. If not, indefiniteness and claim interpretation risk increases.

How dependent claims narrow to specific embodiments

Dependent claims create layered barriers to workarounds:

• Claim 2: soluble form is human ODAR
• Claim 3: lacks a functional transmembrane region
• Claim 4: includes part or all of extracellular domain capable of binding OPG binding protein
• Claim 5: soluble human ODAR fused to a heterologous amino acid sequence
• Claim 6: heterologous sequence comprises human IgG Fc
• Claim 7: human patient
• Claim 8: specific bone disease list
• Claim 9: permissive combination therapy add-ons

From an infringement standpoint:

• If a competitor administers a fully soluble decoy that includes extracellular ODAR and binds OPG binding protein, claims 2-4 are the most relevant.
• If a competitor uses an Fc-fusion format, claim 6 becomes a key touchstone.
• Combination therapy language in claim 9 is generally less likely to be determinative unless the competitor’s label includes co-administration of the same agent(s) in a way that fits the claim’s “further comprising” structure.

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What prior art would most threaten US 6,316,408 ODAR soluble receptor claims

Quick answer: The highest-risk prior art category is soluble decoy receptors or extracellular domain Fc-fusions that target osteoclast regulation pathways by mimicking receptor ligands or binding partners. A second risk category is known ODAR-receptor biology defining ODAR structure and the existence of soluble or engineered forms.

Prior art that typically maps to this claim family

1. Decoy-receptor strategies in osteoclast biology
   • Prior art covering soluble forms of osteoclast-regulatory receptors (or their binding domains) is likely relevant to claim 1’s “soluble form of ODAR” breadth.
2. Fc-fusion half-life extension
   • If earlier references disclose Fc-fused extracellular domains for cytokine/receptor binding, claim 6’s novelty is reduced.
3. Exclusion of transmembrane region
   • Soluble extracellular-domain constructs are standard in biologics. Claim 3 (“lacking functional transmembrane region”) is a common drafting limitation used to distinguish engineered secreted forms from membrane receptors.
4. Binding-competence constraints
   • Claim 4’s “capable of binding to OPG binding protein” is conceptually specific, but the prior art risk depends on whether earlier publications show equivalent binding capability and identify the same ODAR extracellular domain.

Critical evaluation of “functional” claim language risks

Claim 4 includes a functional constraint: binding to “OPG binding protein.” Functional limitations can survive if the specification provides working definitions and assays. They also become vulnerable if:

• the binding partner is not unambiguously defined, or
• “capable of binding” is implemented by diverse constructs without clear correlation.

This matters because the broader claim set invites interpretive latitude, which can reduce enforceability.

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How does US 6,316,408 compare with denosumab, romosozumab, and other bone resorption therapies in mechanism coverage

Quick answer: US 6,316,408 is ODAR-decoy based, not RANKL-neutralizing (denosumab) or sclerostin-inhibiting (romosozumab). Unless an ODAR-based decoy is administered, the core molecule limitation is unlikely to be met.

Mechanism boundary conditions

• Denosumab targets RANKL, a different upstream signaling node than an ODAR decoy receptor.
• Romosozumab targets sclerostin and affects bone formation pathways.
• Bisphosphonates, estrogen/SERM, parathyroid hormone: these are explicitly listed in claim 9 as possible combination agents, but the patent’s infringement anchor remains the administration of soluble ODAR.

Practical implication

A competitor can reduce risk by:

• using agents that do not comprise soluble ODAR as defined, or
• using a different receptor/ligand targeting strategy without the ODAR decoy molecule.

The patent is designed to block a particular molecular approach, not the entire class of bone therapeutics.

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Which formulations are protected by US 6,316,408 ODAR: Fc-fusions, extracellular decoys, and engineered soluble constructs

Quick answer: The claim set is format-sensitive. It protects soluble human ODAR, structurally constrained to lack the transmembrane region, optionally restricted to extracellular-domain content capable of binding OPG binding protein, and optionally fused to heterologous sequences including human IgG Fc.

Protected construct archetypes (from the dependent claims)

1. Secreted soluble human ODAR
   • No functional transmembrane region (claim 3).
2. Extracellular-domain ODAR decoy
   • Part or all extracellular domain; OPG-binding competent (claim 4).
3. Fc-fusion ODAR
   • Soluble human ODAR fused to heterologous amino acids, including IgG Fc (claims 5-6).

What is not directly locked down by the claims

• The claims do not expressly limit:
  • dosing regimen,
  • route of administration,
  • glycosylation pattern,
  • molecular weight or linker sequences (unless those are in the specification).

So infringement for molecule-based method claims may focus on the presence of the ODAR-binding extracellular domain and the engineered “soluble” format.

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Does US 6,316,408 cover method-of-use for osteoporosis and osteolytic metastasis and how broad is the indication language

Quick answer: Claim 8 is broad and enumerates multiple disease categories, giving wide method-of-use coverage once the ODAR soluble molecule requirement is met.

Indication coverage in claim 8 (selected)

• Osteoporosis
• Osteomyelitis
• Hypercalcemia of malignancy
• Osteopenia due to surgery or steroid administration
• Paget’s disease
• Osteonecrosis
• Bone loss due to rheumatoid arthritis
• Periodontal bone loss
• Immobilization
• Prosthetic loosening
• Osteolytic metastasis

Legal impact of broad indication lists

• Broad lists generally strengthen “method” coverage but do not expand chemical scope.
• If a competitor’s marketed indication differs, it still can fall within claim 1 if the patient population is “having reduced bone density or susceptible to reduced bone density,” though claim 8 provides explicit coverage for many common labeled indications.

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What combination therapies are encompassed by claim 9 and what does “further comprising” mean for infringement

Quick answer: Claim 9 is a permissive combination claim that covers co-administration with a wide array of bone-active and anti-inflammatory agents.

Agents recited in claim 9

• Bone morphogenic factor
• TGF-β family member
• Fibroblast growth factor
• IL-1 inhibitor
• TNF-α inhibitor
• Parathyroid hormone
• E series prostaglandin
• Bisphosphonates
• Estrogen
• SERM
• Bone-enhancing mineral

Infringement relevance

• “Further comprising” typically requires that the ODAR soluble molecule be administered along with one or more of the listed agents.
• If a competitor uses ODAR soluble decoy without those combinations, claim 9 is not the best fit.
• If a competitor uses those combinations but without soluble ODAR, claim 9 still fails.

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When does US 6,316,408 lose exclusivity in the US and what “Orange Book” status would matter

Quick answer: Patent 6,316,408 has expired under the normal U.S. utility-patent term framework, so the claim set is primarily relevant to (i) historical infringement, (ii) settlement/legacy licensing, and (iii) assessing whether related continuations or later patents create current exclusivity for an ODAR-soluble biologic.

Exclusivity timing construct (business-use)

• Utility patents in the U.S. expire based on filing date (with adjustments) rather than FDA exclusivity alone.
• Biologics may have separate exclusivity periods (BLA data exclusivity) and market exclusivity, but those are independent of the patent term.

Orange Book applicability caveat

• Orange Book lists NDA drugs; ODAR decoys are likely biologics and typically appear in the Purple Book rather than Orange Book.
• For method-of-use claims tied to biologics, the relevant status framework often involves:
  • biologics exclusivity,
  • 351(a)/(k) reference product exclusivity,
  • and the listing of patents in the Biologics Price Competition and Innovation Act ecosystem.

(Only a fully documented listing record can be used to state actual Orange/Purple Book entries. Those records are not supplied here.)

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What generic entry risks exist for an ODAR soluble decoy under the US patent regime

Quick answer: If the commercial product is a biologic, the “generic” risk is typically biosimilar or interchangeable entry rather than small-molecule generics. Patent 6,316,408’s current enforcement value depends on whether the marketed product is still covered by a still-active related patent family.

Biosimilar risk mapping

• Biosimilar developers face:
  • patent litigation or settlement constraints linked to the patent estate,
  • and the need to avoid practicing protected embodiments (construct-specific or method-of-use specific).
• The molecule-based constraints in dependent claims (soluble human ODAR, extracellular OPG-binding competent, Fc-fusion) create higher design-around specificity if a developer can change format.

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What patent litigation or Paragraph IV challenges would be most relevant to ODAR-soluble molecules

Quick answer: Paragraph IV is an NDA/generic framework. If ODAR soluble ODAR therapy is a biologic, the relevant challenges are biosimilar-related patent disputes rather than Paragraph IV. Litigation, if any, would focus on claim construction of “soluble form,” “ODAR,” and whether the accused construct binds the specified OPG binding protein through the extracellular domain.

Litigation leverage points

• Claim 1’s breadth may drive invalidity/unenforceability fights (solubility and receptor identity).
• Dependent claims may create stronger infringement leverage because they add structural/binding limitations that can be engineered around but are more likely to be asserted selectively.

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How does US 6,316,408’s claim design affect design-around strategies for competitors

Quick answer: The claim set blocks a specific architecture: soluble human ODAR, optionally extracellular-domain-only, and potentially Fc-fused. Competitors can design around by altering one or more of these structural constraints while still modulating osteoclast signaling via other nodes.

Likely design-around options

• Use a different target than ODAR’s functional pathway.
• Use an ODAR-based molecule that does not meet “lacking functional transmembrane region” if the claim is construed strictly (though this is an odd direction biologically).
• Use a construct that does not bind the specified “OPG binding protein” as required by claim 4.
• Use a heterologous fusion format that avoids the Fc embodiment for claim 6 (though claim 5 still covers “fused to heterologous amino acid sequence,” so total avoidance requires changes beyond Fc).

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What business landscape conclusions follow from the ODAR soluble claim scope

Quick answer: The patent is best understood as a claim to a biologic decoy/soluble receptor format aimed at osteoclast differentiation/activation. Its long indication list supports wide clinical use coverage, but enforcement depends on whether a competitor administers a soluble human ODAR meeting the specific structural and binding constraints. For licensing or freedom-to-operate, the decisive analysis is molecular: compare competitor’s expressed fusion construct (domain content, solubility design, binding assay results to the specified binding partner, and fusion domain identity).

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Key Takeaways

• US 6,316,408 claims a method of treating/preventing bone disease by administering a soluble ODAR, with dependent claims tightening to soluble human ODAR lacking a functional transmembrane region.
• The most enforceable molecule-specific elements are the extracellular-domain definition and binding competence to OPG binding protein, plus optional Fc fusion.
• The broad indication list increases method coverage once the ODAR-soluble molecule is used, but it does not expand the chemical scope.
• The current business relevance for new entrants is likely less about this single patent’s enforceability (term likely ended) and more about whether continuations and related patents still cover present-day ODAR soluble biologic formats and clinical claims.

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FAQs

1. What structural features of soluble ODAR typically decide infringement for dependent claims 3-4?
2. Does claiming “capable of binding to OPG binding protein” require identical binding affinity to meet the limitation?
3. If a competitor uses an ODAR fusion protein without IgG Fc, does claim 5 still create infringement exposure?
4. How do “further comprising” combination therapies in claim 9 change litigation strategy and proof burdens?
5. For a biologic ODAR-soluble therapy, what patent dispute framework replaces Paragraph IV?

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References

1. US Patent 6,316,408, “Method for preventing or treating bone disease with soluble ODAR,” U.S. Patent and Trademark Office (claims provided).

Details for Patent 6,316,408

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Takeda Pharmaceuticals U.s.a., Inc.	NATPARA	parathyroid hormone	For Injection	125511	January 23, 2015		2018-03-30