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ChemicallyModifiedNucleosides andOligonucleotides
Themost broadly-applicable of our patents are those that claimmodifiednucleosides andoligonucleotides comprising the
modified nucleosides thatwe incorporate intoour antisense drugs to increase their therapeutic efficacy. Nucleosides and chemically-
modified nucleosides are the basic buildingblocks of our antisense drugs, therefore claims that cover anyoligonucleotide
incorporatingone of our proprietarymodifiednucleosides can apply to awide arrayof antisensemechanisms of action aswell as
several therapeutic targets. Of particular note are our patents coveringour proprietary2’-O-(2-methoxy) ethylmodifiednucleosides,
incorporated into nearly all of our development compounds, aswell as our generation2.5 compounds, the constrained-ethyl
nucleosides, or cEt, nucleosides. In June 2011, Santaris PharmaA/S opposedour grantedpatent inEurope drawn to cEt containing
nucleotides andoligonucleotides andwe intend tovigorouslydefendour patent in these proceedings. The following are some of our
patents in this category:
Jurisdiction
PatentNo.
Title
Expiration
DescriptionofClaims
UnitedStates .....
7,101,993
OLIGONUCLEOTIDES
CONTAINING2’O-
MODIFIEDPURINES
2023
Covers certainMOEnucleosides and
oligonucleotides containing said
nucleotides.
UnitedStates .....
7,399,845
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
UnitedStates .....
7,741,457
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
UnitedStates .....
8,022,193
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
UnitedStates .....
7,569,686
COMPOUNDSAND
METHODSFORSYNTHESIS
OFBICYCLICNUCLEIC
ACIDANALOGS
2027
Coversmethods of synthesizingour cEt
nucleosides.
Europe ...............
EP19843
81
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
UnitedStates .....
7,547,684
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
UnitedStates .....
7,666,854
6-MODIFIEDBICYCLIC
NUCLEICACIDANALOGS
2027
Covers our cEt nucleosides and
oligonucleotides containing these nucleoside
analogs.
AntisenseDrugDesignMotifs
MOEGapmers
Other Isis patents claimoligonucleotides comprising specific antisense drugdesignmotifs, or patterns of nucleoside
modifications at specifiedpositions in the oligonucleotide. Patent claims coveringour antisense drugdesignmotifs are independent of
nucleic acid sequence, so they cover oligonucleotides having the recitedmotif, regardless of cellular target or clinical indication. The
claimedmotifs generally confer properties that optimize oligonucleotides for a particular antisensemechanismof action, such as
RNaseH, RNAi, or splicing.We have designedoligonucleotides incorporatingmotifs, whichwe refer to as chimeric compounds or
gapmers to exploit theRNaseHmechanism to achieve target RNA reduction. Almost all of our drugs, includingKYNAMRO, contain
this gapmer antisense drugdesignmotif. In fact, we own aU.S. patent that covers eachof our secondgenerationgapmer antisense
drugs untilMarch of 2023.We alsohave issued patents covering other gapmer drug designs, andmethods of lowering a target RNA in
an animal with these gapmer compositions. The followingpatents are some examples of our patents in this category:
