`
`PCT/USZOOBIOO 1 602
`
`CLAIMS
`
`1.
`
`A method of evaluating neuroprotective properties of at least one test
`
`compound, the method comprising:
`
`a) contacting a cell with the at least one test compound,
`
`b) determining whether the Nrf2 pathway is upregulated in the cell,
`
`c) determining whether the at least one test compound slows or prevents at
`least one of demyelination, axonal loss, and neuronal death, and
`
`d) selecting the test compound as a candidate for treating neurodegeneration
`
`in a neurological disease if 1) the Nrf2 pathway is upregulated and,
`
`optionally,
`
`e) further determining whether at least one of demyelination, axonal loss, and
`
`neuronal death are prevented or slowed by the compound.
`
`2.
`
`The method of claim 1, wherein the neurological disease is a
`
`demyelinating disease.
`
`3.
`
`The method of claim 2, wherein the demyelinating disease is multiple
`
`sclerosis.
`
`4.
`
`The‘method of claim 1, wherein the cell in step a) is contacted with a
`
`plurality of test compounds.
`
`5.
`
`The method of claim 1, wherein the Ner pathway upregulation is
`
`determined by the levels of expression or activity of NQO1.
`
`6.
`
`The method of claim 1, wherein the Nrf2 pathway is upregulated by at
`
`least 30% as indicated by one or more of the following parameters:
`
`-35-
`
`Page 1 on
`
`Biogen Exhibit 2105
`Mylan v. Biogen
`IPR 2018-01403
`
`Biogen Exhibit 2105
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 3
`
`
`
`Agent Ref. 08201 .0077—00304
`
`PCT/USZOOBIOO 1 602
`
`i) expression levels of at least one of endogenously produced and
`
`exogenously introduced Nrf2;
`
`ii) at least one of subcellular localization and nuclear translocation of Nrf2;
`
`iii)
`
`the expression level of at least one gene under control of Nrf2;
`
`iv)
`
`the level of Ner binding to the Nrf2-binding DNA element ARE;
`
`v)
`
`the stability of Nrf2/Keap1 complexes; and
`
`vi) modification levels of at least one protein selected from Keap1 and other
`
`Nrf2/Keap1-associated proteins.
`
`7.
`
`The method of claim 6, wherein the at least one gene under control of
`
`Nrf2 is an Nrf2-regulated reporter gene in an artificial reporter construct.
`
`8.
`
`The method of claim 1, further comprising comparing the level of Ner
`
`pathway upregulation by the at least one test compound with the level of Ner pathway
`
`upregulation by at least one comparator compound.
`
`9.
`
`The method of claim 8, wherein the at least one comparator compound is
`
`selected from dimethyl fumarate and monomethyl fumarate.
`
`10.
`
`The method of claim 1, wherein the at least one test compound has the
`
`structure of Formula I.
`
`11.
`
`The method of claim 1, wherein the at least one test compound is
`
`selected from fumaric acid, its salts, and fumaric acid derivatives.
`
`12.
`
`The method of claim 1, wherein the at least one test compound is
`
`chosen from FTY 720, ABT—874, GSK683699, NeuroVax, MLN 1202, interferon y,
`
`TysabriTM, Rituxan, TV 5010, NBl-788, MBP8298, Cladribine, Teriflunomide,
`
`Temsirolimus, and Laquinimod.
`
`-36-
`
`Page20f3
`
`Page 2 of 3
`
`
`
`Agent Ref. 08201 .0077-00304
`
`PCTI U $2008/001 602
`
`13.
`
`A method of treating a mammal having a neurological disease,
`
`comprising:
`
`a)
`
`selecting a test compound according to the method of any one of claims
`
`1-10, and
`
`b)
`
`administering the selected test compound a mammal in need thereof,
`
`thereby treating neurodegeneration in the mammal.
`
`14.
`
`A method of treating a mammal having a neurological disease by
`
`combination therapy, the method comprising:
`a) administering to the mammal a therapeutically effective amount of at
`
`least one first compound that upregulates the Ner pathway, and
`
`b) administering a therapeutically effective amount of at least one second
`
`compound that does not upregulate the Ner pathway.
`
`15.
`
`The method of claim 14, wherein the at least one first compound is
`
`selected from fumaric acid, its salts, and fumaric acid derivatives.
`
`16.
`
`The method of claim 13 or 14, wherein the neurological disease is a
`
`demyelinating disease.
`
`17.
`
`The method of claim 16, wherein the demyelinating disease is multiple
`
`sclerosis.
`
`-37-
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`Page 3 0f 3
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`Page 3 of 3
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`
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