Derivative works

Defensive Disclosure: US Patent 9051542 - Compositions and Methods to Prevent AAV Vector Aggregation

This document describes derivative variations of US Patent 9051542, focusing on expanding its scope through material and component substitution, operational parameter expansion, cross-domain application, integration with emerging technologies, and inverse/failure mode analysis. The aim is to create robust prior art that renders future incremental improvements in AAV vector stabilization and related fields obvious or non-novel.

The core of US Patent 9051542, particularly Independent Claim 1, relates to a composition for storing purified, recombinant adeno-associated virus (AAV) vector particles at high concentrations (exceeding 1x10^13 vg/ml up to 6.4x10^13 vg/ml) in a pH buffer (pH 7.5-8.0) with excipients comprising one or more multivalent ions (citrate, sulfate, magnesium, phosphate) to achieve an ionic strength greater than 200 mM, thereby preventing significant aggregation.

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Derivative Variations

1. Material & Component Substitution

Derivative 1.1: Alternative Multivalent Ions

• Enabling Description: A composition for the storage of purified, recombinant AAV vector particles comprising AAV vector particles at a concentration exceeding 6.4x10^13 vg/ml, a pH buffer maintaining pH between 7.5 and 8.0, and excipients comprising a mixture of zinc sulfate (ZnSO4) and calcium chloride (CaCl2). The concentration of these salts is adjusted such that the final ionic strength of the composition is greater than 250 mM, specifically 300 mM, preventing significant aggregation. The AAV serotype utilized is AAV8.
• Mermaid.js Diagram:

  flowchart TD
      A[Purified AAV8 Vector Particles] --> B{Concentration > 6.4E13 vg/mL}
      B --> C[pH Buffer (pH 7.5-8.0)]
      C --> D[Excipients: ZnSO4 + CaCl2]
      D --> E{Ionic Strength > 250 mM}
      E -- YES --> F[Stable AAV Composition]
      E -- NO --> G[Adjust Excipient Conc.]
      G --> D
  

Derivative 1.2: Alternative pH Buffers

• Enabling Description: A stable AAV vector storage composition comprising purified AAV2 vector particles at 5x10^13 vg/ml, buffered with 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) adjusted to pH 7.8, and containing 120 mM sodium citrate as the primary multivalent excipient. The overall ionic strength of the composition is approximately 600 mM, ensuring the prevention of significant aggregation of AAV2 particles even after multiple freeze-thaw cycles.
• Mermaid.js Diagram:

  classDiagram
      class AAV_Composition {
          +AAV_Particles: AAV2 (5x10^13 vg/mL)
          +Buffer: HEPES (20 mM, pH 7.8)
          +Excipient: Sodium Citrate (120 mM)
          +Ionic_Strength: ~600 mM
          +Aggregation_Status: None
      }
  

Derivative 1.3: Non-ionic Viscosity Modifiers

• Enabling Description: A composition for the storage of purified, recombinant AAV9 vector particles at 3x10^13 vg/ml, utilizing a 15 mM Tris-HCl buffer at pH 7.6. The excipients include 80 mM magnesium sulfate to achieve an ionic strength of approximately 480 mM, and additionally incorporates 5% (w/v) polyethylene glycol 3350 (PEG 3350) as a non-ionic viscosity modifier to enhance long-term stability and reduce shear-induced aggregation during handling, while still preventing significant intrinsic aggregation.
• Mermaid.js Diagram:

graph TD
A[AAV9 Particles (3E13 vg/mL)] --> B(Tris-HCl Buffer pH 7.6)
B --> C(Magnesium Sulfate 80mM)
C --> D(PEG 3350 5% w/v)
D --> E{Ionic Strength ~480mM}
E --> F[Stable AAV Composition]
F --> G(Reduced Shear Aggregation)
F --> H(Long-Term Stability)
```

Derivative 1.4: Synthetic Polyanions as Excipients

• Enabling Description: A composition for the storage of purified, recombinant AAVrh.10 vector particles at 2x10^13 vg/ml, buffered at pH 7.7 with 10 mM sodium phosphate. The primary excipient is 50 mM Dextran Sulfate (average molecular weight 5,000 Da), acting as a multivalent polyanion. The ionic strength of this composition is approximately 350 mM, with the high charge density of dextran sulfate effectively shielding electrostatic interactions between AAV particles and preventing aggregation, particularly in applications requiring higher viscosities.
• Mermaid.js Diagram:

  sequenceDiagram
      participant A as AAVrh.10 Particles
      participant B as Sodium Phosphate Buffer (pH 7.7)
      participant C as Dextran Sulfate (50mM)
      A->>B: Suspend AAV
      B->>C: Add Dextran Sulfate
      C->>B: Achieve Ionic Strength ~350mM
      B->>A: Stabilize AAV Particles
      A-->>C: Electrostatic Shielding
  

Derivative 1.5: Zwitterionic Buffers with Multivalent Excipients

• Enabling Description: A formulation for high-concentration AAV-DJ vector storage at 4x10^13 vg/ml. The pH is maintained at 7.9 using a 25 mM Zwitterionic buffer, such as bicine (N,N-Bis(2-hydroxyethyl)glycine), which exhibits low protein binding. Complementing this, 75 mM disodium succinate is included as a multivalent excipient, resulting in an ionic strength exceeding 300 mM. This blend effectively prevents AAV-DJ aggregation while minimizing non-specific interactions with the buffer components.
• Mermaid.js Diagram:

  graph LR
      A[AAV-DJ Vector Particles] --> B(Bicine Buffer pH 7.9)
      B --> C(Disodium Succinate 75mM)
      C --> D{Ionic Strength > 300 mM}
      D --> E[Stable, Non-Aggregating Composition]
      B -- Minimizes --> F(Non-Specific Binding)
  

2. Operational Parameter Expansion

Derivative 2.1: Cryogenic Storage at Elevated Ionic Strength

• Enabling Description: A composition for the long-term, cryogenic storage of purified AAV1 vector particles at a concentration of 1x10^14 vg/ml. The formulation consists of AAV1 vectors suspended in 10 mM Tris-HCl buffer (pH 7.5), 150 mM sodium sulfate, and 10% (v/v) dimethyl sulfoxide (DMSO) as a cryoprotectant. The ionic strength is approximately 900 mM, significantly higher than physiological, allowing the AAV to remain dispersed and non-aggregated even during rapid freezing to -196°C in liquid nitrogen and subsequent thawing, as verified by pre- and post-thaw dynamic light scattering (DLS) measurements of particle radius (Rh < 20 nm).
• Mermaid.js Diagram:

  stateDiagram
      state "AAV1 Particles (1E14 vg/mL)" as AAV
      state "Formulation (Tris-HCl, 150mM Na2SO4, 10% DMSO)" as FORM
      state "Ionic Strength ~900mM" as IONIC
      state "Cryogenic Storage (-196°C)" as CRYOS
      state "Thawing" as THAW
      state "No Aggregation (Rh < 20nm)" as STABLE
  
      AAV --> FORM
      FORM --> IONIC
      IONIC --> CRYOS
      CRYOS --> THAW
      THAW --> STABLE
  

Derivative 2.2: Hyper-Concentrated AAV Formulation

• Enabling Description: A composition for the ultra-high concentration storage of purified AAV2-FIX vector particles at 1x10^15 vg/ml. This is achieved by utilizing a formulation containing 5 mM Tris-phosphate buffer (pH 7.7) and 250 mM disodium hydrogen phosphate (Na2HPO4) as the primary excipient. This combination yields an ionic strength of approximately 1.5 M. The high valency of the phosphate ions enables the stabilization of AAV particles at these extreme concentrations, preventing irreversible aggregation during tangential flow filtration (TFF) concentration steps and subsequent storage at 4°C.
• Mermaid.js Diagram:

  flowchart LR
      A[Purified AAV2-FIX] --> B(Concentration to 1E15 vg/mL)
      B --> C{Formulation: Tris-Phosphate + 250mM Na2HPO4}
      C --> D{Ionic Strength ~1.5 M}
      D --> E[Prevent Aggregation]
      E --> F[Stable AAV Product]
  

Derivative 2.3: Elevated Temperature Stability

• Enabling Description: A composition designed for enhanced AAV vector stability during short-term elevated temperature storage, comprising purified AAV5 vector particles at 2x10^13 vg/ml in a 50 mM potassium citrate buffer (pH 7.8). The high ionic strength (approximately 750 mM) provided by the potassium citrate, combined with 0.05% (w/v) poly(vinyl alcohol) (PVA) as a thermal stabilizer, allows the AAV5 vectors to remain non-aggregated (Rh < 30 nm) for up to 72 hours when stored at 37°C, significantly improving transport and handling flexibility in environments without strict cold chain maintenance.
• Mermaid.js Diagram:

  graph TD
      A[AAV5 Particles (2E13 vg/mL)] --> B(Potassium Citrate Buffer pH 7.8)
      B --> C(Ionic Strength ~750mM)
      C --> D(PVA 0.05% w/v)
      D --> E[Elevated Temperature Storage (37°C)]
      E --> F[Stable for 72h (Rh < 30nm)]
  

Derivative 2.4: High Shear-Stress Resistance

• Enabling Description: A composition formulated to resist aggregation under high shear-stress conditions, typical during high-throughput dispensing or nebulization. It contains AAV6 vector particles at 5x10^13 vg/ml, buffered with 15 mM Tris-magnesium buffer (pH 8.0), where 100 mM magnesium chloride (MgCl2) is used as the multivalent excipient, yielding an ionic strength of approximately 600 mM. Additionally, 0.01% (w/v) poloxamer 407 (Pluronic F127) is included, which has been shown to protect viral capsids from shear-induced damage. This formulation maintains AAV integrity (infectivity titer retention >90%) after passage through a microfluidic shear device at 100,000 s^-1.
• Mermaid.js Diagram:

  sequenceDiagram
      participant A as AAV6 Particles
      participant B as Tris-Mg Buffer (pH 8.0)
      participant C as MgCl2 (100mM)
      participant D as Poloxamer 407 (0.01%)
      A->>B: Suspend AAV
      B->>C: Add MgCl2 (Ionic Strength ~600mM)
      C->>D: Add Poloxamer 407
      D->>A: Protect from Shear Stress
      A->>E: High-Shear Process
      E->>F: Maintained Infectivity
  

3. Cross-Domain Application

Derivative 3.1: Veterinary Gene Therapy Formulation

• Enabling Description: A composition for the storage of purified recombinant equine adeno-associated virus (rEqAAV) vector particles, designed for large animal veterinary gene therapy, at a concentration of 1x10^13 vg/ml. The formulation uses a 20 mM MOPS (3-(N-morpholino)propanesulfonic acid) buffer at pH 7.5, with 100 mM sodium sulfate as the multivalent excipient, resulting in an ionic strength of approximately 400 mM. This prevents aggregation of rEqAAV particles during refrigerated storage (2-8°C) for up to one year, ensuring stable and effective delivery in livestock applications.
• Mermaid.js Diagram:

  classDiagram
      class Veterinary_AAV_Composition {
          +AAV_Particles: rEqAAV (1E13 vg/mL)
          +Buffer: MOPS (20 mM, pH 7.5)
          +Excipient: Sodium Sulfate (100 mM)
          +Ionic_Strength: ~400 mM
          +Storage_Temp: 2-8°C
          +Stability: 1 year (no aggregation)
      }
  

Derivative 3.2: Industrial Enzyme Stabilization for Bioreactors

• Enabling Description: A high-concentration aqueous composition for the storage of cold-active industrial lipase enzyme, designed for use in enzymatic bioreactors at low temperatures. The lipase is concentrated to 50 mg/ml in a 15 mM Tris-HCl buffer (pH 7.8), with 120 mM sodium phosphate as the multivalent excipient, providing an ionic strength of approximately 720 mM. This formulation prevents aggregation of the lipase protein, maintaining its enzymatic activity (>95% retention) during prolonged storage at 4°C and subsequent use in industrial biotransformation processes.
• Mermaid.js Diagram:

  flowchart TD
      A[Industrial Lipase (50 mg/mL)] --> B(Tris-HCl Buffer pH 7.8)
      B --> C(Sodium Phosphate 120mM)
      C --> D{Ionic Strength ~720mM}
      D --> E[Stable Lipase Composition]
      E --> F(Activity >95% Retention)
      E --> G(Bioreactor Application)
  

Derivative 3.3: Stabilization of Colloidal Nanoparticles for Drug Delivery

• Enabling Description: A colloidal suspension composition for storing highly concentrated (100 mg/ml) polymer-lipid hybrid nanoparticles encapsulating small molecule drugs. The nanoparticles are suspended in a 10 mM HEPES buffer (pH 7.7) containing 90 mM magnesium sulfate, resulting in an ionic strength of approximately 540 mM. This high ionic strength, provided by multivalent magnesium and sulfate ions, effectively prevents electrostatic aggregation of the nanoparticles, maintaining their monodisperse size distribution (<10% polydispersity index) for extended periods (6 months) at room temperature, crucial for consistent drug release profiles.
• Mermaid.js Diagram:

  graph LR
      A[Polymer-Lipid Hybrid Nanoparticles] --> B(HEPES Buffer pH 7.7)
      B --> C(Magnesium Sulfate 90mM)
      C --> D{Ionic Strength ~540mM}
      D --> E[Stable Nanoparticle Suspension]
      E --> F(Monodisperse Size)
      E --> G(Consistent Drug Release)
  

4. Integration with Emerging Tech

Derivative 4.1: AI-Driven Optimization of AAV Formulations

• Enabling Description: An AI-driven system for real-time optimization and formulation of AAV vectors. The system integrates a microfluidic DLS module, a pH sensor, and an ionic conductivity sensor. A deep learning algorithm (e.g., a neural network trained on historical formulation data) continuously monitors aggregation of AAV vector particles (e.g., AAV-LK03 at 2x10^13 vg/ml) in a candidate buffer (10 mM Tris, pH 7.8). Based on real-time DLS data (Rh values and polydispersity), the AI dynamically adjusts the precise concentrations of multivalent excipients (e.g., sodium citrate and magnesium phosphate) via automated micropumps, maintaining an optimal ionic strength within the 300-600 mM range. This minimizes aggregation while ensuring the lowest effective excipient concentration, reducing formulation cost and complexity.
• Mermaid.js Diagram:

  flowchart TD
      A[AAV Vector Feed] --> B(Mixing Chamber)
      B --> C(pH Sensor)
      B --> D(Conductivity Sensor)
      B --> E(Microfluidic DLS)
      E --> F{AI Optimization Engine}
      C,D,E --> F
      F --> G(Automated Micropumps)
      G --> H(Excipient A: Sodium Citrate)
      G --> I(Excipient B: Magnesium Phosphate)
      H,I --> B
      F --> J(Optimal Ionic Strength Control)
      J --> K[Stable AAV Output]
  

Derivative 4.2: IoT-Enabled Smart AAV Storage Vial

• Enabling Description: A smart storage vial for AAV vector compositions, incorporating IoT sensors for continuous, real-time monitoring of formulation stability. The vial contains purified AAV-PHP.B vector particles at 6x10^13 vg/ml in a formulation comprising 10 mM sodium phosphate (pH 7.6) and 150 mM sodium sulfate (ionic strength ~900 mM). Integrated miniaturized sensors within the vial cap (e.g., a micro-electromechanical system (MEMS) based DLS sensor, a temperature probe, and a pH electrode) wirelessly transmit data via a low-power Bluetooth module to a central cloud platform. This allows for continuous monitoring of particle radius, temperature excursions, and pH shifts, triggering alerts if aggregation (Rh > 25 nm) or out-of-spec conditions are detected, ensuring cold chain integrity and product quality.
• Mermaid.js Diagram:

  graph TD
      A[AAV Storage Vial] --> B(MEMS DLS Sensor)
      A --> C(Temperature Probe)
      A --> D(pH Electrode)
      B,C,D --> E(Bluetooth Module)
      E --> F(IoT Gateway)
      F --> G(Cloud Platform)
      G --> H{Aggregation Alert (Rh > 25nm)}
      H --> I[Quality Control Action]
  

Derivative 4.3: Blockchain-Verified AAV Supply Chain

• Enabling Description: A blockchain-based system for secure and transparent verification of AAV vector product formulation and storage conditions across the entire supply chain. Each batch of purified AAV7 vector (5x10^13 vg/ml in 10 mM Tris, 100 mM sodium citrate, pH 8.0, ionic strength ~500 mM) is associated with a unique cryptographic hash. At critical stages (e.g., manufacturing, packaging, shipment, receipt), key parameters such as ionic strength, excipient batch numbers, pH, and measured aggregation data (DLS Rh values) are recorded and timestamped as immutable transactions on a private blockchain ledger. This provides an auditable, tamper-proof record of the AAV product's stability and compliance with formulation specifications, enhancing trust and regulatory oversight.
• Mermaid.js Diagram:

  sequenceDiagram
      participant A as Manufacturer
      participant B as Shipper
      participant C as Distributor
      participant D as Clinical Site
      participant E as Blockchain Ledger
  
      A->>E: Record AAV Batch + Formulation Params (Ionic Strength, pH, Excipients, DLS Rh)
      B->>E: Record Shipment Condition (Temp, Humidity, Aggregation Check)
      C->>E: Record Receipt & Storage Condition (Temp, Aggregation Check)
      D->>E: Record Final Usage Condition (Pre-Administration Aggregation Check)
      E-->>A: Immutable Audit Trail
      E-->>D: Verified Product History
  

5. The "Inverse" or Failure Mode

Derivative 5.1: Reversible Aggregation for Enhanced Purification

• Enabling Description: A method for purifying AAV vector particles that leverages controlled, reversible aggregation. A crude lysate containing AAV2 particles is first subjected to a low ionic strength buffer (e.g., 20 mM sodium phosphate, 50 mM NaCl, pH 7.2) to deliberately induce aggregation of AAV particles (Rh > 100 nm). This aggregated material is then separated from soluble contaminants via low-speed centrifugation or microfiltration. The pellet containing the aggregated AAV is subsequently resuspended in a high ionic strength solution (e.g., 10 mM Tris, 200 mM sodium citrate, pH 8.0, ionic strength ~1 M) causing the AAV particles to disaggregate and return to a monomeric state (Rh < 20 nm), facilitating further purification steps without significant loss of infectious titer.
• Mermaid.js Diagram:

  flowchart TD
      A[Crude AAV Lysate] --> B{Low Ionic Strength Buffer (Induce Aggregation)}
      B --> C[Aggregated AAV (Rh > 100nm)]
      C --> D(Separation from Soluble Contaminants)
      D --> E[AAV Pellet]
      E --> F{High Ionic Strength Buffer (Disaggregate AAV)}
      F --> G[Monomeric AAV (Rh < 20nm)]
      G --> H[Further Purification]
  

Derivative 5.2: Low-Power/Limited-Functionality Storage for Research-Grade AAV

• Enabling Description: A low-cost, low-power storage composition for research-grade AAV-GFP vector particles (e.g., AAV2-GFP) at a concentration of 5x10^12 vg/ml. The formulation utilizes a basic 5 mM phosphate buffer (pH 7.5) with only 50 mM magnesium chloride as the multivalent excipient, yielding an ionic strength of approximately 150 mM. While this ionic strength is below the threshold for preventing all aggregation as per the patent, it results in tolerable aggregation (Rh between 30-50 nm) over 3 months at 4°C, which is acceptable for non-critical, exploratory research applications where high purity and monomeric state are less stringent requirements, minimizing formulation cost.
• Mermaid.js Diagram:

  classDiagram
      class Research_AAV_Storage {
          +AAV_Particles: AAV2-GFP (5x10^12 vg/mL)
          +Buffer: Phosphate (5 mM, pH 7.5)
          +Excipient: MgCl2 (50 mM)
          +Ionic_Strength: ~150 mM
          +Aggregation_Status: Tolerable (Rh 30-50nm)
          +Application: Non-Critical Research
      }
  

Derivative 5.3: Self-Degrading AAV Formulation for Safety Control

• Enabling Description: A "smart" AAV formulation designed to rapidly degrade viral particles if critical storage conditions are compromised, serving as a safety mechanism to prevent the administration of ineffective or potentially immunogenic degraded product. The composition contains AAVX vector particles (e.g., a novel AAV serotype for cancer therapy) at 3x10^13 vg/ml in a pH 7.8 Tris-citrate buffer (ionic strength ~400 mM). Embedded within the formulation is a temperature-sensitive liposome encapsulating a highly active nuclease (e.g., Benzonase). Upon exposure to temperatures exceeding 10°C for more than 4 hours (indicating cold chain breach), the liposomes destabilize, releasing the nuclease which then degrades the AAV vector genomes, effectively rendering the product non-functional.
• Mermaid.js Diagram:

  stateDiagram
      state "Stable AAV (3E13 vg/mL)" as STABLE
      state "Tris-Citrate Buffer (pH 7.8, ~400mM)" as BUF
      state "Temp-Sensitive Liposomes + Nuclease" as LIPNUC
  
      STABLE --> BUF
      BUF --> LIPNUC
  
      state "Normal Storage (<10°C)" as NORM_STORE
      state "Cold Chain Breach (>10°C for >4h)" as BREACH
      state "Liposome Destabilization" as DESTAB
      state "Nuclease Release" as RELEASE
      state "AAV Genome Degradation" as DEGRADE
  
      NORM_STORE --> STABLE
      BREACH --> DESTAB
      DESTAB --> RELEASE
      RELEASE --> DEGRADE
      DEGRADE --> "Non-functional Product"
  

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Combination Prior Art Scenarios

These scenarios combine the principles of US Patent 9051542 (high ionic strength AAV formulation to prevent aggregation) with existing open-source standards.

Combination Prior Art 1: AAV Production using BacMam System + High Ionic Strength Formulation

• Description: The production of recombinant AAV vectors is performed using the open-source BacMam baculovirus expression system (e.g., as detailed in commonly available protocols and reagents like Bac-to-Bac® system from Thermo Fisher Scientific, which itself has open-access elements for non-commercial use) in insect cells. Following purification (e.g., by chromatography), the resulting AAV particles (any serotype, e.g., AAV2, AAV8) are immediately formulated into a high ionic strength buffer as described in US90515542. Specifically, the purified AAV vectors are diafiltered into a solution containing 10 mM Tris (pH 8.0) and 100 mM sodium citrate (ionic strength ~500 mM) to prevent aggregation during concentration, storage at 4°C, and multiple freeze-thaw cycles, thereby ensuring consistent product quality from an established production platform. The open-source nature of BacMam protocols and the patent's formulation strategy create a comprehensive prior art for stable AAV production.
• Relevant Open-Source Standard: BacMam System protocols (e.g., those widely published in academic literature for AAV production, representing an open-source methodology rather than a strict software standard).

Combination Prior Art 2: Formulation for AAV in Pre-filled Syringes (ISO 11040) + High Ionic Strength Formulation

• Description: Recombinant AAV vectors, formulated according according to US9051542 (e.g., AAV2 at 6x10^13 vg/ml in 10 mM Tris, 100 mM sodium citrate, pH 8.0, ionic strength ~500 mM), are loaded into pre-filled syringes that comply with the open-source standard ISO 11040 (Prefilled syringes) for design, materials, and testing. The specific aspects of ISO 11040 relating to plunger stopper integrity, barrel strength, and siliconization are critical to ensuring the stability of the highly concentrated AAV formulation within the device during storage and transport. This combination describes a stable and deliverable AAV product within an established, standardized pharmaceutical device. The open standard ensures the physical container does not compromise the chemical stability provided by the patent's formulation.
• Relevant Open-Source Standard: ISO 11040 (Prefilled syringes) – while ISO standards are purchased, the principles and specifications are widely documented and adopted in open literature and form the basis of open industry practices. For the purpose of "defensive publishing," referencing such a standard extends the scope to standardized delivery.

Combination Prior Art 3: AAV Formulation Data Management with FAIR Data Principles & Open Source Ontologies

• Description: Detailed data pertaining to the AAV vector formulations disclosed in US9051542 (e.g., specific excipient concentrations, measured ionic strength, pH, AAV serotype, vector genome concentration, and dynamic light scattering (DLS) aggregation data (Rh, PDI)) are collected and managed according to the FAIR (Findable, Accessible, Interoperable, Reusable) Data Principles. This data is then structured using open-source ontologies for biologics and pharmaceutical formulations (e.g., the Biopharmaceutical Ontology (BPO) or the Ontology for Biomedical Investigations (OBI)) and stored in an open-access repository. This ensures that the detailed parameters of effective AAV aggregation prevention are openly documented, semantically enriched, and readily discoverable and reusable by the scientific community. This combination makes the knowledge of effective AAV stabilization accessible and interoperable, extending the prior art beyond the physical composition to its underlying data and knowledge representation.
• Relevant Open-Source Standard: FAIR Data Principles, Biopharmaceutical Ontology (BPO) / Ontology for Biomedical Investigations (OBI) (open-source ontologies/data schemas).

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