Document:

EXHIBIT 10.34

 

Summary
of Executive Salary and Bonus Arrangements

 

The table below summarizes the current annual salary
and bonus arrangements we have with each of our current executive officers. All
of the compensation arrangements we have with our executive officers, including
with respect to annual salaries and bonuses, are reviewed and may be modified
from time to time by the Compensation Committee of our Board of Directors. The
Compensation Committee approved the annual salary and bonus arrangements noted
in the table below.

 

We have written employment arrangements with each of
our executive officers, and a copy of each such employment arrangement is filed
as an exhibit to the accompanying Annual Report on Form 10-K. The
non-salary and bonus components of our compensation arrangements with our
executive officers, including with respect to severance, option grants and
other benefits, are described in those respective agreements. We generally pay
bonuses, if any, to our executive officers on a quarterly basis. Certain of our
executive officers participate in the executive bonus plan that was adopted by
the Compensation Committee on August 21, 2009, a description of which is
filed as Exhibit 10.3 to the Quarterly Report on Form 10-Q for the
quarterly period ended September 30, 2009, filed with the SEC on November 9,
2009. In addition to the bonus arrangements noted in the table below, all of
our executive officers are eligible for discretionary bonuses as determined
from time to time by the Compensation Committee.

 

Additional information regarding our compensation
arrangements with our executive officers will be included in our definitive
Proxy Statement to be filed in connection with our 2010 Annual Meeting of
Stockholders.

 

	
  Executive Officer

  	
   

  	
  Annual

  Base Salary

  	
   

  	
  Bonus

  	
   

  
	
  Frank F. Khulusi

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Chairman, President and Chief Executive Officer

  	
   

  	
  $

  	
  807,919

  	
   

  	
   

  	
  (1)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Brandon H. LaVerne

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Chief Financial Officer, Treasurer and Assistant
  Secretary

  	
   

  	
  $

  	
  279,413

  	
   

  	
   

  	
  (1)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Kristin M. Rogers

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Executive Vice President—Sales and Marketing

  	
   

  	
  $

  	
  339,414

  	
   

  	
   

  	
  (1)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Robert I. Newton

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Executive
  Vice President and General Counsel

  	
   

  	
  $

  	
  304,413

  	
   

  	
   

  	
  (2)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Daniel J. DeVries

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Executive Vice President—MacMall

  	
   

  	
  $

  	
  282,819

  	
   

  	
   

  	
  (1)

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Joseph B. Hayek

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Executive Vice President—Corporate Development and
  Investor Relations

  	
   

  	
  $

  	
  255,193

  	
   

  	
   

  	
  (3)

  

 

(1)  Mr. Khulusi,
Mr. LaVerne, Ms. Rogers and Mr. DeVries are eligible to
participate in our executive bonus plan referenced above.

(2)  Mr. Newton
is eligible to receive an annual bonus of up to $120,000, paid in quarterly
installments, as well as discretionary bonuses as determined from time to time
by the Compensation Committee.

(3)  Mr. Hayek
is eligible to receive an annual discretionary bonus in the initial targeted
annual amount of $50,000, which will be paid annually in accordance with a to
be established bonus plan or program.EXHIBIT 10.35

 

Summary
of Director Compensation Arrangements

 

We currently pay each director who is not employed by
us or any of our affiliates (i.e., all of our directors except for our
Chairman, Frank F. Khulusi) a quarterly retainer of $7,000, plus $2,500 for
each regular board meeting attended in person or telephonically, $1,000 for
each special board meeting attended in person or telephonically and $1,000 for
each committee meeting attended in person or telephonically. We also pay the
chairperson of the Audit Committee of our Board of Directors an additional
quarterly retainer of $3,125 and the chairperson of the Compensation Committee
of our Board of Directors an additional quarterly retainer of $1,250 for
serving in such capacities. Directors who are employed by us or any of our
affiliates are not paid any additional compensation for their service on our
Board of Directors. We reimburse each of our directors for reasonable
out-of-pocket expenses that they incur in connection with attending board or committee
meetings. We have entered into indemnification agreements, a form of which is
attached as an exhibit to the accompanying Annual Report on Form 10-K,
with each of our directors.

 

Our directors are also eligible to participate in our
1994 Stock Incentive Plan, as amended, which is administered by our
Compensation Committee under authority delegated by our Board of Directors. The
terms and conditions of option and stock bonus grants to our non-employee
directors under our 1994 Stock Incentive Plan, as amended, are determined in
the discretion of our Compensation Committee, and must be consistent with the
terms of the 1994 Stock Incentive Plan, as amended, which is filed as an
exhibit to the accompanying Annual Report on Form 10-K.

 

The compensation arrangements we have with our
directors are reviewed and may be modified from time to time by our Board of
Directors.

 

Additional information regarding our compensation
arrangements with our directors will be included in our definitive Proxy
Statement to be filed in connection with our 2010 Annual Meeting of
Stockholders.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.

 

 

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:

 

 

(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 

 

 

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.

 

 

(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 

 

 

(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.

 

 

 

(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 

 

 

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 

 

 

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:

 

 

	
  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 

 

 

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 

 

 

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.

 

 

(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 

 

 

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.

 

 

 

(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 

 

 

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 

 

 

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.

 

 

(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.

 

 

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, 

 

 

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 

 

 

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 

 

 

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.

 

 

 

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.

 

 

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

  

 

 

	
  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.

 

 

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:

 

 

	
  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.

 

 

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

  
					

 

 

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 

 

 

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, 

 

 

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.

 

 

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).

 

 

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;

 

 

(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

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00170-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00170-of-00352.parquet"}], [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00170-of-00352.parquet"}]]