Exhibit 10.78

 

Portions of this document have been redacted pursuant to a confidential
treatment request and filed separately with the Securities and Exchange
Commission.  Redaction portions are marked with “*****.”

 

COLLABORATION AND LICENSE AGREEMENT

 

This Collaboration and License Agreement (the “Agreement”) between ISIS
PHARMACEUTICALS, INC. of 2292 Faraday Avenue, Carlsbad, CA 92008, USA (“Isis”)
and ERCOLE BIOTECH, INC., of 202 Glenview Place, Chapel Hill, NC 27514
(“Ercole”) is entered into and made effective this 16th day of May, 2003 (the
“Effective Date”).

 

INTRODUCTION AND OVERVIEW

 

Cross License

 

Isis and Ercole each possess Patents related to RNA Splicing.  Each Party wishes
to cross license its Patents related to RNA Splicing to the other Party in
exchange for a license to the other Party’s RNA Splicing Patents.

 

Each Party will choose a fixed pool of exclusive Gene Targets for their research
and development efforts and will receive an exclusive license to use the other
Party’s RNA Splicing Patents to discover and develop Products that modulate such
exclusive Gene Targets (either “Ercole Exclusive Products” or “Isis Exclusive
Products,” each as further defined below). In exchange for these exclusive
licenses, each Party will pay royalties and milestones on their respective
Exclusive Products.

 

Any Gene Target that is not exclusively reserved by a Party will be referred to
as a “Nonexclusive Target” (as further defined below). Each Party may also use
the other Party’s RNA Splicing Patents to discover or develop Products that
modulate a Nonexclusive Target (“Nonexclusive Products” as further defined
below) on a non-exclusive basis (as further described below).

 

Collaboration

 

The Parties also wish to collaborate in the areas of drug discovery, medicinal
chemistry and antisense, as further described below and in the Research Plan.

 

At Ercole’s request and on Ercole’s behalf, Isis will discover 2’-MOE modified
Splicing Modulators (“MOE Products,” as further defined below) that modulate the
Ercole Exclusive Targets. For each MOE Product, Isis will grant Ercole a
non-exclusive license to Isis’ MOE Patents in exchange for an additional
royalty.

 

In addition, Isis will grant Ercole an exclusive license to use the PNA Patents
to discover, research, develop and commercialize Ercole Exclusive Products for a
license fee and additional royalties and milestones (as further described
below).

 

Isis will collaborate with Ercole to discover Splicing Modulators that modulate
the Gene Target Bcl-x and will grant Ercole an exclusive license to Isis’ Bcl-x
Patents in exchange for an additional royalty for each Bcl-x Product.  Bcl-x
will count as an Ercole Exclusive Target and Bcl-x Products will be considered
Ercole Exclusive Products.

 

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As part of the collaboration, Ercole will, among other things, develop the MOE
Products and PNA Products, evaluate medicinal chemistries and will test certain
Splicing Modulators (as further described below and in the Research Plan).

 

Capitalized terms used in this Agreement have the meanings set forth in
Exhibit 1.

 

AGREEMENT

 

ARTICLE 1

COLLABORATIVE RESEARCH PLAN

 

1.1                               General; Collaboration Term.

 

(a)                                  Ercole and Isis will work together under
the Research Plan to develop Splicing Modulators.  At Ercole’s request, Isis
will discover and design Splicing Modulators to modulate the Ercole Exclusive
Targets as further provided for in the Research Plan.

 

(b)                                 The Collaboration Term will begin on the
Effective Date and will continue for 3 years unless earlier terminated due to
termination of the Agreement under Sections 8.2 or 8.3, or unless terminated or
extended upon mutual agreement of the Parties.

 

1.2                               Targets: General.

 

Ercole and Isis will each select exclusive Gene Targets for their research and
development efforts (the “Isis Exclusive Targets” or the “Ercole Exclusive
Targets”).  Exhibit 2 hereto will contain a list of the initial Isis Exclusive
Targets and Ercole Exclusive Targets. Gene Targets may be added to and removed
from Exhibit 2 in accordance with the terms of this Section and Section 1.3.

 

1.3                               Targets: Number of, Designation, Approval and
Replacement.

 

(a)                                  Number of Exclusive Targets.  As noted
above, Exhibit 2 will list the initial Isis Exclusive Targets and Ercole
Exclusive Targets agreed upon by the Parties. Isis will be able to designate
twenty (20) Gene Targets as Isis Exclusive Targets at any time and Ercole will
be able to designate twenty (20) Gene Targets as Ercole Exclusive Targets at any
time; provided, however, that each Party may increase its respective Gene Target
limit beyond the initial twenty (20) Gene Targets by paying the other Party
***** per each additional Gene Target.  Promptly after the Effective Date the
Parties will meet to select their initial Exclusive Targets.

 

(b)                                 Exclusive Target Designation.  The Parties
will designate their respective Exclusive Targets as follows:

 

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(i)                                    Target Request.  The Party who wishes to
designate a new Gene Target as one of its Exclusive Targets (the “Requesting
Party”) will provide the other Party (the “Reviewing Party”) with written notice
(the “Request Notice”) of the Gene Target it wishes to designate as an Exclusive
Target (the “Proposed Exclusive Target”). The Request Notice will include the
gene name and the NCBI accession number or nucleic acid sequence for the
Proposed Exclusive Target.

 

(ii)                                 Target Review.  Within thirty (30) days of
receiving the Request Notice, the Reviewing Party will notify the Requesting
Party in good faith and in writing regarding (a) whether the Proposed Exclusive
Target is subject to the Reviewing Party’s own Active Program and (b) the nature
of any contractual obligations to a Third Party in effect at the time of the
Request Notice that would preclude the Reviewing Party from granting a license
under Section 2 or collaborating with the Requesting Party with respect to the
Proposed Exclusive Target (the “Review Notice”).

 

(iii)                              Target Rejection due to Active Program.  If
the Proposed Exclusive Target is subject to the Reviewing Party’s own Active
Program, the Proposed Exclusive Target will be rejected and will not become an
Exclusive Target of the Requesting Party. Rejected Proposed Exclusive Targets
will remain Nonexclusive Gene Targets. Subject to subsection (iv) below, if the
Proposed Exclusive Target is not rejected under this subsection (iii), the
Proposed Exclusive Target will become an Exclusive Target of the Requesting
Party and will be added to the Requesting Party’s list of Exclusive Targets on
Exhibit 2.

 

(iv)                             Target Acceptance; Limitations.  If the
Proposed Exclusive Target is subject to contractual limitations as identified in
the Review Notice under Section 1.3(b)(ii), then within fifteen (15) days of
receiving the Review Notice, the Requesting Party must notify the Reviewing
Party whether or not it accepts the Proposed Exclusive Target subject to the
contractual limitations set forth in the Review Notice. If the Requesting Party
accepts the Proposed Exclusive Target, then the accepted Proposed Exclusive
Target will become an Exclusive Target of the Requesting Party and will be added
to the Requesting Party’s list of Exclusive Targets on Exhibit 2; provided,
however that, with respect to such accepted Exclusive Target, the licenses
granted under Section 2 below will be limited as described in the Review Notice.

 

(v)                                Target Rejection = Request.  If the Reviewing
Party rejects a Proposed Exclusive Target, such rejection will constitute a
Request

 

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Notice by the Reviewing Party for such Proposed Exclusive Target that will then
be processed according to this Section 1.3(b).

 

(c)                                  Exclusive Target Removal.  After the
Effective Date, a Party may remove Gene Targets from its list of Exclusive
Targets on Exhibit 2, by (i) providing the other Party written notice of its
election to do so and (ii) updating the list on Exhibit 2 to remove the Gene
Target; provided, however, that each Party may only remove up to five (5) Gene
Targets from its list of Exclusive Targets in any six month period. In addition,
once a Party removes a Gene Target from its list of Exclusive Targets, such
Party cannot attempt to re-designate the removed Gene Target as an Exclusive
Target until two years have passed from the date such Gene Target was removed.
Any Exclusive Target removed under this section will become a Nonexclusive
Target.

 

1.4                               Collaborative Research Plan.

 

(a)                                  General Overview.  Upon Ercole’s request,
Isis will identify Splicing Modulators that modulate the splicing of Ercole
Exclusive Targets as more specifically described in the Research Plan. The
ownership and use of all materials, including Splicing Modulators, and of all
data and information generated as a result of identifying such Splicing
Modulators or as otherwise provided to Ercole by Isis pursuant to this
Agreement, is governed by the Research Plan. The Parties will collaborate
together as more specifically described in the Research Plan.

 

ARTICLE 2

LICENSE GRANTS AND OTHER RIGHTS

 

2.1                               License Term.  As used herein, “License Term”
means the term beginning on the Effective Date and continuing, on a
Product-by-Product and country-by-country basis, for the life of the Patent
rights upon which such Product is based on or utilizes in such country.

 

2.2                               Isis License Grants.  Subject to the
limitations set forth in Section 1.3(b)(iv) and termination provisions set forth
in Sections 2.2(b) below, Isis grants Ercole the following licenses:

 

(a)                                  License Grants.

 

(i)                                    Isis grants Ercole an exclusive worldwide
license to the Isis Splicing Patents solely to research, develop, make and have
made, offer for sale, sell, import and export Ercole Exclusive Products.

 

(ii)                                 Isis grants Ercole a non-exclusive
worldwide license to the Isis Splicing Patents solely to research, develop, make
and have made, offer for sale, sell, import and export Ercole Nonexclusive
Products.

 

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(iii)                              Isis grants Ercole a non-exclusive worldwide
license to the MOE Patents solely to develop, make and have made, offer for
sale, sell, import and export MOE Products.

 

(iv)                             Isis grants Ercole an exclusive worldwide
license to the Bcl-x Patents solely to research, develop, make and have made,
offer for sale, sell, import and export Ercole Exclusive Products.

 

(v)                                Isis grants Ercole an exclusive worldwide
license to the PNA Patents solely to develop, make and have made, offer for
sale, sell, import and export PNA Products.

 

(vi)                             Isis grants Ercole an exclusive worldwide
license to the Jointly Owned Invention Patents (as defined in Section 4.1)
solely to research, develop, make and have made, offer for sale, sell, import
and export Ercole Exclusive Products.

 

(b)                                 Termination of Licenses.

 

(i)                                    Upon written notice to Ercole, Isis may
terminate the licenses granted under Subsections (i), (iii), (iv), (v) and
(vi) of this Section 2.2(a) with respect to any Ercole Exclusive Target for
which Ercole has discovered a Splicing Modulator (either on its own or with Isis
as part of the Research Plan) if Isis provides Ercole with written notice that
Isis believes such Ercole Exclusive Target is not part of an Active Program and
Ercole does not make such Ercole Exclusive Target part of an Active program
within 12 months following receipt of such notice.

 

(ii)                                 Upon written notice to Ercole, Isis may
terminate the licenses granted under Subsections (i), (iii), (iv), (v) and
(vi) of this Section 2.2 with respect to any Bcl-x Products if Bcl-x does not
continue to be an Ercole Exclusive Target.

 

(iii)                              Upon written notice to Ercole, Isis may
terminate the licenses granted under Subsections (i), (iii), (iv), (v) and
(vi) of this Section 2.2 with respect to Bcl-x Products if a Bcl-x Product does
not meet the Bcl-x Milestones. For clarification, so long as any Ercole Bcl-x
Product meets the Bcl-x Milestones, Isis cannot invoke this
Section 2.2(b)(iii) to terminate the licenses granted under subsections (i),
(iii), (iv), (v) and (vi) of Section 2.2(a).

 

(iv)                             The license to the PNA Patents granted under
Section 2.2(v) will terminate with respect to each Ercole Exclusive Target
(including each Ercole Exclusive Product that modulates such Ercole Exclusive
Target) unless Ercole pays Isis a ***** license fee for each such Ercole
Exclusive Target before the two-year anniversary of the date upon which Ercole
Initiates Phase I Trials

 

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(either on its own or with another party) for a compound that modulates such
Ercole Exclusive Target.

 

2.3                               Sublicenses Under Isis Patent Rights and Third
Party Patent Rights.

 

(a)                                 Subject to the terms and conditions of this
Agreement and during the License Term, Ercole will have the right to grant
sublicenses under the licenses from Isis set forth in Section 2.1 to Third
Parties as follows:

 

(i)                                    Ercole may grant a sublicense to a Third
Party collaborator under the Bcl-x Patents solely for the purpose of enabling
such Third Party collaborator to develop and commercialize a Bcl-x Product.

 

(ii)                                 Ercole may grant a sublicense to a Third
Party collaborator under the MOE Patents solely for the purpose of enabling such
Third Party to develop and commercialize MOE Products.

 

(iii)                              Ercole may grant a sublicense to a Third
Party under the Isis Splicing Patents solely for the purposes of

 

(1)                                 Enabling such Third Party to discover,
develop and commercialize Ercole Exclusive Products; and

 

(2)                                 Enabling such Third Party to conduct
pre-clinical research (which specifically excludes clinical development or
commercialization) on Ercole Nonexclusive Products.

 

(iv)                             Ercole may grant a sublicense to a Third Party
collaborator under the PNA Patents solely for the purpose of enabling such Third
Party to develop and commercialize PNA Products.

 

(b)                                 Any sublicense granted by Ercole under this
Agreement is subject to and will be consistent with the terms and conditions of
this Agreement. The grant of any such sublicense hereunder will not relieve
Ercole of its obligations under this Agreement. Ercole will promptly notify Isis
of all sublicenses granted by Ercole, as well as sublicensee contact
information.

 

(c)                                  In the event of a material default by any
sublicensee under an Ercole sublicense, Ercole will inform Isis and take
commercially reasonable efforts to cause the sublicensee to cure the default or
will terminate the Ercole sublicense.

 

2.4                               Ercole License Grants.  Subject to the
limitation set forth in Section 1.3(b)(iv), Ercole grants Isis the following
licenses:

 

--------------------------------------------------------------------------------

 

(a)                                  License Grants.

 

(i)                                    Ercole grants to Isis an exclusive
worldwide license to the Ercole Splicing Patents solely to research, develop,
make and have made, offer for sale, sell, import and export Isis Exclusive
Products.

 

(ii)                                 Ercole grants to Isis a nonexclusive
worldwide license to the Ercole Splicing Patents solely to research, develop,
make and have made, offer for sale, sell, import and export Isis Nonexclusive
Products.

 

(iii)                              Ercole grants Isis an exclusive worldwide
license to the Jointly Owned Invention Patents (as defined in Section 4.1)
solely to research, develop, make and have made, offer for sale, sell, import
and export Isis Exclusive Products.

 

(iv)                             Ercole grants to Isis a worldwide license to
any Sponsored Inventions solely to research, develop, make and have made, offer
for sale, sell, import and export Isis Products. With respect to Isis Exclusive
Products this license will be exclusive and with respect to Isis Nonexclusive
Products this license will be nonexclusive. Ercole will secure the right to
license to Isis any Sponsored Inventions on terms that are substantially similar
to those set forth in the UNC License Agreement.

 

In the event Ercole does not wish to license any Sponsored Invention from UNC,
then Ercole will provide written notice to Isis including UNC’s proposed terms
to license such Sponsored Invention and Ercole’s decision not to license such
Sponsored Invention (a “UNC Rejection Notice”). Thereafter, Isis will have
30 days from the date it receives the UNC Rejection Notice to notify Ercole that
Isis wishes Ercole to secure a license to such Sponsored Invention on the terms
proposed by UNC (an “Isis UNC Acceptance Notice”). If Isis does not respond to
Ercole within such 30 day period, Ercole may waive its right to license such
Sponsored Invention. If Isis does provide Ercole an Isis UNC Acceptance Notice
within such 30 day period, Ercole will use all reasonable efforts to secure a
license to such Sponsored Invention on the terms outlined in the UNC Rejection
Notice, solely for the benefit of Isis and its sublicensees (and not for the
benefit of Ercole or any of its Third Party sublicensees) and Isis will be
responsible for paying any license fees, milestones and royalties arising from
such license.

 

2.5                               Sublicenses Under Ercole Patent Rights and
Third Party Patent Rights.

 

(a)                                  Any sublicense granted by Isis under this
Agreement is subject to and will be consistent with the terms and conditions of
this Agreement. The grant of any such sublicense hereunder will not relieve Isis
of its obligations under this Agreement.

 

(b)                                 Subject to the terms and conditions of this
Agreement and during the License Term, Isis may grant a sublicense to a Third
Party collaborator under the Ercole Splicing Patents solely for the purpose of:

 

--------------------------------------------------------------------------------

 

(i)                                    Enabling such Third Party to discover,
develop and commercialize Isis Exclusive Products; and

 

(ii)                                 Enabling such Third Party to conduct
pre-clinical research (which specifically excludes clinical development or
commercialization) on Isis Nonexclusive Products.

 

(c)                                  Any sublicense granted by Isis under this
Agreement is subject to and will be consistent with the terms and conditions of
this Agreement. The grant of any such sublicense hereunder will not relieve Isis
of its obligations under this Agreement. Isis will promptly notify Ercole of all
sublicenses granted by Isis, as well as sublicensee contact information. In the
event of a material default by any sublicensee under an Isis sublicense, Isis
will inform Ercole and take commercially reasonable efforts to cause the
sublicensee to cure the default or Isis will terminate the sublicense.

 

(d)                                 Isis acknowledges that the license grants by
Ercole hereunder are subject to the terms and conditions of that certain License
Agreement with UNC, as amended, (the “UNC License Agreement”) a copy of which is
attached as Appendix 1. Ercole agrees not to amend such agreement in a manner
that would adversely affect the rights of Isis hereunder and further agrees to
use commercially reasonable efforts not to breach such agreement.

 

2.6                               Effect of Termination of Isis Licenses.

 

Upon termination of any license granted to Ercole under Section 2.2, Ercole will
promptly return to Isis all quantities of Splicing Modulators that (a) are
Covered by the terminated license, (b) were provided by Isis under this
Agreement, and (c) have not been used. In addition, Ercole will promptly provide
to Isis all information and materials relating to a Jointly Owned Invention
under Section 4.1 that was Covered by the terminated license.

 

In addition, if the license to the Bcl-x Patents granted under
Section 2.2(a)(iv) is terminated, Ercole will promptly provide to Isis all
information and materials related to Ercole Bcl-x Products and will grant Isis a
royalty free, perpetual, exclusive license to use such information and
materials.

 

Upon the termination of any license granted to Isis under Section 2.3, Isis will
promptly provide to Ercole all information and materials relating to a Jointly
Owned Invention under Section 4.1 that was Covered by the terminated license.

 

2.7                               Right of First Negotiation.

 

(a)                                 During the term of this Agreement, Isis will
have a right of first negotiation for licensing of any Ercole MOE Products or
any Ercole PNA Products, other than those Ercole Products arising specifically
from research programs at least 50% of the cost of which was specifically funded
by Third Parties.

 

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(b)                                 Under Isis’ right of first negotiation,
Ercole will provide written notice to Isis if Ercole elects to offer to license
to a Third Party (other than a license for a drug candidate arising from
research programs at least 50% of the cost of which was specifically funded by
Third Parties) the right to develop and commercialize an Ercole MOE Product or
an Ercole PNA Product. Such notice will include all information possessed and
disclosable by Ercole that supports the development of such Ercole Product and
is reasonably necessary for Isis to assess the commercial potential of such
Ercole Product. Within 60 days of receipt of such notice, Isis will provide
written notice to Ercole indicating whether it is interested in negotiating with
Ercole to obtain the rights to develop and commercialize such Ercole Product.

 

(c)                                  If Isis fails to respond to Ercole’s
notification within 30 days or indicates that it is not interested in developing
and commercializing such Ercole Product with Ercole, Ercole will thereafter be
free to conclude an agreement with one or more Third Parties regarding the
development and commercialization of such Ercole Product.

 

(d)                                 If Isis timely indicates its interest in
obtaining such rights to develop and commercialize such Ercole Product with
Ercole, the Parties will negotiate in good faith the terms of a separate
development and commercialization agreement, which terms will be commercially
reasonable, during the period up to 120 days following Ercole’s receipt of Isis’
notice. If the Parties are unable to execute such an agreement within such time
period, despite good faith negotiations by each Party, Ercole will be free to
develop and commercialize such Ercole Product with one or more Third Parties,
provided that Ercole may not enter into an agreement with a Third Party to
develop and commercialize such Ercole Product with financial terms that when
taken as a whole are less favorable than those offered by Isis during the
negotiation period.

 

ARTICLE 3

ROYALTIES AND PAYMENTS

 

3.1                               Royalties Payable to Isis by Ercole on Sales
of Products by Ercole.

 

Subject to the terms and conditions of, and during the term of, this Agreement,
Ercole will pay to Isis royalties on sales of Products by Ercole, its Affiliates
or sublicensees, according to the terms set forth below.

 

(a)                                  Ercole Exclusive Products.  The royalty
payable to Isis by Ercole for sales by Ercole, its Affiliates or sublicensees of
any Ercole Exclusive Products that are not PNA Products or MOE Products is *****
of Net Sales for so long as there are issued and unexpired claims within the
Isis Splicing Patents or any Jointly Owned Invention Patents that Cover such
Ercole

 

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Exclusive Product. The royalty under this Section 3.1(a) will also apply to any
Ercole Nonexclusive Product that modulates a Gene Target that was once an Ercole
Exclusive Target.

 

(b)                                 MOE Products. The royalty payable to Isis by
Ercole for sales of any MOE Product by Ercole, its Affiliates or sublicensees is
***** of Net Sales for so long as there are issued and unexpired claims within
the MOE Patents that Cover such MOE Product. Thereafter, the royalty payable to
Isis by Ercole for sales of any MOE Product by Ercole, its Affiliates or
sublicensees is ***** of Net Sales for so long as there are issued and unexpired
claims within the Isis Splicing Patents or any Jointly Owned Invention Patents
that Cover such MOE Product.

 

(c)                                  PNA Products.  The royalty payable to Isis
by Ercole for sales of any PNA Products by Ercole, its Affiliates or
sublicensees is ***** of Net Sales for so long as there are issued and unexpired
claims within the PNA Patents that Cover such PNA Product. Thereafter, the
royalty payable to Isis by Ercole for sales of any PNA Products by Ercole, its
Affiliates or sublicensees is ***** of Net Sales for so long as there are issued
and unexpired claims within the Isis Splicing Patents or any Jointly Owned
Invention Patents that Cover such PNA Products.

 

(d)                                 Bcl-X Products. The royalty payable to Isis
by Ercole for sales of any Ercole Bcl-x Product by Ercole, its Affiliates or
sublicensees, is as follows:

 

(i)                                    for sales of any Ercole Bcl-x Product
(which is a PNA Product or a MOE Product) by Ercole, its Affiliates or
sublicensees is ***** of Net Sales for so long as there are issued and unexpired
claims within (x) the Bcl-x Patents or any Jointly Owned Invention Patents that
Cover such Bcl-x Product and (y) the MOE Patents or PNA Patents that Cover such
Bcl-x Product. Thereafter, the royalty payable to Isis by Ercole for sales of
such Ercole Bcl-x Product (which is a PNA Product or a MOE Product) by Ercole,
its Affiliates or sublicensees is ***** of Net Sales for so long as there are
issued and unexpired claims within the Bcl-x Patents, Isis Splicing Patents or
any Jointly Owned Invention Patents that Cover such Bcl-x Product.

 

(ii)                                 for sales of any Ercole Bcl-x Product
(which is not a PNA Product or a MOE Product) by Ercole, its Affiliates or
sublicensees, is ***** of Net Sales for so long as there are issued and
unexpired claims within the Bcl-x Patents, Isis Splicing Patents or any Jointly
Owned Invention Patents that Cover such Bcl-x Product.

 

(e)                                  No Stacking.  For the sake of
clarification, the foregoing royalties are not cumulative. Accordingly, the
obligation of Ercole to pay a royalty

 

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hereunder with respect to the sale of any Product by Ercole, its Affiliates or
sublicensees will be limited to the single, highest applicable royalty under
paragraph (a), (b), (c) or (d).

 

3.2                               Royalties Payable to Ercole by Isis on Sales
of Products by Isis.

 

Subject to the terms and conditions of, and during the term of, this Agreement,
Isis will pay to Ercole royalties on sales of Isis Exclusive Products by Isis,
its Affiliates or sublicensees, according to the terms set forth below.

 

(a)                                  The royalty payable to Ercole by Isis for
sales of any Isis Exclusive Products by Isis, its Affiliates or sublicensees is
***** of Net Sales for so long as there are issued and unexpired claims within
the Ercole Splicing Patents, any Jointly Owned Invention Patents or any Patent
within the Sponsored Inventions (except those Sponsored Inventions accessed by
Isis under Section 2.4(a)(iv) as the result of an Isis UNC Acceptance Notice),
that Cover such Isis Exclusive Product. The royalty under this Section 3.2(a),
will also apply to any Isis Nonexclusive Product that modulates a Gene Target
that was once an Isis Exclusive Target.

 

3.3                               Development Milestones.

 

(a)                                  Ercole Exclusive Products, MOE Products.
Ercole, its Affiliates or sublicensees will pay to Isis the following milestone
payments for (i) each Ercole Exclusive Product, including MOE Products, that is
not a PNA Product or a Bcl-x Product and (ii) each Ercole Nonexclusive Product
that modulates a Gene Target that was once an Ercole Exclusive Target, within
sixty (60) days after achievement of each of the following events in the
specified jurisdiction, or where no jurisdiction is specified, in the first
Major Market Country:

 

Milestone Event

 

Milestone Payment

 

Start of IND-Enabling Tox Studies

 

 

*****

 

Filing of IND

 

 

*****

 

First Initiation of Phase II Trial

 

 

*****

 

US NDA Approval

 

 

*****

 

EC Approval

 

 

*****

 

Japanese Approval

 

 

*****

 

 

(b)                                 Ercole Bcl-x Products.  Ercole, its
Affiliates or sublicensees will pay to Isis the following milestone payments for
each Bcl-x Product (determined according to whether or not such Bcl-x Product is
also a PNA Product) within sixty (60) days after achievement of each of the
following events in the specified jurisdiction, or where no jurisdiction is
specified, in the first Major Market Country:

 

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Milestone Event

 

Milestone Payment if
Not a PNA Product

 

Milestone Payment
if a PNA Product

 

Start of IND-Enabling Tox Studies

 

 

*****

 

 

*****

 

Filing of IND

 

 

*****

 

 

*****

 

First Initiation of Phase II Trial

 

 

*****

 

 

*****

 

Filing NDA in US (or EC Equivalent)

 

*****

 

 

*****

 

US NDA Approval

 

 

*****

 

 

*****

 

EC Approval

 

 

*****

 

 

*****

 

Japanese Approval

 

 

*****

 

 

*****

 

 

With respect to Bcl-X Products that are also PNA Products, once there are no
longer any issued and unexpired claims within the PNA Patents that Cover the
applicable Bcl-x Product, then the ***** milestone payment above attributable to
filing an IND will be reduced to ***** and the ***** payment above attributable
to filing an NDA in the US (or EC equivalent) will be eliminated. Any milestone
payments that were triggered prior to such expiration will survive such
expiration and any milestones paid prior to such expiration will not be
refundable or creditable.

 

(c)                                  Ercole PNA Products. Ercole, its Affiliates
or sublicensees will pay to Isis the following milestone payments for each PNA
Product that is not a Bcl-x Product within sixty (60) days after achievement of
each of the following events in the specified jurisdiction, or where no
jurisdiction is specified, in the first Major Market Country:

 

Milestone Event

 

Milestone Payment

 

Start of IND-Enabling Tox Studies

 

 

*****

 

Filing of IND

 

 

*****

 

First Initiation of Phase II Trial

 

 

*****

 

US NDA Approval

 

 

*****

 

EC Approval

 

 

*****

 

Japanese Approval

 

 

*****

 

 

With respect to PNA Products, once there are no longer any issued and unexpired
claims within the PNA Patents that Cover the applicable PNA Product, then the
***** milestone payment above attributable to filing an IND will be reduced to
***** and the ***** payment above attributable to filing an NDA in the US (or EC
equivalent) will be eliminated. Any milestone payments that were triggered prior
to such expiration will survive such expiration and any milestones paid prior to
such expiration will not be refundable or creditable.

 

(d)                                 Isis Exclusive Products. Isis, its
Affiliates or sublicensees will pay to Ercole the following milestone payments
for (i) each Isis Exclusive Product and (ii) each Isis Nonexclusive Product that
modulates a Gene Target that was once an Isis Exclusive Target within sixty (60)
days after

 

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achievement of each of the following events in the specified jurisdiction, or
where no jurisdiction is specified, in the first Major Market Country:

 

Milestone Event

 

Milestone Payment

 

Start of IND-Enabling Tox Studies

 

 

*****

 

Filing of IND

 

 

*****

 

First Initiation of Phase II Trial

 

 

*****

 

US NDA Approval

 

 

*****

 

EC Approval

 

 

*****

 

Japanese Approval

 

 

*****

 

 

3.4                               Commercial Success Milestones.

 

In consideration for the collective benefit each Party is receiving as a result
of the synergies created by the collaborative nature of this Agreement, the
Parties agree to pay the following milestones:

 

(a)                                  Ercole Products. For (i) each Ercole
Exclusive Product, including MOE Products and PNA Products and (ii) each Ercole
Nonexclusive Product that modulates a Gene Target that was once an Ercole
Exclusive Target, Ercole, its Affiliates or sublicensees will pay to Isis a
milestone payment equal to ***** if such Ercole Product has Net Sales of *****
or more in any Calendar Year. Such milestone will be payable in quarterly
installments of ***** over the ***** years following the year in which the
milestone was met. Any royalties paid to Isis under Section 3.1 for such Ercole
Product will be creditable against this commercial success milestone.

 

(b)                                 Isis Products. For (i) each Isis Exclusive
Product and (ii) each Isis Nonexclusive Product that modulates a Gene Target
that was once an Isis Exclusive Target, Isis, its Affiliates or sublicensees
will pay to Ercole a milestone payment equal to ***** if such Isis Product has
Net Sales of ***** or more in any Calendar Year. Such milestone will be payable
in quarterly installments of ***** over the ***** years following the year in
which the milestone was met. Any royalties paid to Ercole under Section 3.2 for
such Isis Product will be creditable against this commercial success milestone.

 

3.5                               Applicability of Milestones.

 

With respect to Ercole Products, the milestone payments set forth in Sections
3.3 and 3.4 will only apply to the Ercole Products specified in such sections
that when discovered, developed, manufactured or commercialized were Covered by
a claim within the Isis Patents or the Jointly Owned Invention Patents. With
respect to Isis Products, the milestone payments set forth in Sections 3.3 and
3.4 will only apply to the Isis Products specified in such sections that when

 

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discovered, developed, manufactured or commercialized were Covered by a claim
within the Ercole Splicing Patents or the Jointly Owned Invention Patents.

 

3.6                               Payment of Royalties and Milestones; Reports.

 

Each Party will make royalty payments to the other Party for each Product sold
during a Calendar Quarter within 60 days of the last day of that Calendar
Quarter. Each royalty payment will be accompanied by a written report for that
Calendar Quarter showing the calculation of Net Sales of the Product sold by
such Party, its Affiliates and its Sublicensees worldwide during the quarterly
reporting period and the calculation of the royalties, and Milestones payable
under this Agreement, all on a country-by-country and Product-by-Product basis.

 

3.7                               Payment Modalities; Foreign Currency
Conversion; Late Payment Charges.

 

(a)                                  Payments. All payments by a Party under
this Agreement will be made in United States Dollars by bank wire transfer in
next day available funds to such bank account in the United States designated in
writing by Ercole or Isis, from time to time. Except as explicitly provided for
in Section 3.4, all amounts payable to Isis hereunder are noncreditable and
nonrefundable.

 

(b)                                 Late Payments; Collections. In the event
that any payment, including royalty or milestone payments, due hereunder is not
made when due, the payment will bear interest from the date due at the lesser of
(i) 1.5% per month, compounded monthly, or (ii) the highest rate permitted by
law; provided, however, that in no event will such rate exceed the maximum legal
annual interest rate. If a Party disputes in writing the amount of an invoice
presented by the other Party within 30 days of receipt of such invoice, the late
fees will only apply to the correct amount as later determined or agreed. The
payment of such interest will not limit a Party from exercising any other rights
it may have as a consequence of the lateness of any payment. In addition, each
Party agrees to pay all costs of collection, including reasonable attorneys’
fees, incurred by the other Party in enforcing the payment obligations after a
due date has passed under this Agreement.

 

3.8                               Audits Rights.

 

(a)                                  Upon the written request of Isis or Ercole,
as the case may be, and not more than once in each Calendar Year, Isis or Ercole
will permit the other Party’s independent certified public accountant to have
access during normal business hours to its records as may be reasonably
necessary to verify the accuracy of the royalty reports hereunder for the
current year and the preceding 2 years prior to the date of such request. The
accounting firm will disclose to the auditing Party only whether the royalty
reports are correct or incorrect, the specific details concerning any
discrepancies, and the corrected amount of Net Sales and royalty payments. No
other information will be provided to the auditing Party.

 

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(b)                                 If such accounting firm concludes that
additional royalties were owed during such period, the delinquent Party will pay
the additional royalties within 90 days of the date such Party receives the
accounting firm’s written report. The fees charged by such accounting firm will
be paid by the auditing Party unless the additional royalties, milestones or
other payments owed by the audited Party exceed 5% of the royalties, milestones
or other payments paid for the time period subject to the audit, in which case
the audited Party will pay the reasonable fees and expenses charged by the
accounting firm.

 

(c)                                  Each Party will treat all financial
information subject to review under this Section 3.7 or under any sublicense
agreement in accordance with the confidentiality provisions of Article 5, and
will cause its accounting firm to enter into an acceptable confidentiality
agreement obligating such firm to retain all such financial information in
confidence pursuant to such confidentiality agreement.

 

3.9                               Taxes.

 

If laws, rules or regulations require withholding of income taxes or other taxes
imposed upon payments set forth in this Article 3, each Party will make such
withholding payments as required and subtract such withholding payments from the
payments set forth in this Article 3. Each Party will submit appropriate proof
of payment of the withholding taxes to the other Party within a reasonable
period of time.

 

ARTICLE 4

INTELLECTUAL PROPERTY

 

4.1                               Ownership of Inventions.

 

(a)                                  Neither Party hereto will be deemed by this
Agreement to have been granted any license or other rights to the other Party’s
rights in any inventions, technology, discoveries, or other proprietary property
(collectively, “Inventions”) existing as of the Effective Date of this
Agreement, except as expressly provided herein.

 

(b)                                 Except as provided otherwise herein, each
Party will solely own all Inventions that are made (as determined by U.S.
rules of inventorship) solely by employees of or consultants to that Party under
this Agreement, even if such Invention was made under the Research Plan. Such an
Invention will be an “Isis Invention” or an “Ercole Invention,” as the case may
be, and Patents claiming such Inventions will be “Isis Invention Patents” or
“Ercole Invention Patents,” respectively.

 

(c)                                  Except as provided otherwise herein, Isis
and Ercole will jointly hold title to all Inventions, whether or not patentable,
that are made (as determined by the U.S. rules of inventorship) jointly by
employees of or Consultants

 

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to Isis and Ercole, as well as to Patents filed thereon. Such Inventions will be
“Jointly Owned Inventions,” and Patents claiming such Jointly Owned Inventions
will be “Jointly Owned Invention Patents.” Isis and Ercole will promptly provide
each other with notice whenever a Jointly Owned Invention is made. The Parties
agree and acknowledge that, except insofar as this Agreement provides otherwise,
the default rights conferred on joint owners under US patent law, including the
right of each Party to independently practice, license and use a Joint Patent,
will apply in relation to the Jointly Owned Invention Patents throughout the
world as though US patent law applied worldwide.

 

(d)                                 The Parties agree that an Invention created
by Ercole using a Splicing Modulator provided to Ercole by Isis will also be a
Jointly Owned Invention. Similarly, the Parties understand that the discovery of
a method of treating human disease by inhibiting a particular gene product using
a Splicing Modulator provided to Ercole by Isis, where Isis’ Splicing Modulator
data are used to support the claims of the Patent, will be a Jointly Owned
Invention.

 

(e)                                  The Parties agree, upon reasonable request,
to execute any documents reasonably necessary to effect and perfect each other’s
ownership of any Invention.

 

4.2                               Filing, Prosecution, Maintenance, Enforcement
and Defense of Jointly Owned Invention Patents.

 

(a)                                  Jointly Owned Invention Patents Covering
Products.

 

(i)                                    With respect to Jointly Owned Invention
Patents that either claim a method of using a Product or claim the composition
of matter of a Product (“Product JOIPs”), the Party who is developing and
commercializing such Product (either on its own or with a Third Party) (the
“Controlling Party”) will have the sole and exclusive right, in its sole
discretion and at its expense, to file, prosecute, maintain, enforce and defend
such Product JOIPs. Nothing in this paragraph will be deemed to alter or
supercede the provision of this agreement governing the filing, prosecuting,
maintaining, enforcing and defending the Ercole Splicing Patents or the Isis
Patents.

 

(ii)                                 Each Party will promptly advise the
Controlling Party if it becomes aware of any suspected or actual infringement of
such Product JOIPs.

 

(iii)                              The Controlling Party will be entitled to all
damages and monetary awards recovered as a result of enforcing its respective
Product JOIPs.

 

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(b)                                 Jointly Owned Invention Patents Not Covering
Products.

 

(i)                                    Except as provided otherwise herein, Isis
will have the sole and exclusive right to file, prosecute, maintain, enforce and
defend Jointly Owned Invention Patents that are not Product JOIPs (“Nonproduct
JOIPs”), regardless of inventorship. Isis will consider Ercole’s input with
respect to the prosecution, maintenance, enforcement and defense of any such
Patents. As used herein, Patent prosecution includes, without limitation, the
handling of interference proceedings, oppositions, reexaminations and reissues.
In the case of defense of such Nonproduct JOIPs, Isis will not admit the
invalidity or unenforceability of any Nonproduct JOIP, grant a license to the
allegedly infringing Third Party or enter into any settlement agreement without
Ercole’s prior written consent, such consent not to be unreasonably withheld.

 

(ii)                                 In the event Ercole proposes the filing of
a Nonproduct JOIP pursuant to subsection (i) and Isis does not wish to file and
prosecute such Nonproduct JOIP, Ercole will have the right to file, prosecute,
maintain, enforce and defend such Nonproduct JOIP at Ercole’s own expense.
Ercole will consider Isis’ input with respect to the prosecution, maintenance,
enforcement and defense of any such Nonproduct JOIPs. In the event that Isis
elects not to participate in the prosecution or maintenance of any such
Nonproduct JOIP, Isis shall so notify Ercole of such determination. Thereafter,
Isis shall have no responsibility for any costs relating thereto, shall not
share in any recovery relating to the enforcement thereof and shall retain
solely a royalty-free, nonexclusive license without the right to sublicense to
practice such Nonproduct JOIP for its own research and development activities.

 

(iii)                              Ercole will reimburse Isis for 50% of the
reasonable materials and out of pocket expenses incurred in connection with
filing, prosecuting, maintaining, enforcing and defending the Nonproduct JOIPs.
As used herein, materials and out-of-pocket expenses means costs, including
without limitation costs of Isis’ internal labor, travel, supplies, outside
services, and consultants. The foregoing expenses will be passed through to
Ercole at cost. Isis will invoice Ercole on an annual basis and Ercole will
submit payment to Isis consistent with the provisions of Article 3 herein. In
the event that Ercole elects not to participate in the prosecution or
maintenance of any Nonproduct JOIP, Ercole shall so notify Isis of such
determination. Thereafter, Ercole shall have no responsibility for any costs
relating thereto, shall not share in any recovery relating to the enforcement
thereof and shall retain solely a royalty-free, nonexclusive license without the
right to sublicense

 

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to practice such Nonproduct JOIP for its own research and development
activities.

 

(iv)                              Isis will promptly advise Ercole if Isis
becomes aware of any suspected or actual infringement of such Nonproduct JOIPs
by any person. Similarly, Ercole will promptly advise Isis if Ercole becomes
aware of any suspected or actual infringement of a Nonproduct JOIP by any
person.

 

(v)                                 If Isis fails to initiate proceedings
against any actual or suspected infringement of the Nonproduct JOIPs or to
defend any claim of infringement against the Parties pertaining to such rights
within 60 days of receipt of a notice from Ercole asking Isis to do so, Ercole
will be entitled to initiate those proceedings at Ercole’s expense; provided,
however, that Ercole will not admit the invalidity or unenforceability of any
Nonproduct JOIP, grant a license to the allegedly infringing Third Party or
enter into any settlement agreement without Isis’ prior written consent, which
consent will not be unreasonably withheld.

 

(vi)                              Ercole and Isis will negotiate in good faith
an appropriate allocation of any amounts recovered in enforcing the Nonproduct
JOIPs, which will, in any event, provide first for the full reimbursement of the
reasonable costs incurred by each Party with respect to the prosecution and
enforcement of such Nonproduct JOIPs.

 

4.3                               Filing, Prosecution, Maintenance, Enforcement
and Defense of Patents Owned or Controlled by Isis.

 

(a)                                  Isis Patents.

 

(i)                                    Isis will have the sole and exclusive
right, in its sole discretion and at its expense, to file, prosecute, maintain,
enforce and defend any Patents within the Isis Patent Rights and the Isis
Invention Patents.

 

(ii)                                 Ercole will promptly advise Isis if Ercole
becomes aware of any suspected or actual infringement of the Isis Patent Rights
and the Isis Invention Patents by any person.

 

(iii)                             Isis will be entitled to all damages and
monetary awards recovered as a result of enforcing the Isis Patent Rights and
the Isis Invention Patents; provided, however, that with respect to damages or
monetary awards recovered as a result of enforcing the Isis Patent Rights or the
Isis Invention Patents in connection with the infringement of a Patent claiming
the composition of matter of an Ercole Product, then the Parties will negotiate
in good faith an appropriate allocation of any amounts recovered, taking into

 

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consideration the reasonable costs incurred by each Party with respect to the
enforcement of such Patents and the royalties and milestones Isis would have
otherwise received had the infringing party obtained a sublicense from Ercole.

 

(b)                                 Bcl-x Patents.

 

(i)                                     Except as otherwise provided herein,
Isis will have the sole and exclusive right, in its sole discretion, to file,
prosecute and maintain any Patents within the Bcl-x Patents. So long as the
license to the Bc1-x Patents granted to Ercole under Section 2.2(a)(iv) is still
effective and except as otherwise provided herein, Ercole will have the sole and
exclusive right, in its sole discretion to enforce and defend the Patents within
the Bcl-x Patents. Isis will consider Ercole’s input with respect to the
prosecution and maintenance of the Bcl-x Patents.

 

(ii)                                  Ercole will reimburse Isis for 100% of
Isis’ reasonable materials and out of pocket expenses incurred after the
Effective Date in connection with filing, prosecuting and maintaining the Bcl-x
Patents. As used herein, materials and out-of-pocket expenses means costs,
including without limitation costs of Isis’ internal labor, travel, supplies,
outside services, and consultants. The foregoing expenses will be passed through
to Ercole at cost. Isis will invoice Ercole on a quarterly basis and Ercole will
submit payment to Isis consistent with the provisions of Article 3 herein.

 

(iii)                              So long as the license to the Bcl-x Patents
granted to Ercole under Section 2.2(a)(iv) is still effective, with respect to
the Bcl-x Patents, Isis will promptly advise Ercole if Isis becomes aware of any
suspected or actual infringement of such Bcl-x Patents by any person. Similarly,
Ercole will promptly advise Isis if Ercole becomes aware of any suspected or
actual infringement of the Bcl-x Patents by any person. Notwithstanding the
foregoing, Ercole may elect not to reimburse Isis for any costs associated with
filing, prosecuting and maintaining, the Bcl-x Patents in any country, in which
case Ercole will forfeit its license and its right to share any recovery related
to the Bcl-x Patents in that country.

 

(iv)                              If Ercole fails to initiate proceedings
against any actual or suspected infringement of the Bcl-x Patents exclusively
licensed to Ercole hereunder or to defend any claim of infringement against the
Parties pertaining to such rights within 60 days of receipt of a notice from
Isis asking Ercole to do so, Isis will be entitled to initiate those proceedings
at Isis’ expense.

 

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(v)                                 Ercole and Isis will negotiate in good faith
an appropriate allocation of any amounts recovered in enforcing the Bcl-x
Patents, which will, in any event, provide first for the full reimbursement of
the reasonable costs incurred by each Party with respect to the prosecution and
enforcement of such Bcl-x Patents.

 

4.4                               Filing, Prosecution, Maintenance, Enforcement
and Defense of Patents Owned or Controlled by Ercole.

 

(a)                                  Except as provided otherwise herein, Ercole
will have the sole and exclusive right and responsibility at its own expense, to
file, prosecute, maintain, enforce and defend the Ercole Splicing Patents and
the Ercole Invention Patents. Ercole will consider Isis’ input with respect to
the prosecution, maintenance, enforcement and defense of the Ercole Splicing
Patents.

 

(b)                                 So long as the license to the Ercole
Splicing Patents granted to Isis under Section 2.3 is still effective, if Ercole
fails to initiate proceedings against any actual or suspected infringement of
the Ercole Splicing Patents exclusively licensed to Isis hereunder or to defend
any claim of infringement against the Parties pertaining to such rights within
60 days of receipt of a notice from Isis asking Ercole to do so, Isis will,
subject to the terms of the license agreement with the Third Party that licensed
such patents to Ercole, be entitled to initiate those proceedings at Isis’
expense; provided, however, that Isis will not admit the invalidity or
unenforceability of any Ercole Splicing Patent, grant a license to the allegedly
infringing Third Party or enter into any settlement agreement without Ercole’s
prior written consent, which consent shall not be unreasonably withheld.

 

(c)                                  With respect to the Ercole Splicing
Patents, Isis will promptly advise Ercole if Isis becomes aware of any suspected
or actual infringement of such Ercole Splicing Patents by any person. Similarly,
Ercole will promptly advise Isis if Ercole becomes aware of any suspected or
actual infringement of the Ercole Splicing Patents by any person.

 

(d)                                 If Ercole fails to initiate proceedings
against any actual or suspected infringement of the Ercole Splicing Patents or
to defend any claim of infringement against the Parties pertaining to such
rights, Isis will be entitled to initiate those proceedings.

 

(e)                                 Ercole and Isis will negotiate in good faith
an appropriate allocation of costs, expenses and amounts recovered arising from
enforcing the Ercole Splicing Patents, which will, in any event, provide first
for the full reimbursement of the reasonable costs incurred by each Party with
respect to the prosecution and enforcement of such Jointly Owned Invention
Patents.

 

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ARTICLE 5

CONFIDENTIALITY

 

5.1                               Nondisclosure Obligation.

 

All Confidential Information disclosed by one Party to the other Party hereunder
will be maintained in confidence by the receiving Party and will not be
disclosed to a Third Party or Affiliate or used for any purpose except as set
forth below.

 

5.2                               Permitted Disclosures.

 

Except as otherwise provided herein, a Party may disclose Confidential
Information received from the other Party:

 

(a)                                  to governmental or other regulatory
agencies in order to obtain Patents or approval to conduct clinical trials, or
to gain Marketing Approval; provided that such disclosure may be made only to
the extent reasonably necessary to obtain such patents or approvals;

 

(b)                                 to Affiliates, sublicensees, agents,
consultants, and/or other Third Parties for the development, manufacturing
and/or marketing of the Product (or for such Parties to determine their interest
in performing such activities) in accordance with this Agreement on the
condition that such Affiliates, sublicensees and Third Parties agree to be bound
by the confidentiality obligations contained in this Agreement; or

 

(c)                                  if such disclosure is required by law or
court order. Either Party may disclose (i) a copy of this Agreement on a
confidential basis to prospective investors and (ii) a mutually agreed upon
redacted copy of this Agreement on a confidential basis to prospective
collaborators; provided, however, that a Party can never disclose the other
Party’s Exclusive Targets without the express prior written consent of such
Party.

 

ARTICLE 6

PUBLICATION AND PUBLICITY

 

6.1                               Publication.

 

(a)                                 The Parties agree that it is customary in
the industry to publish results obtained from clinical trials and other studies
of a Product, and that each Party may publish such information obtained by such
Party in the performance of the Research Plan, subject to the provisions of this
Section.

 

(b)                                 Except as provided otherwise herein, the
Parties will be entitled to publish or present on the results of the Research
Plan hereunder and any Product,

 

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provided that the Party seeking to publish will deliver to the other Party for
its review a copy of any proposed publication, poster or an abstract of any oral
presentation at scientific meetings involving any Product hereunder, or the
Confidential Information of the other Party, at least 45 days prior to
submission of scientific publications or abstracts of oral presentations. The
reviewing Party will have the absolute right to request that any of its
Confidential Information be deleted from such publication or presentation, and
the disclosing Party will comply with that request. If the disclosing Party does
not receive any feedback from the reviewing Party within that 45-day period, the
disclosing Party will be free to proceed with the publication or presentation,
except Ercole cannot publish on matters relating to any Isis Splicing Patents,
Isis MOE Patents, PNA Patents or any other Compound or Product developed by Isis
during the term of this Agreement without the prior written approval of Isis,
which may be given at Isis’ sole discretion and Isis cannot publish on matters
relating to any compound or Product developed by Ercole during the term of this
Agreement without the prior written approval of Ercole, which may be given at
Ercole’s sole discretion.

 

6.2                               Publicity.

 

(a)                                 Except as otherwise provided herein or
required by law, neither Party will originate any publication, news release or
other public announcement, written or oral, whether in the public press, or
stockholders’ reports, or otherwise, relating to this Agreement, and neither
Party will use the name, trademark, trade name, logo or likeness of the other
Party or its employees in any publicity, news release or disclosure relating to
this Agreement, or its subject matter, without the prior express written
permission of the other Party.

 

(b)                                 Ercole will inform Isis of any press
releases relating to a Product permitted hereunder or required to be made by law
in advance of general release to the public.

 

ARTICLE 7

INDEMNIFICATION

 

7.1                               Indemnification by Ercole.

 

Ercole will indemnify, defend and hold Isis and its agents, employees, officers
and directors (the “Isis Indemnitees”) harmless from and against any and all
liability, damage, loss, cost or expense (including reasonable attorneys’ fees)
arising out of Third Party claims or suits related to (a) Ercole’s performance
of its obligations under this Agreement; (b) breach by Ercole of its
representations and warranties set forth in Article 9; (c) patent infringement
allegations or claims asserted by a Third Party against Isis arising out of
Isis’ performance of activities for Ercole pursuant to this Agreement;
(d) Ercole’s choice of Ercole Exclusive Targets pursuant to Article 

 

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1; or (e) the manufacture, use, importation or commercialization (including
marketing) of Ercole Products; provided, however, that Ercole’s obligations
pursuant to this Section 7.1 will not apply to the extent such claims or suits
result from (y) the gross negligence or willful misconduct of any of the Isis
Indemnitees or (z) a breach by Isis of its representations and warranties set
forth in Section 9.1.

 

7.2                               Indemnification by Isis.

 

Isis will indemnify, defend and hold Ercole and its Affiliates and each of their
respective agents, employees, officers and directors (the “Ercole Indemnitees”)
harmless from and against any and all liability, damage, loss, cost or expense
(including reasonable attorney’s fees) arising out of Third Party claims or
suits related to (a) Isis’ performance of its obligations under this Agreement;
(b) breach by Isis of its representations and warranties set forth in Article 9;
(c) Isis’ choice of Isis Exclusive Targets pursuant to Article I; or (d) the
manufacture, use, importation or commercialization (including marketing) of Isis
Products; provided however, that Isis’ obligations pursuant to this Section 7.2
will not apply to the extent that such claims or suits result from (x) Ercole’s
choice of Ercole Exclusive Targets pursuant to Article 1, (y) the gross
negligence or willful misconduct of any of the Ercole Indemnitees or (z) a
breach by Ercole of its representations and warranties set forth in Article 9.

 

7.3                               Notification of Claims; Conditions to
Indemnification Obligations.

 

As a condition to a Party’s right to receive indemnification under this
Article 9, it will (i) promptly notify the other Party as soon as it becomes
aware of a claim or action for which indemnification may be sought pursuant
hereto, (ii) cooperate with the indemnifying Party in the defense of such claim
or suit, and (iii) permit the indemnifying Party to control the defense of such
claim or suit, including without limitation the right to select defense counsel.
In no event, however, may the indemnifying Party compromise or settle any claim
or suit in a manner which admits fault or negligence on the part of the
indemnified Party without the prior written consent of the indemnified Party.
The indemnifying Party will have no liability under this Article 7 with respect
to claims or suits settled or compromised without its prior written consent.

 

ARTICLE 8

TERM AND TERMINATION OF AGREEMENT

 

8.1                               Term and Termination of Agreement.

 

This Agreement will be effective as of the Effective Date and unless terminated
earlier pursuant to Sections 8.2 or 8.3 below, the term of this Agreement will
continue in effect until expiration of the License Term.

 

8.2                               Termination upon Material Breach.

 

This Agreement may be terminated upon written notice by either Party to the
other at any time during the term of this Agreement if the other Party is in
material breach of its obligations hereunder and has not cured such breach
within 90 days after written notice requesting cure of the breach; provided,
however, that (a) in the event of a good faith dispute with respect to the

 

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existence of such a material breach, the 90-day cure period will be stayed until
such time as the dispute is resolved pursuant to Section 12.6 hereof, (b) so
long as the breaching Party takes substantial steps to cure the breach promptly
after receiving notice of the breach from the nonbreaching Party and thereafter
diligently prosecutes the cure to completion as soon as is practicable, the
non-breaching Party may not terminate this Agreement, and (c) any license
granted under this Agreement may not be terminated for a material breach under
this Section 8.2 (except for an uncured failure to pay the undisputed portion of
milestones or royalties under Section 3) to the extent such license is necessary
to research, develop, make and have made, offer for sale, sell, import and
export a Product, so long as such Product (i) remains part of an Active Program
and satisfies the Bcl-x Milestones, if applicable, and (ii) has at least reached
the Initiation of Phase I Trial stage of development.

 

8.3                               Termination upon Bankruptcy; Rights in
Bankruptcy.

 

This Agreement may be terminated with written notice by either Party at any time
during the term of this Agreement upon the filing or institution of bankruptcy,
reorganization, liquidation or receivership proceedings by the other Party or
upon an assignment of a substantial portion of the assets for the benefit of
creditors by the other Party; provided, however, in the case of any involuntary
bankruptcy proceeding such right to terminate will only become effective if the
party consents to the involuntary bankruptcy or such proceeding is not dismissed
within 90 days of the filing thereof.

 

All rights and licenses granted under or pursuant to this Agreement by Isis or
Ercole are, and will otherwise be deemed to be, for purposes of
Section 365(n) of the U.S. Bankruptcy Code, licenses of right to “intellectual
property” as defined under Section 101 of the U.S. Bankruptcy Code. The Parties
agree that the Parties, as licensees of such rights under this Agreement, will
retain and may fully exercise all of their rights and elections under the U.S.
Bankruptcy Code. The Parties further agree that, in the event of the
commencement of a bankruptcy proceeding-by or against either Party under the
U.S. Bankruptcy Code, the Party hereto which is not a Party to such proceeding
will be entitled to a complete duplicate of (or complete access to, as
appropriate) any such intellectual property and all embodiments of such
intellectual property, and same, if not already in their possession, will be
promptly delivered to them (i) upon any such commencement of a bankruptcy
proceeding upon their written request therefor, unless the Party subject to such
proceeding elects to continue to perform all of its obligations under this
Agreement, or (ii) if not delivered under (i) above, following the rejection of
this Agreement by or on behalf of the Party subject to such proceeding upon
written request therefor by the non-subject Party.

 

8.4                               Accrued Rights and Surviving Obligations.

 

Expiration or termination of the Agreement will not relieve the Parties of any
obligation accruing prior to such expiration or termination, including, but not
limited to, obligations to pay royalties and/or milestones under Section 3.
Sections 3.6, 4.1, and 9.3, and Articles 5, 6, 7, 8, 10, 11, 12 and Exhibit 1
will survive expiration or termination of the Agreement. Provisions concerning
reporting requirements will continue in effect in accordance with any applicable
timetables set forth herein. Any expiration or early termination of this
Agreement will be without prejudice to the rights of either Party against the
other accrued or accruing under this Agreement prior to termination, including
the obligation to pay royalties for Products sold prior to such termination.

 

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The rights of any sublicensee under any permitted sublicense granted pursuant to
Section 2.3 or 2.4 will survive the termination of this Agreement.

 

ARTICLE 9

REPRESENTATIONS AND WARRANTIES; DISCLAIMER

 

9.1                               Representations and Warranties of the Parties.

 

Each Party represents and warrants to the other Party that, as of the date of
this Agreement:

 

(a)                                  Such Party is duly organized and validly
existing under the laws of the state of its incorporation and has full corporate
power and authority to enter into this Agreement and to carry out the provisions
hereof;

 

(b)                                 Such Party has taken all corporate action
necessary to authorize the execution and delivery of this Agreement and the
performance of its obligations under this Agreement;

 

(c)                                  This Agreement is a legal and valid
obligation of such Party, binding upon such Party and enforceable against such
Party in accordance with the terms of this Agreement. The execution, delivery
and performance of this Agreement by such Party does not conflict with any
agreement, instrument or understanding, oral or written, to which such Party is
a Party or by which such Party may be bound, and does not violate any law or
regulation of any court, governmental body or administrative or other agency
having authority over such Party. All consents, approvals and authorizations
from all governmental authorities or other Third Parties required to be obtained
by such Party in connection with this Agreement have been obtained;

 

(d)                                 Such Party has the full and exclusive right,
power and authority to enter into this Agreement, to perform its obligations
under this Agreement (including the Research Plan) and to grant the licenses
granted hereunder;

 

(e)                                  There are no agreements between such Party
and any Third Parties which would preclude or otherwise limit such Party’s
ability to conduct its tasks and obligations under the Research Plan or
otherwise fulfill its obligations under this Agreement; and

 

(f)                                    All individuals who will perform any
activities on such Party’s behalf in connection with the Research Plan have
assigned to such Party or its Affiliates the whole of their rights in any
intellectual property conceived or reduced to practice by them as a result of
either program.

 

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9.2                               Representations and Warranties of Ercole.

 

By adding an Ercole Exclusive Target to Exhibit 2, Ercole warrants and
represents that, to the best of its knowledge, the Ercole Exclusive Targets
listed on Exhibit 2 are not encumbered by any Third Party rights including,
without limitation, intellectual property rights, that would interfere with
Isis’ ability to carry out the activities contemplated by the Parties hereunder.
By adding an Ercole Exclusive Target to Exhibit 2, Ercole further warrants and
represents that, to the best of its knowledge, if Isis makes an Splicing
Modulator to any of the Ercole Exclusive Targets, it will not constitute an
infringement of any Third Party rights and that Ercole will indemnify Isis, as
set forth in Section 7.1 herein, should a subsequent determination be made that
Third Party rights were infringed.

 

9.3                               Disclaimers.

 

THE SPLICING MODULATORS BEING PROVIDED TO ERCOLE HEREUNDER ARE PROVIDED “AS IS”
AND WITHOUT ANY REPRESENTATION OR WARRANTY, EXPRESS OR IMPLIED, INCLUDING
WITHOUT LIMITATION ANY IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY
PARTICULAR PURPOSE OR ANY WARRANTY THAT THE USE OF THE MATERIALS WILL NOT
INFRINGE OR VIOLATE ANY PATENT OR OTHER PROPRIETARY RIGHTS OF ANY THIRD PARTY.

 

THE PARTIES EXPRESSLY DISCLAIM ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING
WITHOUT LIMITATION WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR
PURPOSE, OR NON-INFRINGEMENT OF THIRD PARTY RIGHTS, UNLESS OTHERWISE EXPRESSLY
PROVIDED IN THIS AGREEMENT.

 

ARTICLE 10

NOTICE

 

10.1                        Notice.

 

All notices which are required or permitted hereunder will be in writing and
sufficient if delivered personally, sent by facsimile (and promptly confirmed by
personal delivery, registered or certified mail or overnight courier), sent by
nationally-recognized overnight courier or sent by registered or certified mail,
postage prepaid, return receipt requested, addressed as follows:

 

if to Isis, to:

Isis Pharmaceuticals, Inc.

 

Carlsbad Research Center

 

2292 Faraday Avenue

 

Carlsbad, CA  92008

 

Attention:  Executive Vice President

 

Fax No.:  +1 (760) 931-9639

 

 

with a copy to:

Attention: General Counsel

 

Fax No.:  +1 (760) 268-4922

 

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if to Ercole, to:

107 Weslyn Trace Drive

 

Durham, NC 27703

 

Attention:  President

 

 

 

 

 

 

 

 

with a copy to:

Hutchison and Mason PLLC

 

3110 Edwards Mill road, Suite 100

 

Raleigh, NC 27612

 

Attn:  William N. Wofford

 

Fax No: 1 (919) 829 9696

 

or to such other address as the Party to whom notice is to be given may have
furnished to the other Party in writing in accordance herewith. Any such notice
will be deemed to have been given when delivered if personally delivered or sent
by facsimile on a business day, on the business day after dispatch if sent by
nationally-recognized overnight courier and on the third business day following
the date of mailing if sent by mail.

 

ARTICLE 11

RECORDS

 

11.1                        Records.

 

Each Party will maintain records, in sufficient detail and in good scientific
manner, which will fully and properly reflect all work done and results achieved
in the performance of its responsibilities under the Research Plan hereunder.
Each Party will have the right, during normal business hours and upon reasonable
prior notice, to inspect and copy those records of the other Party referred to
herein that are necessary or useful to the inspecting Party for the purposes of
making any required filings with Regulatory Authorities in order to obtain
manufacturing approvals and/or Marketing Approvals. Each Party will maintain
such records and the information disclosed therein in confidence in accordance
with Article 5.

 

ARTICLE 12

MISCELLANEOUS PROVISIONS

 

12.1                        Relationship of the Parties.

 

It is expressly agreed that Isis and Ercole will be independent contractors and
that the relationship between the two Parties will not constitute a partnership,
joint venture or agency. Neither Isis nor Ercole will have the authority to make
any statements, representations or commitments of any kind, or to take any
action, which will be binding on the other, without the prior consent of the
other Party.

 

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12.2                        Successors and Assigns.

 

Neither this Agreement nor any interest hereunder may be assigned or otherwise
transferred, nor, except as expressly provided hereunder, may any right or
obligations hereunder be assigned or transferred by either Party without the
prior written consent of the other Party; provided, however, that either Party
may, without such consent, assign the Agreement and its rights and obligations
hereunder to an Affiliate or in connection with the transfer or sale of all or
substantially all of its business to which this Agreement relates (whether by
sale of stock, sale of assets or merger). Any permitted assignee will assume all
obligations of its assignor under the Agreement, except that no intellectual
property of any Third Party acquirer of Ercole or Isis will be included in the
licenses granted hereunder. This Agreement will be binding upon the successors
and permitted assigns of the Parties. Any attempted assignment not in accordance
with this Section 12.2 will be void.

 

12.3                        Entire Agreement; Amendments.

 

This Agreement, the Loan Agreement and Warrant Agreement contain the entire
understanding of the Parties with respect to the license, development and
commercialization of Products hereunder. All express or implied agreements and
understandings, either oral or written, heretofore made by the Parties on the
same subject matter are expressly superseded by this Agreement. The Agreement
may be amended, or any term hereof modified, only by a written instrument duly
executed by both Parties hereto.

 

12.4                        Force Majeure.

 

Neither Party will be held liable or responsible to the other Party nor be
deemed to have defaulted under or breached the Agreement for failure or delay in
fulfilling or performing any term of the Agreement when such failure or delay is
caused by or results from causes beyond the reasonable control of the affected
Party including, without limitation, embargoes, acts of war (whether war be
declared or not), insurrections, riots, civil commotions, strikes, lockouts or
other labor disturbances, or acts of God. The affected Party will notify the
other Party of such force majeure circumstances as soon as reasonably practical
and will make every reasonable effort to mitigate the effects of such force
majeure circumstances.

 

12.5                        Applicable Law.

 

The Agreement will be governed by and construed in accordance with the laws of
the State of Delaware without reference to any rules of conflict of laws.

 

12.6                        Dispute Resolution.

 

(a)                                  The Parties recognize that disputes may
from time to time arise between the Parties during the term of this Agreement.
In the event of such a dispute, either Party, by written notice to the other
Party, may have such dispute referred to the Parties’ respective executive
officers designated below or their successors, for attempted resolution by good
faith negotiations within 30 days after such notice is received. Said designated
officers are as follows:

 

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For Isis:

Vice President

For Ercole:

COO

 

If the dispute is not resolved as provided above, the Executive Vice President
of Isis and the COO of Ercole will meet for attempted resolution by good faith
negotiations within 15 days after the expiration of the preceding 30 day period.

 

(b)                                 In the event the designated executive
officers are not able to resolve such dispute after such 30-day period, each
Party may pursue its rights and remedies in law or equity in any court of
competent jurisdiction.

 

12.7                        No Consequential Damages.

 

IN NO EVENT WILL EITHER PARTY OR ANY OF ITS RESPECTIVE AFFILIATES BE LIABLE TO
THE OTHER PARTY OR ANY OF ITS AFFILIATES FOR SPECIAL, INDIRECT, INCIDENTAL OR
CONSEQUENTIAL DAMAGES, WHETHER IN CONTRACT, WARRANTY, TORT, NEGLIGENCE, STRICT
LIABILITY OR OTHERWISE, INCLUDING, BUT NOT LIMITED TO, LOSS OF PROFITS OR
REVENUE, OR CLAIMS OF CUSTOMERS OF ANY OF THEM OR OTHER THIRD PARTIES FOR SUCH
OR OTHER DAMAGES.

 

12.8                        Captions.

 

The captions to the several Articles and Sections hereof are not a part of the
Agreement, but are merely a convenience to assist in locating and reading the
several Articles and Sections hereof.

 

12.9                        Waiver.

 

The waiver by either Party hereto of any right hereunder, or the failure to
perform, or a breach by the other Party will not be deemed a waiver of any other
right hereunder or of any other breach or failure by said other Party whether of
a similar nature or otherwise.

 

12.10                 Compliance With Law.

 

Nothing in this Agreement will be deemed to permit a Party to export, re-export
or otherwise transfer any Product sold under this Agreement without compliance
with applicable laws.

 

12.11                 Severability.

 

In the event any one or more of the provisions contained in this Agreement
should be held invalid, illegal or unenforceable in any respect, the validity,
legality and enforceability of the remaining provisions contained herein will
not in any way be affected or impaired thereby, unless the absence of the
invalidated provision(s) adversely affect the substantive rights of the Parties.
The Parties will in such an instance use their best efforts to replace the
invalid, illegal or unenforceable provision(s) with valid, legal and enforceable
provision(s) which, insofar as practical, maintains the balance of the rights
and obligations of the Parties under this Agreement.

 

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12.12                 Waiver of Rule of Construction.

 

Each Party has had the opportunity to consult with counsel in connection with
the review, drafting and negotiation of this Agreement. Accordingly, the rule of
construction that any ambiguity in this Agreement will be construed against the
drafting Party will not apply.

 

12.13                 Counterparts.

 

This Agreement may be executed in two or more counterparts, each of which will
be deemed an original, but all of which together will constitute one and the
same instrument.

 

IN WITNESS WHEREOF, the Parties have executed this Agreement as of the Effective
Date.

 

ERCOLE BIOTECH, INC.

 

ISIS PHARMACEUTICALS, INC.

 

 

 

 

 

 

By:

/s/ Athanasios Maroglou

 

By:

/s/ B. Lynne Parshall

Name: Athanasios Maroglou

 

Name: B. Lynne Parshall

Title: President

 

Title: Executive Vice President and CFO

 

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EXHIBIT 1

 

DEFINITIONS

 

1.1                              “Active Program” means with respect to a Gene
Target, an Ercole Exclusive Target or an Isis Exclusive Target, any reasonable
(as defined below) ongoing research, development, or commercialization
(including research, development or commercialization activities conducted by a
Third Party pursuant to a valid sublicense under this Agreement), of a Product
directed to such Gene Target.

 

For purposes of clarification, research, development and commercialization
efforts with respect to an Ercole Exclusive Target or an Isis Exclusive Target
or Product shall be deemed reasonable if the applicable Party’s research and
development efforts with respect to such Gene Target or Product are reasonably
comparable with other projects in such Party’s portfolio at a similar stage of
development and of similar market potential. Reasonable research, development
and commercialization efforts should include preclinical studies, human clinical
studies and development aimed at obtaining regulatory approval for marketing a
Product that modulates such Gene Target.

 

1.2                              “Affiliate” with respect to either Party means
any person, organization, corporation or other business entity (collectively,
“Person”) controlling, controlled by, or under common control with such Party.
For purposes of this definition, “control” refers to the possession, directly or
indirectly, of the power to direct the management or policies of a Person,
whether through the ownership of voting securities, by contract or otherwise, of
a Person.

 

1.3                              “Bcl-x” means the Gene Target bcl-x, also known
as _BCL2-like 1, BCL2L1, Locus Link ID = 598, Prototype Genebank Accesion number
NM_001191, Ensembl Gene ID ENSG BCL2L.

 

1.4                              “Bcl-x Milestones” means, with respect to an
Ercole Bcl-x Product that modulates Bel- x, (i) completing IND-Enabling Studies
by Ercole for such Product within 18 months of Ercole’s receipt of a Splicing
Modulator from Isis that modulated Bcl-x; (ii) filing an IND for such Product
within 6 months of completing the IND-Enabling Studies; (iii) Initiating Phase I
Trial for such Product within 12 months from filing the IND for such Product;
(iv) Initiation of Phase II Trials within 36 months from the filing of the IND
for such Product; (v) Initiation of Phase III Studies not later than 3 years
after the Initiation of Phase II Studies; (vi) filing of an NDA not later than
18 months after the successful completion of a Phase III Study; and (vii) the
use of commercially reasonable efforts by Ercole to bring each Ercole Bcl-x
Product to market and to maximize the commercial value of each such Product
worldwide.

 

If Ercole will not be able to meet a Bcl-x Milestone set forth above for
circumstances beyond Ercole’s control but has proceeded in good faith in its
development efforts, Ercole will be granted a 12-month extension on any of the
milestones identified above, provided that Ercole (i) gives Isis at least 3
months’ prior written notice that it is unlikely to achieve the relevant
milestone on the date specified above, and (ii) demonstrates to Isis that it has
made substantial progress in the development of the relevant Bcl-x Product and

 

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reasonably anticipates that it will achieve the relevant milestone within 12
months of the original deadline noted above.

 

1.5                              “Bcl-x Patents” means the Patents listed in
Exhibit 7.

 

1.6                              “Bcl-x Product” means an Ercole Exclusive
Product that modulates Bcl-x.

 

1.7                              “Calendar Quarter” means the respective periods
of 3 consecutive calendar months ending on March 31, June 30, September 30 and
December 31.

 

1.8                              “Calendar Year” means each successive period of
12 months commencing on January 1 and ending on December 31.

 

1.9                              “Collaboration Term” means the term of the
Research Plan as set forth in Section 1.1.

 

1.10                       “Confidential Information” means information which is
(a) of a confidential and proprietary nature; and (b) not readily available to
that Party’s competitors and which, if known by a competitor of that Party,
might lessen any competitive advantage of that Party or give such competitor a
competitive advantage.

 

For the purposes of this Agreement, “Confidential Information” includes, without
limitation, (a) information that is proprietary or confidential or which is
treated by that Party as confidential and which relates either directly or
indirectly to the business of that Party regardless of the form in which that
information is constituted, and which is not lawfully in the public domain; and
(b) any confidential information in relation to Patents, technology, know-how,
or any improvements owned or controlled by a Party hereto.

 

“Confidential Information” will not include any information that the receiving
Party can establish by written records:

 

(i)                                    was known by it prior to the receipt of
Confidential Information from the disclosing Party;

 

(ii)                                 was disclosed to the receiving Party by a
Third Party having the right to do so;

 

(iii)                              was, or subsequently became, in the public
domain through no fault of the receiving Party, its officers, directors,
employees or agents;

 

(iv)                             was concurrently or subsequently developed by
personnel of the receiving Party without having had access to the disclosing
Party’s Confidential Information;

 

(v)                                was disclosed with the prior written consent
of the disclosing Party; or

 

(vi)                             was disclosed by the receiving Party pursuant
to any judicial or governmental request, requirement or order.

 

1.11                       “Covered by a “Patent” means any process, method,
organism or part thereof, composition of matter, biological compound or part
thereof which when made,

 

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used, practiced or sold would, but for the applicable license granted pursuant
to this Agreement constitute an infringement of any valid claim, or claims, in
the referenced Patent.

 

1.12                       “EC Approval” means approval of a Product for
marketing in the European Union by the European Commission (“EC”) or, if a Party
seeks approval through mutual recognition therein, by the Ministry of Health of
the United Kingdom, France, Germany, Italy or Spain (each a “Major European
Country”), without the requirement for price having been approved. If a Product
can be sold in a Major European Country without EC or Ministry of Health
approval, EC Approval will be deemed to have been obtained on the first sale of
a Product in a Major European Country.

 

1.13                       “Ercole Exclusive Product” means a Splicing Modulator
that modulates an Ercole Exclusive Target. An Ercole Exclusive Product can
either be discovered and developed by Ercole or discovered and developed by Isis
on Ercole’s behalf under the Research Plan. In order for a Product to remain an
Ercole Exclusive Product, Ercole must perform on its own (or with Isis under the
Research Plan) and not with a Third Party at least 50% of the work to discover
and develop the Ercole Exclusive Product during the period from the point in
time at which the Ercole Exclusive Target has been designated through the
completion of IND-Enabling Studies.

 

1.14                       “Ercole Exclusive Target” has the meaning set forth
in Section 1.2.

 

1.15                       “Ercole Invention” has the meaning set forth in
Section 4.1(b).

 

1.16                       “Ercole Invention Patent” has the meaning set forth
in Section 4.1(b).

 

1.17                       “Ercole Nonexclusive Product” means a Splicing
Modulator discovered and developed by Ercole that modulates a Nonexclusive
Target.

 

1.18                       “Ercole Product” means an Ercole Exclusive Product
and an Ercole Nonexclusive Product.

 

1.19                       “Ercole Splicing Patents” means the Patents listed in
Exhibit 4.

 

1.20                       “Gene Target” means a transcriptional unit of a gene,
and any protein product of such transcriptional unit, including all splice
variants.

 

1.21                       “Gene Walk” has the meaning set forth in the Research
Plan.

 

1.22                       “IND” means an Investigational New Drug Application
or similar application or submission for approval to conduct human clinical
investigations filed with or submitted to a Regulatory Authority in conformity
with applicable Regulatory Authority regulations.

 

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1.23                        “IND-Enabling Studies” means, at a minimum, the
pharmacokinetic and toxicology studies required to meet the safety regulations
for filing an IND, as well as any additional studies required by a Regulatory
Authority as a prerequisite to filing an IND.

 

1.24                        “Initiation of Phase I Trial” means the dosing of
the first patient in the first human clinical trial conducted on normal
volunteers and designed to evaluate safety of a product.

 

1.25                        “Initiation of Phase II Trial” means the dosing of
the first patient in the first human clinical trial conducted in patients and
designed to indicate a statistically significant level of efficacy for a Product
in the desired indication, as well as to obtain some indication of the dosage
regimen required.

 

1.26                        “Initiation of Phase III Trial” means the dosing of
the first patient in the first human clinical trial conducted in patients and
designed to establish Product safety and efficacy and required to obtain
clinical registration of a product with health regulatory authorities such as
the FDA (a “Phase III Trial”).

 

1.27                        “Invention” has the meaning set forth in Section 4.1
herein.

 

1.28                        “Isis Exclusive Product” means a Splicing Modulator
discovered and developed by Isis that modulates an Isis Exclusive Target. In
order for a Product to remain an Isis Exclusive Product, Isis must perform on
its own and not with a Third Party at least 50% of the work to discover and
develop the Isis Exclusive Product during the period from the point in time at
which the Isis Exclusive Target has been selected through the completion of
IND-Enabling Studies.

 

1.29                        “Isis Exclusive Target” has the meaning set forth in
Section 1.2.

 

1.30                        “Isis Invention” has the meaning set forth in
Section 4.1(b).

 

1.31                        “Isis Invention Patent” has the meaning set forth in
Section 4.1(b).

 

1.32                        “Isis Patent Rights” means all rights in Patents
owned by Isis that are within the Isis Splicing Patents, the MOE Patents, the
PNA Patents and the Bcl-x Patents.

 

1.33                        “Isis Nonexclusive Product” means a Splicing
Modulator discovered and developed by Isis that modulates a Nonexclusive Target.

 

1.34                        “Isis Product” means an Isis Exclusive Product and
an Isis Nonexclusive Product.

 

1.35                        “Isis Splicing Patents” means the Patents listed in
Exhibit 5.

 

1.36                        “Jointly Owned Invention” has the meaning set forth
in Section 4.1(c).

 

1.37                        “Jointly Owned Invention Patent” has the meaning set
forth in Section 4.1(c).

 

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1.38                        “Japanese Approval” means the approval of a Product
for marketing in Japan by the Japanese Ministry of Health and Welfare (or any
future equivalent process), together with any other approval necessary to make
and sell Product commercially in Japan without the requirement for price having
been approved. If a Product can be sold in Japan without Ministry of Health and
Welfare approval, Japanese Approval will be deemed to have been obtained on the
first sale of a Product in Japan.

 

1.39                        “License Term” has the meaning set forth in
Section 2.1.

 

1.40                        “Major Market” means any one of the following
countries: the United States, Japan, the United Kingdom, France, Germany, Italy
or Spain.

 

1.41                        “Marketing Approval” means the act of a Regulatory
Authority necessary for the marketing and sale of the Product in a country or
regulatory jurisdiction, including, without limitation, the approval of the NDA
by the FDA, EC Approval, and Japanese Approval.

 

1.42                        “MOE Patents” means the Patents listed in Exhibit 6.

 

1.43                        “MOE Chemistry” means adding one or more
methoxy-ethoxy groups to the sugar moiety of one or more nucleosides in a
Splicing Modulator.

 

1.44                        “MOE Product” means an Ercole Exclusive Product that
is discovered and developed by Isis for Ercole pursuant to this Agreement that
incorporates the MOE Chemistry.

 

1.45                        “NDA” means New Drug Application or similar
application or submission for approval to market and sell a new pharmaceutical
product filed with or submitted to a Regulatory Authority in conformity with
applicable Regulatory Authority regulations.

 

1.46                        “Net Sales” means, with respect to a Product, the
gross amount received by Ercole or Isis, as appropriate, or by their Affiliates
or sublicensees, to unrelated Third Parties for the Product, less:

 

(a)                                 Trade, quantity and cash discounts allowed;

 

(b)                                 Commissions, discounts, refunds, rebates,
chargebacks, retroactive price adjustments, and any other allowances which
effectively reduce the net selling price;

 

(c)                                  Credits for actual Product returns;

 

(d)                                 Any tax imposed on the production, sale,
delivery or use of the Product, including, without limitation, sales, use,
excise or value added taxes;

 

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(e)                                  Allowance for distribution expenses at
levels customary in the industry; and

 

(f)                                   Any other similar and customary
deductions.

 

“Net Sales” excludes:

 

(i)                                     The transfer of reasonable and customary
quantities of free samples of Product(s) and the transfer of Product(s) as
clinical trial materials, other than for subsequent resale;

 

(ii)                                  Sales or transfers of Product(s) among
Ercole or Isis and their respective Affiliates, unless the receiving Party is
the consumer or user of the Product;

 

(iii)                               Use by Ercole or Isis or their respective
Affiliates or sublicensees of Product for any use connected with the securing of
regulatory approval or validating of a manufacturing process or the obtaining of
other necessary Marketing Approvals for Product (unless such Product is
subsequently sold); and

 

(iv)                              Royalties received by a Party or its
Affiliates from any Third Party with respect to Products.

 

Notwithstanding the foregoing, if (i) a Party enters an arms-length license
agreement with a Third Party with respect to a Product and (ii) the definition
of Net Sales is different in such license agreement than as described above,
then, the Parties will use the definition described in the third party license
for the calculation of royalties hereunder. The Parties acknowledge that the
“net sales” definition under the licenses to which Isis obtained the rights to
certain of the MOE Patents and certain of the PNA Patents is different than the
Net Sales definition above.

 

1.47                        “Nonexclusive Target” means a Gene Target that is
not an Isis Exclusive Target or an Ercole Exclusive Target.

 

1.48                        “Party” means either Ercole or Isis, as the case may
be and “Parties” means both Ercole and Isis.

 

1.49                        “Patent” or “Patents” means (a) patent applications
(including provisional applications); (b) any patents issuing from such patent
applications; (c) any continuations-in-part, but only to the extent that they
Cover the same invention claimed in the foregoing, (d) all patents and patent
applications worldwide based on, corresponding to, or claiming the priority
date(s) of any of the foregoing; (e) any reissues, substitutions, confirmations,
registrations, validations, re-examinations, additions, continuations, continued
prosecution applications, requests for continued examination, or divisions of or
to any of the foregoing; and

 

--------------------------------------------------------------------------------

 

(f) term extension or other governmental action which provide exclusive rights
to a Product beyond the original patent expiration date.

 

1.50                        “PNA Patents” means the Patents listed in Exhibit 8.

 

1.51                        “PNA Product” means an Ercole Exclusive Product,
which when made, used, practiced or sold would, but for the license granted
under Section 2.2(b)(v), infringe a claim in the PNA Patents.

 

1.52                        “Product” means an Ercole Product or an Isis
Product.

 

1.53                        “Regulatory Authority” means any applicable
government regulatory authority involved in granting approvals for the marketing
and/or pricing of a Product worldwide including, without limitation, the United
States Food and Drug Administration (“FDA”) and any successor government
authority having substantially the same function, and foreign equivalents
thereof.

 

1.54                        “Research Plan” is the Research Plan attached hereto
as Exhibit 3.

 

1.55                        “Splicing Modulator” means an oligonucleotide or
analog thereof that selectively modulates RNA Splicing or polyadenylation by a
non-Rnase dependent mechanism at the nucleic acid level by specifically binding
to the sequence of a selected messenger or viral ribonucleic acid (RNA) by
base-pairing, thus causing a selective pattern of gene expression.

 

1.56                        “Sponsored Invention” means any invention or other
discovery made by UNC and/or any of its employees or Affiliates (or any Third
Party under contract with UNC) pursuant to a research or collaboration agreement
sponsored by Ercole, and any Patents that may issue thereon.

 

1.57                        “Third Party” means any Party other than Isis or
Ercole and their respective Affiliates.

 

1.58                        “Third Party Intellectual Property” means any
intellectual property owned by a Third Party.

 

1.59                        “UNC” means the University of North Carolina at
Chapel Hill.

 

--------------------------------------------------------------------------------

 

Exhibit 2

 

Isis and Ercole Exclusive Targets

 

Isis Exclusive Targets

 

 

Ercole Exclusive Targets

 

Bcl-x

 

--------------------------------------------------------------------------------

 

 

Exhibit 3

 

Research Plan

 

*****

 

--------------------------------------------------------------------------------

 

Exhibit 4

 

Ercole Splicing Patents

 

US Patent No. 5,976,879 entitled “Antisense Oligonucleotides which combat
aberrant splicing and methods of using the same.”

 

US Patent No. 5,627,274 entitled “Antisense Oligonucleotides which combat
aberrant splicing and methods of using the same.”

 

US Patent No. 5,665,593 entitled “Antisense Oligonucleotides which combat
aberrant splicing and methods of using the same.”

 

US Patent No. 5,916,808 entitled “Antisense Oligonucleotides which combat
aberrant splicing and methods of using the same.”

 

--------------------------------------------------------------------------------

 

Exhibit 5

 

Isis Splicing Patents

 

US Patent No. 6,210,892 entitled “Alteration of Cellular Behavior by Antisense
Modulation of mRNA Processing.”

 

--------------------------------------------------------------------------------

 

Exhibit 6

 

MOE Patents

 

US Patent No. 5,969,116 entitled “Nucleosides and Oligonucleotides having 2’
ether groups.”

 

US Patent No. 5,914,396 entitled “2’-O-Modified Nucleosides and
Phosphoramidites.”

 

--------------------------------------------------------------------------------

 

Exhibit 7

 

Bcl-x Patents

 

Docket No.

 

Title

 

Country

 

Filing Date

 

Status

ISPH-0324

 

Antisense Modulation of Bcl-X Expression

 

United States

 

10/7/1998

 

ISSUED
6,172,216
1/9/2001

ISPH-0368

 

Antisense Modulation Of Bcl-X Expression

 

United States

 

6/2/1999

 

ISSUED
6,214,986
4/10/2001

ISPH-0410

 

Antisense Modulation of Bcl-X Expression

 

PCT

 

9/28/1999

 

Entered
National
Phase

ISPH-0552

 

Antisense Modulation of Bcl-X Expression

 

Australia

 

9/28/1999

 

Pending

ISPH-0553

 

Antisense Modulation of Bcl-X Expression

 

Canada

 

9/28/1999

 

Pending

ISPH-0554

 

Antisense Modulation of Bcl-X Expression

 

EPO

 

9/28/1999

 

Pending

ISPH-0555

 

Antisense Modulation of Bcl-X Expression

 

Japan

 

9/28/1999

 

Pending

ISPH-0556

 

Antisense Modulation of Bcl-X Expression

 

United States

 

4/3/2001

 

Pending

ISPH-0719

 

Antisense Modulation of Bcl-X Expression

 

United States

 

11/21/2002

 

Pending

 

--------------------------------------------------------------------------------

 

 

Exhibit 8

 

PNA Patents

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

ISIS-0516

 

PEPTIDE NUCLEIC ACIDS (PNA)

 

Buchardt
Egholm
Neilson
Berg

 

PCT

 

5/22/1992

 

Entered
National
Phase
11/24/1993

ISIS-0540

 

PEPTIDE NUCLEIC ACIDS, COMPOSITIONS THEREOF AND PROCESSES FOR USING THE SAME (as
amended)

 

Buchardt
Egholm
Neilson
Berg

 

US

 

11/22/1993

 

ISSUED
5/28/2002
6,395,474

ISIS-1017

 

NOVEL PEPTIDE NUCLEIC ACIDS

 

Neilson
Buchardt
Egholm
Berg

 

US

 

4/26/1993

 

ISSUED
7/23/1996
5,539,082

ISIS-1052

 

CLEAVING DOUBLE - STRANDED DNA WITH PEPTIDE NUCLEIC ACIDS

 

Ecker
Buchardt
Egholm
Nielsen
Berg
Mollegaard

 

US

 

07/02/1993

 

ISSUED
06/24/1997
5,641,625

ISIS-1108

 

DOUBLE-STRANDED PEPTIDE NUCLEIC ACIDS

 

Norden
Wittung
Buchardt
Egholm
Nielsen
Berg

 

US

 

07/02/1993

 

ISSUED
05/08/2001
6,228,982

ISIS-1122

 

PEPTIDE NUCLEIC ACID COMBINATORIAL LIBRARIES AND IMPROVED METHODS OF SYNTHESIS

 

Cook
Kiely
Sprankle

 

US

 

02/23/1994

 

ISSUED
07/23/1996
5,539,083

ISIS-1158

 

PEPTIDE NUCLEIC ACID CONJUGATES

 

Nielsen
Buchardt
Hoist
Lohse
Egholm
Manoharan

 

US

 

10/06/1994

 

Pending

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

 

 

 

 

Kiely
Griffith
Sprankle

 

 

 

 

 

 

ISIS-1236

 

PNA-DNA-PNA CHIMERIC MACROMOLEULES

 

Cook

 

US

 

11/24/1993

 

ISSUED
12/23/1997
5,700,922

ISIS-1422

 

NOVEL PEPTIDE NUCLEIC ACIDS

 

Buchardt
Egholm
Neilson
Berg

 

PCT

 

4/25/1994

 

Entered
National
Phase
10/26/1995

ISIS-1504

 

DOUBLE-STRANDED PEPTIDE NUCLEIC ACIDS

 

Buchardt
Egholm
Nielsen
Berg
Norden
Wittung

 

PCT

 

07/01/1994

 

Entered
National
Phase
12/11/1995

ISIS-1524

 

HIGHER ORDER STRUCTURE AND BINDING OF PEPTIDE NUCLEIC ACIDS

 

Ecker
Buchardt
Egholm
Nielsen
Berg
Mollegaard

 

PCT

 

06/28/1994

 

Entered
National
Phase
01/02/1996

ISIS-1577

 

NOVEL PEPTIDE NUCLEIC ACIDS

 

Egholm
Nielsen
Buchardt
Dueholm
Christensen
Coull
Kiely
Griffith

 

US

 

7/15/1994

 

ISSUED
9/17/2002

ISIS-1714

 

CHIRAL PEPTIDE NUCLEIC ACID MONOMERS AND OLIGOMERS

 

Nielsen
Buchardt
Lagriffoul

 

US

 

12/28/1994

 

ISSUED
11/02/1999
5,977,296

ISIS-1746

 

PNA-DNA-PNA CHIMERIC MACROMOLEULES

 

Cook

 

PCT

 

11/23/1994

 

Entered
National
Phase
5/24/1996

ISIS-1936

 

PNA COMBINATORIAL LIBRARIES AND IMPROVED METHODS OF SYNTHESIS

 

Cook
Kiely
Sprankle

 

PCT

 

02/22/1995

 

Entered
National
Phase
08/13/1996

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

ISIS-1958

 

PNA COMBINATORIAL LIBRARIES AND IMPROVED METHODS OF SYNTHESIS

 

Cook
Kiely
Sprankle

 

U.S.

 

08/13/1996

 

ISSUED
11/03/1998
5,831,014

ISIS-1993

 

PEPTIDE NUCLEIC ACIDS AND SYNTHETIC PROCEDURES THEREFOR

 

Buchardt
Egholm
Nielsen
Berg

 

US

 

6/5/1995

 

Pending

ISPS-1999

 

PEPTIDE NUCLEIC ACIDS (PNA)

 

Buchardt
Egholm
Neilson
Berg

 

US

 

6/6/1995

 

Pending

ISIS-2017

 

PEPTIDE NUCLEIC ACID COMBINATORIAL LIBRARIES AND IMPROVED METHODS OF SYNTHESIS

 

Cook
Kiely
Sprankle

 

U.S.

 

06/06/1995

 

Pending

ISIS-2018

 

COMPLEXES OF TWO PEPTIDE NUCLEIC ACID STRANDS AND ONE NUCLEIC ACID STRAND (as
amended)

 

Ecker
Buchardt
Egholm
Nielsen
Berg
Mollegaard

 

US

 

06/07/1995

 

ISSUED
11/16/1999
5,986,053

ISIS-2020

 

LINKED PEPTIDE NUCLEIC ACIDS

 

Egholm
Kiely
Griffith
Coull
Nielsen
Buchardt
Christensen
Dueholm

 

PCT

 

07/13/1995

 

Entered
National
Phase
01/15/1997

ISIS-2041

 

LINKED PEPTIDE NUCLEIC ACIDS

 

Egholm
Kiely
Griffith
Coull
Nielsen
Buchardt
Christensen

 

US

 

04/23/1997

 

ISSUED
8/27/2002
6,441,130

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

 

 

 

 

Dueholm

 

 

 

 

 

 

ISIS-2091

 

PEPTIDE NUCLEIC ACID CONJUGATES

 

Nielsen
Buchardt
Hoist
Lohse
Egholm
Manoharan
Kiely
Griffith
Sprankle

 

PCT

 

10/06/1995

 

Entered
National
Phase
04/06/1997

ISIS-2112

 

PEPTIDE NUCLEIC ACID CONJUGATES

 

Nielsen
Buchardt
Hoist
Lohse
Egholm
Manoharan
Kiely
Griffith
Sprankle

 

US

 

4/4/1997

 

Pending

ISIS-2113

 

NOVEL PEPTIDE NUCLEIC ACIDS

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

02/01/1996

 

ISSUED
6/30/1998
5,773,571

ISIS-2141

 

PEPTIDE NUCLEIC ACID COMBINATORIAL LIBRARIES

 

Cook
Kiely
Sprankle

 

U.S.

 

01/17/1996

 

ISSUED
01/26/1999
5,864,010

ISIS-2169

 

SUBSTITUTED NUCLEIC ACID MIMICS FOR TRIPLEX AVOIDANCE

 

Christensen
Hansen
Nielsen

 

US

 

03/08/1996

 

Pending

ISIS-2270

 

PEPTIDE NUCLEIC ACIDS HAVING AMINO ACID SIDE CHAINS

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

07/24/1996

 

ISSUED
02/17/1998
5,719,262

ISIS-2271

 

PEPTIDE NUCLEIC ACIDS HAVING ENHANCED BINDING AFFINITY, SEQUENCE SPECIFICITY AND
SOLUBILITY

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

07/24/1996

 

ISSUED
02/03/1998
5,714,331

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

ISIS-2272

 

PEPTIDE NUCLEIC ACIDS HAVING 2, 6-DIAMINOPURINE NUCLEOBASES

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

07/24/1996

 

ISSUED
07/02/2002
6,414,112

ISIS-2273

 

PEPTIDE NUCLEIC ACIDS HAVING ENHANCED BINDING AFFINITY AND SEQUENCE SPECIFICITY

 

Nielsen
Buchardt
Berg
Egholm
Nielsen
Haaima
Eldrup

 

US

 

07/24/1996

 

ISSUED
06/16/1998
5,766,855

ISIS-2418

 

PEPTIDE NUCLEIC ACID MONOMERS AND OLIGOMERS (as amended)

 

Nielsen
Haaima
Eldrup

 

US

 

05/23/1997

 

Pending

ISIS-2425

 

SUBSTITUTED NUCLEIC ACID MIMICS

 

Christensen
Hansen
Nielsen

 

PCT

 

03/07/1997

 

Entered
National
Phase
10/02/1998

ISIS-2447

 

SUBSTITUTED NUCLEIC ACID MIMICS

 

Christensen
Hansen
Nielsen

 

US

 

01/27/1999

 

Pending

ISIS-2451

 

CHIRAL PEPTIDE NUCLEIC ACIDS AND METHODS FOR PREPARING SAME

 

Teng

 

US

 

4/11/1997

 

ISSUED
1/18/2000
6,015,887

ISIS-2455

 

PEPTIDE NUCLEIC ACIDS HAVING AMINO ACID SIDE CHAINS

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

05/01/1997

 

ISSUED
07/28/1998
5,786,461

ISIS-2456

 

PEPTIDE NUCLEIC ACIDS HAVING ENHANCED BINDING AFFINITY, SEQUENCE SPECIFICITY AND
SOLUBILITY

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

05/01/1997

 

ISSUED
04/07/1998
5,736,336

ISIS-2508

 

PNA-DNA-PNA CHIMERIC MACROMOLEULES

 

Cook

 

US

 

6/17/1997

 

Pending

ISIS-2513

 

PEPTIDE NUCLEIC ACIDS HAVING

 

Nielsen
Buchardt

 

PCT

 

07/24/1997

 

Entered Nat’l
Phase

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

 

 

ENHANCED BINDING AFFINITY, SEQUENCE SPECIFICALLY AND SOLUBILITY

 

Berg
Egholm

 

 

 

 

 

01/20/1999

ISIS-2535

 

PEPTIDE NUCLEIC ACIDS HAVING 2, 6-DIAMINOPURINE NUCLEOBASES

 

Nielsen
Buchardt
Egholm
Berg

 

US

 

03/10/1999

 

Pending

ISIS-2918

 

CHIRAL PEPTIDE NUCLEIC ACIDS AND METHODS FOR PREPARING SAME

 

Teng

 

PCT

 

4/8/1998

 

Entered
National
Phase
10/11/1999

ISIS-3018

 

PEPTIDE NUCLEIC ACID MONOMERS AND OLIGOMERS

 

Nielsen
Haaima
Eldrup

 

PCT

 

05/22/1998

 

Entered
National
Phase
11/23/1999

ISIS-3044

 

PEPTIDE NUCLEIC ACID MONOMERS AND OLIGOMERS

 

Nielsen
Haaima
Eldrup

 

US

 

05/22/1998

 

Pending

ISIS-3045

 

CONJUGATED PEPTIDE NUCLEIC ACIDS HAVING ENHANCED CELLULAR UPTAKE

 

Nielsen
Knudsen

 

WO

 

05/28/1998

 

Entered
National
Phase
11/28/1999

ISIS-3070

 

CONJUGATED PEPTIDE NUCLEIC ACIDS HAVING ENHANCED CELLULAR UPTAKE

 

Nielsen

 

US

 

02/15/2000

 

Under Final
Rejection
10/17/2002

ISIS-3102

 

PNA-DNA-PNA CHIMERIC MACROMOLEULES

 

Cook

 

US

 

7/1/1998

 

ISSUED
8/21/2001
6,277,603

ISIS-3135

 

NOVEL PEPTIDE NUCLEIC ACIDS

 

Nielsen
Buchardt
Egholm
Berg

 

US

 

06/29/1998

 

Pending

ISIS-3155

 

PNA COMBINATORIAL LIBRARIES AND

 

Cook
Kiely
Sprankle

 

U.S.

 

08/07/1998

 

ISSUED
03/20/2001
6,204,326

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

 

 

IMPROVED METHODS OF SYNTHESIS

 

 

 

 

 

 

 

 

ISIS-3292

 

PEPTIDE NUCLEIC ACIDS HAVING ANTIBACTERIAL ACTIVITY

 

Nielsen Good

 

US

 

07/06/2000

 

Pending

ISIS-3303

 

PEPTIDE NUCLEIC ACID INCORPORATING A CHIRAL BACKBONE

 

Nielsen
Lagriffoul
Buchardt

 

US

 

12/10/1998

 

ISSUED
03/13/2001
6,201,103

ISIS-3314

 

HISTIDINE-CONTAINING PEPTIDE NUCLEIC ACIDS

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

01/04/1999

 

ISSUED
08/22/2000
6,107,470

ISIS-3809

 

PEPTIDE NUCLEIC ACIDS HAVING 2, 6-DIAMINOPURINE NUCLEOBASES

 

Buchardt
Nielsen
Egholm
Berg

 

US

 

06/21/1999

 

Pending

ISIS 4181

 

CONJUGATED PEPTIDE NUCLEIC ACIDS HAVING ENHANCED CELLULAR UPTAKE

 

Nielsen
Knudsen

 

US

 

09/23/1999

 

ISSUED
02/26/2002
6,350,853

ISIS-4290

 

HIGHER ORDER STRUCTURE AND BINDING OF PEPTIDE NUCLEIC ACIDS

 

Ecker
Buchardt
Egholm
Nielsen
Berg
Mollegaard

 

US

 

11/16/1999

 

Pending

ISIS-4399

 

MODULATION OF CELLULAR TRANSCRIPTION FACTOR ACTIVITY (as amended)

 

Norden
Wittung
Buchardt
Egholm
Nielsen
Berg

 

US

 

07/06/2000

 

Pending

ISIS-4800

 

PEPTIDE NUCLEIC ACIDS HAVING 2, 6-DIAMINOPURINE NUCLEOBASES

 

Nielsen
Buchardt
Berg
Egholm

 

US

 

09/18/2001

 

Published
10/10/2002

ISIS-4801

 

MODIFIED PEPTIDE NUCLEIC

 

Manoharan,
Rajeev

 

U.S.

 

05/24/2002

 

Pending

 

--------------------------------------------------------------------------------

 

Docket
No.

 

Title

 

Inventor

 

Country

 

Filing
Date

 

Status

 

 

ACIDS

 

 

 

 

 

 

 

 

ISIS-4946

 

CONJUGATED PEPTIDE NUCLEIC ACIDS HAVING ENHANCED CELLULAR UPTAKE

 

Nielsen
Knudsen

 

US

 

11/19/2001

 

Published
12/12/2002

ISIS-5042

 

LINKED PEPTIDE NUCLEIC ACIDS

 

Egholm
Nielsen
Buchardt
Dueholm
Christensen
Coull
Kiely
Griffith

 

US

 

07/01/2002

 

Pending

ISIS-5064

 

PEPTIDE NUCLEIC ACIDS (PNA)

 

Buchardt
Egholm
Nielsen
Berg

 

US

 

05/23/2002

 

Pending

ISIS-5065

 

MODIFIED PEPTIDE NUCLEIC ACIDS

 

Manoharan,
Rajeev

 

PCT

 

05/24/2002

 

Pending

 

--------------------------------------------------------------------------------