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Protected elements in Test Guidelines

 

With the development of new technologies, new ways of testing chemicals have emerged and will increasingly develop. These new methods generally include Intellectual Property Rights (IPR). IPR aim to stimulate innovation by enabling inventors to appropriate the returns on their investments. To date, many Test Guidelines for in vitro methods already include proprietary elements. This should not hamper their use for generating chemical safety data but should be accompanied by good licensing practices, as encouraged by OECD. 

In the past, a template for Material Transfer Agreement (MTA) was developed for users of Test Guidelines making use of MTA. The MTA template applies for several in vitro Test Guidelines and is used to clarify between provider and recipient the conditions of transfer and use of protected material. While MTAs are now common practice, other types of agreements exist, such as a license agreement, which provides a licensee the right to commercially use intellectual property such as a patent or copyright.

Table 1 provides an overview of the various protected elements in the currently adopted Test Guidelines. Table 2 compiles the same type of information for test methods currently on the TG workplan but not yet approved. Table 2 is a working document and might not be exhaustive. The information it contains may need to be refined as progress is made towards the development of the respective Test Guidelines. 

 

Test Guidelines including protected elementszz

TG Nb (date of last update) TG title Protected elements and type of protection Type of agreement Elements can be obtained from:  
TG 248 (2019)

Xenopus Embryo Thyroid Assay

Transgenic X. laevis line 

Licensing agreement from French national center for scientific research (CNRS)

Commercial company

TG 249 (2021)

Fish Cell Line Acute Toxicity - The RTgill-W1 cell line assay

- RTgill W1 cell line

- fluorescent dyes alamarBlue®/PrestoBlue®

- Consult ATCC for specific rules

- No agreement needed

- ATCC

- Commercial companies

TG 250 (2021)

EASZY assay - Detection of Endocrine Active Substances, acting through estrogen receptors, using transgenic tg(cyp19a1b:GFP) Zebrafish embrYos

Transgenic tg(cyp19a1b:GFP) zebrafish embryos

MTA

INERIS ([email protected])

TG 431 (2016)

In vitro skin corrosion: reconstructed human epidermis (RHE) test method

- EpiSkinTM

- EpiDermTM

- SkinEthicTM RHE

- epiCS®

Trademarked tissues

No need for MTA or licence agreement Commercial companies 
TG 435 (2015) In vitro Membrane Barrier Test Method for Skin Corrosion

Corrositex®

Registered trademark

Proprietary biomembrane and chemical detection technology

No need for MTA or licence agreement Commercial companies
TG 439 (2015) In vitro Skin Irritation: Reconstructed Human Epidermis Test Method

- EpiSkin™

- EpiDerm™ SIT (EPI-200)

- SkinEthic™ RHE

- LabCyte EPI-MODEL24 SIT

- EpiCS RhE® model

- Skin +

- KeraSkinTM SIT

Trademarked tissues
No need for MTA or licence agreement Commercial companies

TG 442C
(2021)

In chemico skin sensitisation assay addressing AOP key event of covalent binding to proteins (DPRA, ADRA and k-DPRA test methods

NAC/NAL (Formulas with Cystéine
and Lysine)
No agreement needed Commercial company
TG 442D (2015) In vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method

KeratinoSensTM: Luciferase gene contained in the cell line is patented by a commercial company. The laboratory providing the cells holds a licence from the commercial company to transfer the cells under defined conditions 

- Trademarked assay

- Patented detection gene

Licence agreement  Commercial companies
TG 442E (2015) In Vitro Skin Sensitisation: h-CLAT assay

- Human monocytic leukaemia cell line, THP-1

Each cell bank has their own registered cells 

- Antibodies (FITC Mouse Anti-Human CD86, CD54, or mouse IgG1 antibodies)

No agreement Cell Banks

 

Commercial companies

TG 442E (2017) In Vitro Skin Sensitisation: U-SENS assay Human histiocytic lymphoma cell line, U937 clone CRL1593.2.

Each cell bank has their own registered cells

Trademarked assay

ATCC specifies that “commercial entities are allowed to purchase and use the U-937 cell line, without further licensing fee with ATCC or Professor Nilsson, for testing in OECD member countries for purposes of assessment and other uses relating to the protection of man and environment; …” Cell Banks
TG 442E (2017) In Vitro Skin Sensitisation: IL8-Luc assay Recombinant THP-G8 cell line MTA
Initially patented cell line - The Secretariat was informed in February 2017 that an Application for cancellation of registration of patent rights per waiver had been submitted and accepted. Accordingly, no licence is needed to get the cells but signature of MTA.
Commercial company
TG 455 (2016)

PBTG for STTA in vitro assays to detect estrogen receptor agonists and antagonists

- HeLa assay

Stably transfected hERα-HeLa-9903 cell line MTA Cell banks
TG 455 (2016)

PBTG for STTA in vitro assays to detect estrogen receptor agonists and antagonists

- VM7Luc4E2 assay

 Stably transfected VM7Luc4E2 cell line  Licence agreement One University and one commercial company
TG 455 (2016)

PBTG for STTA in vitro assays to detect estrogen receptor agonists and antagonists


- ERα CALUX assay

Stably transfected U2OS ERα CALUX cell line Licence agreement Commercial company 
TG 458 (2016) Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals AR-EcoScreenTM cell line

Trademarked cell line

MTA
Although the AR-EcoScreenTM cell line was initially claimed as only needing signature of a MTA it appears that there are licencing fees associated with its use. These fees have been temporary waived until Performance Standards are developed and approved by WNT. The TG will then be revised accordingly.
Cell bank (JCRB)
TG 488 (2013) Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays  - MutaTMMouse

- Big BlueTM

Trademarked animals
Licence agreement Commercial companies
TG 490 (2015) In vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene

For MLA: L5178Y TK+/- clone (3.7.2C)

Each cell bank has their own registered cells

A disclosure is present in the ATCC description for a specific TM clone:
This material is cited in a US or other Patent and may not be used to infringe the claims. Depending on the wishes of the Depositor, ATCC may be required to inform the Patent Depositor of the party to which the material was furnished. This material may not have been produced or characterized by ATCC.

Such disclosure is not mentioned in the JCRB description where the cells can also be obtained.
Cell banks
TG 491 (2015) Short Time Exposure In Vitro Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage Rabbit cornea cell line SIRC [Statens Seruminstitut Rabbit Cornea]

Each cell bank has their own registered cells

No agreement needed Cell banks
TG 492 (2017) Reconstructed human Cornea-like Epithelium (RhCE) test method for identifying chemicals not requiring classification and labelling for eye irritation or serious eye damage

- EpiOcular™ tissue

- SkinEthic™ HCE tissue

- LabCyte CORNEA-MODEL 24 EIT

- MCTT HCE™EIT

Trademarked tissues

No agreement needed Commercial companies
TG 494 (2021) Vitrigel-Eye Irritancy Test Method for Identifying Chemicals Not Requiring Classification and Labelling for Eye Irritation or Serious Eye Damage

- hCE cell and Collagen Vitrigel membrane

No agreement needed Commercial company

TG 495
(2019)

ROS (Reactive Oxygen Species) Assay for Photoreactivity

Quartz reaction container

No agreement needed Commercial company

TG 496
(2021)

In vitro Macromolecular Test Method for Identifying Chemicals Inducing Serious Eye Damage and Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage Ocular Irrection®

Registered Trademark

Proprietary macromolecular matrix with irritancy measuring system

No agreement needed Commercial company

TG 497 (2021)

Defined Approaches on Skin Sensitisation

- Combinations of various TG elements: refer to TG 442C (DPRA), TG 442D (Keratinosens), TG 44E (h-CLAT)

- Derek software

License agreement

Commercial company 

TG 498 (2021)

In vitro Phototoxicity - Reconstructed Human Epidermis Phototoxicity test method

- EpiDerm™

Trademarked tissue

No need for MTA or licence agreement Commercial companies

 

Protected elements in test methods under development (on TG work plan)

 

Project number Project title Protected elements and type of protection (information from tje SPSF) Type of agreement
2.39

New TG on a Xenopus Embryonnic Thyroid Signallig Assay

Test subject to a patent

License

2.61

New TG RADAR assay – Rapid Androgen Disruption Animal Replacement assay

- No patent specific to the spiggin1-gfp medaka transgenic line or the RADAR assay

- The access model being followed will be the same as that for the Xenopus Embryonic Thyroid Assay (XETA) 

?

4.73

Performance-Based Test Guideline on AR Transactivation Assays

Stably transfected U2OS AR CALUX cell line: AR CALUX®

Licence agreement

4.76

PBTG for the Establishment on Human-derived hepatic system to investigate biotransformation and toxicity of compounds by evaluation of CYP450 induction comptence

- The cryopreserved HepaRG® cells and the culture media are patented.

- Cryopreserved Human Hepatocytes and respective culture media components are commercially available from different international companies. 

Licence

MTA for research purposes for academic scientists 

4.87 In vitro Macromolecular Test Method for Eye Hazard Potential

Registered trademark on the Ocular Irritection® Assay System

Commercially available without the need for licence or MTA
4.93 New Test Guideline for the Pig-a Assay an in vivo Gene Mutation Assay that Promotes the 3Rs Principles

A commercial CRO holds a patent on measuring the frequency of Pig-a mutant phenotype erythrocytes via flow cytometry.

However, a different mutant cell scoring procedure, which also conforms to the IWGT testing recommendations can be used.

Licence (depending on measurement system used).

No MTA needed.

4.99

Androgen-Receptor Transactivation assay for the detection of compounds with (anti)androgenic potential using 22Rv1/MMTV cells

There are no IPR-protected components.

22Rv1/MMTV cells are available from the Ministry of Food and Drug Safety (MFDS).
MTA
4.105 ROS Assay: An In chemico Method for Identifying the Phototoxic Potential of Chemicals

There are patents related to the ROS assay.

Licence?
4.106 Genomic Assay Rapid Detection test for skin (GARDskin) test

Genomic Assay Rapid Detection test for skin (GARDskin) test

Licences?
4.107 Toxicogenomic analysis on 3D reconstituted epidermis for measuring skin sensitization potency– the SENS-IS assay

The SENS-IS assay is covered by patents.

Since the patents delivered so far not only cover the described biomarkers but also the use of a reconstituted 3D skin model for skin sensitization evaluation, a second license proposal was generated to encourage further research studies on new skin sensitization biomarkers that could enhance the predictivity of the SENS-IS assay
Licences
1.112 Update of TG 492 for inclusion of LabCyte test method LabCyte24 EIT is not a subject of any intellectual property rights. Commercially available without the need for licence or MTA
1.113

New TG on Vitrigel test method for Eye Irritation Testing

All components and reagents used for the Vitrigel-EIT test method are commercially available. HCE-T cells can be globally distributed from RIKEN BioResource Center. The Vitrigel-EIT method is available without any restriction by its intellectual property rights. Vitrigel is registered trade mark of National Agriculture and Food Research Organization (Tsukuba, Japan). Commercially available without the need for licence or MTA
1.114

Update of TG 437 for inclusion of laser light-based opacitometer (LLBO)

An agreement is made between VITO and Peira (the company responsible for production of LLBO and distribution). No IPR is claimed. ?
4.117

Update of TG 442D on in vitro skin sensitisation ARE- Nrf2 luceriferase for inclusion of LuSens test method

The LuSens cell line itself is not protected by a trade mark (IP).

However, similar to the KeratinoSensTM assay, the same Promega licencing conditions apply regarding the use of their reagents for the detection of luciferase activity.
Licence
1.123 Embryonic Stem Cell Test: in vitro assay detecting disruption to differentiation of rodent embryonic stem cells into cardiomyocytes using the Hand1 gene

Intellectual property rights on the test method employed in this study are covered by a patent.

Commercial test cells can be used without license as long as no cell stock is done by the user.
?
1.125 ToxTracker assay: a stem-cell-based reporter assay for mechanistic carcinogenicity hazard assessment

Part of the ToxTracker assay is protected by Intellectual property rights.

  • A patent application for the Bscl2 reporter as biomarker for genotoxicity The other ToxTracker biomarkers are not protected by patents.
  • ToxTracker is a trademark name,
The ToxPlot software for data analysis is proprietary and copyright protected. 
Licence is being explored

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