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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549



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FORM 10-K/A

(Amendment No. 1)



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|x | ANNUAL REPORT PURSUANT TO SECTION 13 or 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
|- | ------------------------------------------------------------------------------------



For the fiscal year ended December 31, 2003



OR



| ̈ | TRANSITION REPORT PURSUANT TO SECTION 13 or 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
|- | ----------------------------------------------------------------------------------------



For the transition period from              to



Commission File Number 0-23223



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CURAGEN CORPORATION

(Exact name of registrant as specified in its charter)



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|                                                               |  |                                     
|-------------------------------------------------------------- |  | ------------------------------------
|Delaware                                                       |  | 06-1331400                          
|(State or other jurisdiction of incorporation or organization) |  | (I.R.S. Employer Identification No.)



|                                                         |  |           
|-------------------------------------------------------- |  | ----------
|555 Long Wharf Drive, 11th Floor, New Haven, Connecticut |  | 06511     
|(Address of principal executive offices)                 |  | (Zip Code)



Registrants
telephone number, including area code: (203) 401-3330



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Securities registered pursuant to Section 12(b) of the Act: None



Securities registered pursuant to Section 12(g) of the Act:

Common Stock, $0.01 par value

Preferred Stock Purchase Rights

(Title of Class)



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Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was
required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.    Yes  x    No ̈



Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of the registrants knowledge, in definitive proxy
or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ̈



Indicate by check mark whether the registrant is an accelerated filer (as
defined in Rule 12b-2 of the Act).    Yes  x    No ̈



The aggregate market value of common stock held by
non-affiliates of the registrant (without admitting that any person whose shares are not included in determining such value is an affiliate) computed by reference to the average bid and asked price of the common stock, as of the last business day of
the registrants most recently completed second fiscal quarter, was $235,673,966.



The number of shares outstanding of the registrants common stock as of March 1, 2004 was 49,951,600.



Documents Incorporated by Reference



The registrant intends to file a definitive proxy statement pursuant to Regulation 14A within 120 days of the end of the fiscal year ended December 31,
2003. Portions of such proxy statement are incorporated by reference into Part III of this report.



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EXPLANATORY NOTE



The purpose of this amendment is to amend and restate in its entirety Item 7 of our Form 10-K for the fiscal year ended
December 31, 2003 entitled Managements Discussion and Analysis of Financial Condition and Results of Operations in response to comments received from the Securities and Exchange Commission. This amendment to our Form 10-K does not
reflect events occurring after the filing of our original Form 10-K or modify or update those disclosures affected by subsequent events. No other modifications or changes have been made to our Form 10-K as originally filed or the exhibits filed
therewith.



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Item 7.Managements Discussion and Analysis of Financial Condition and Results of
Operations



Overview



We are a genomics-based pharmaceutical development company dedicated to
improving the lives of patients by developing novel protein, antibody and small molecule therapeutics in the areas of oncology, inflammatory diseases, obesity and diabetes, and central nervous system disorders. Our pipeline of therapeutics is based
on targets from the human genome that we believe play a role in important mechanisms underlying disease.



We have taken a systematic approach to identifying and validating the most promising therapeutic targets from the human genome that are both applicable
and amenable to drug development. We use internal resources to develop our protein therapeutics and have established development alliances with Abgenix, Inc. (Abgenix) to support our antibody projects and Bayer AG (Bayer) to
support small molecule projects.



As our pipeline has matured
over the past few years, we have decreased our early-stage target discovery efforts and focused our resources on the advancement of our pipeline of protein, antibody and small molecule therapeutics into clinical development. In 2003, we received
U.S. Food and Drug Administration (FDA) clearance to conduct Phase I clinical trials for CG53135, a potential protein therapeutic for the treatment of oral mucositis in cancer patients that are undergoing chemotherapy and radiotherapy.
CR002, which is the most advanced fully-human monoclonal antibody stemming from our collaboration with Abgenix, is currently in preclinical development and we anticipate filing an investigational new drug application (IND) for, and
initiating clinical trials of, CR002 in the near future. CR002 is a novel fully-human monoclonal antibody with the potential to treat a form of kidney inflammation that if left untreated could progress to kidney failure. In addition to CG53135 and
CR002, we have over 15 potential protein, antibody and small molecule therapeutics currently being evaluated in animal studies or being prepared for animal studies. Many of the INDs that we anticipate filing in the future will be identified from
these programs.



To enable us to focus on our pipeline, we
announced the formation of 454 Life Sciences Corporation (454) in June 2000. This majority-owned subsidiary is developing novel nanoscale instrumentation and technologies for rapidly and comprehensively determining the nucleotide
sequence  whole genome sequencing  of entire genomes. 454s proprietary technology is expected to have widespread applications in industrial processes, agriculture, animal health, biodefense, human health care, including
drug discovery and development, and disease diagnosis. Currently, 454 is focusing on the analysis of viruses and bacteria and anticipates that it will begin scaling its technology to analyze bacteria, fungi, larger model organisms, human DNA, and
other genomic applications during 2004. 454 plans to sell both genomic analysis services and complete genomic analysis systems, including instrumentation, reagents and software to end-users.



We expect to generate value for our shareholders by focusing our resources on
developing genomics-based therapeutics to improve the lives of patients. We expect to become profitable by commercializing a subset of therapeutics stemming from our development pipeline, and establishing partnerships with pharmaceutical and
biotechnology companies for the co-development and co-commercialization of other therapeutics from our development pipeline. Our failure to successfully develop pharmaceutical products that we can commercialize would materially adversely affect our
business, financial condition and results of operations. Royalties or other revenue generated from commercial sales of products developed through the application of our technologies and expertise are not expected for several years, if at all. We
expect that our revenue or income sources for at least the next several years may be limited to: interest income; payments under various collaboration agreements to the extent milestones are met; royalty payments from collaborators under existing or
future arrangements (to the extent that we enter into any future arrangements); and 454 service and product revenue (which is expected in 2004, as 454s technology is commercialized and its applications across the life sciences industry become
accepted).



We expect to continue to incur substantial expenses
relating to our research and development efforts, as we focus on preclinical and clinical trials required for the development of therapeutic protein, antibody and small molecule product candidates, and as 454 focuses on the continued development and
commercialization of its technology for whole genome analysis. Conducting clinical trials is a lengthy, time-consuming and expensive process. Before obtaining regulatory approvals for the commercial sale of any product, we must demonstrate through
various studies that a product is both effective and safe for use in humans. We will incur substantial expenses for, and devote a significant amount of time to, these studies. As a result, we expect to incur continued and increasing losses over the
next several years, unless we are able to realize additional revenues under existing or new collaboration agreements or through 454s sales of genomic analysis services and/or complete genomic analysis systems. The timing and amounts of such
revenues, if any, cannot be predicted with certainty and may fluctuate. Results of operations for any period may be unrelated to the results of operations for any other period. In addition, historical results should not be viewed as indicative of
future operating results.



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The 2002 and 2001 consolidated financial statements have been reclassified to conform to the
classifications used in 2003. All dollar amounts in tabular presentations are shown in thousands, unless otherwise noted.



Critical Accounting Policies and Use of Estimates



The discussion and analysis of our financial condition and results of operations are based upon our consolidated financial statements, which have been
prepared in accordance with accounting principles generally accepted in the United States of America. The preparation of these consolidated financial statements requires us to make estimates and judgments that affect the reported amount of assets
and liabilities, revenues and expenses and as such, actual results may differ from our estimates under different assumptions or conditions.



While our significant accounting policies are more fully described in Note 1 to our consolidated financial statements, we believe the following to be our
critical accounting policies and uses of estimates:



Research and development expenses. Research and development costs have been our most significant costs to date and primarily include personnel costs, supplies and reagents, clinical trial related costs such as contractual
services and manufacturing costs, depreciation of lab equipment and allocated facility costs. Such costs are charged to research and development expenses as incurred unless recoverable under contract. Our research and development expenses also
include accruals for clinical trial related costs such as contractual services and current manufacturing costs. At each period end, we estimate the costs incurred to date but not yet invoiced, and we analyze the progress of these services based upon
information received from the supplier when evaluating the adequacy of the accrued liabilities. Significant judgments and estimates must be used in determining the related accruals in any accounting period. Actual results could differ significantly
from our estimates under different assumptions.



Revenue
recognition. We have entered into certain collaborative research agreements that provide for the partial or complete funding of specified projects in exchange for access to, and certain rights in, the data discovered under the related
projects. Collaboration revenue is recognized based upon defined metrics of completion that include percentage of completion milestones, and project specific initiatives as defined in each of the respective research plans. The defined metrics are
reviewed internally each month to determine the work performed, whether deliverables have been accepted by the collaborator and the appropriate revenue to be recognized. We have also entered into a collaborative research exchange agreement in which
services and technology access are exchanged between the collaborative partner and us. Collaboration revenues and expenses under this exchange agreement include the fair value of the work performed by each collaborative partner. Deferred revenue
arising from payments received from collaborative research agreements is recognized as income when earned.



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Results of Operations



The following table sets forth a comparison of the components of our net loss for the years ended December 31, 2003 and 2002 (in millions):



|                                     |  |      |      |      |   |          |  |   |          |   |  |     |   
|------------------------------------ |  | ---- | ---- | ---- | - | -------- |  | - | -------- | - |  | --- | --
|                                     |  | 2003 |      | 2002 |   | $ Change |  |   | % Change |  
|Collaboration revenue                |  | $    | 6.9  |      | $ | 18.2     |  | $ | (11.3    | ) |  | (62 | )%
|Research and development expenses    |  |      | 64.5 |      |   | 81.6     |  |   | (17.1    | ) |  | (21 | )%
|General and administrative expenses  |  |      | 19.2 |      |   | 22.9     |  |   | (3.7     | ) |  | (17 | )%
|Restructuring and related charges    |  |      | 2.9  |      |   | 11.0     |  |   | (8.1     | ) |  | (74 | )%
|Interest income                      |  |      | 8.9  |      |   | 11.7     |  |   | (2.8     | ) |  | (24 | )%
|Interest expense                     |  |      | 9.8  |      |   | 10.2     |  |   | (0.4     | ) |  | (4  | )%
|Income tax benefit                   |  |      | 0.4  |      |   | 1.5      |  |   | (1.1     | ) |  | (73 | )%
|Minority interest in subsidiary loss |  |      | 5.7  |      |   | 3.9      |  |   | 1.8      |   |  | 47  | % 
|Net loss                             |  |      | 74.5 |      |   | 90.4     |  |   | (15.9    | ) |  | (18 | )%



Collaboration
revenue. The decrease in collaboration revenue for the year ended December 31, 2003 was primarily a result of a decline in revenue recognized from the Abgenix strategic alliance. Also reflected in the decrease was the on-going change in our
business strategy, which is to establish strategic research and development alliances with companies for the co-development and co-commercialization of therapeutics from our development pipeline, rather than focusing on short-term revenue generating
service-based collaborations. In addition, during 2002 the setup phase of the Bayer alliance was completed and we received a related milestone payment, resulting in a transition to the production phase of that alliance. We expect that 2004
collaboration revenue will remain fairly constant as compared to 2003, reflecting continued progress of the Bayer alliance and various other collaborations, as well as the inclusion of nominal revenues expected from the commercialization of
454s new technology.



Research and development expenses.



The following table sets forth a comparison of research and
development expenses by segment, for the years ended December 31, 2003 and 2002 (in millions):



|                                   |  |      |      |      |   |          |  |       |          |  |     |   
|---------------------------------- |  | ---- | ---- | ---- | - | -------- |  | ----- | -------- |  | --- | --
|                                   |  | 2003 |      | 2002 |   | $ Change |  |       | % Change | 
|Research and development expenses: |  |      |      |      |   |          |  |       |          |  |     |   
|CuraGen                            |  | $    | 52.6 |      | $ | 73.3     |  | (20.7 | )        |  | (28 | )%
|454                                |  |      | 11.9 |      |   | 8.3      |  | 3.6   |          |  | 43  | % 
|                                   |  |      |      |      |   |          |  |       |          |  |     |   
|Total                              |  | $    | 64.5 |      | $ | 81.6     |  |       |          |  |     |   
|                                   |  |      |      |      |   |          |  |       |          |  |     |   



Research and
development expenses consist primarily of salary and benefits, supplies and reagents, contractual services, and facility costs. Our research and development efforts are concentrated on four major project areas: collaborations; preclinical drug
candidates; clinical trials; and our majority-owned subsidiary, 454. With the exception of 454, we budget and monitor our research and development costs by expense category, rather than by project, because these costs often benefit multiple projects
and/or our technology platform. However, once we receive FDA clearance to conduct a Phase I clinical trial for a therapeutic, we begin to track the direct research and development costs associated with that clinical candidate. As of December 31,
2003, we had incurred approximately $6.2 million of direct research and development expenses related to our initial clinical candidate, CG53135, for which we received FDA clearance to commence a Phase I clinical trial for oral mucositis in March
2003. Below is a summary that reconciles our total research and development expenses for the years ended December 31, 2003 and 2002 into the major categories mentioned above (in millions):



|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   
|--------------------------------------- |  | ---- | ---- | ---- | - | -------- |  | - | -------- | - |  | --- | --
|                                        |  | 2003 |      | 2002 |   | $ Change |  |   | % Change |  
|Salary and benefits                     |  | $    | 24.6 |      | $ | 31.3     |  | $ | (6.7     | ) |  | (21 | )%
|Supplies and reagents                   |  |      | 12.5 |      |   | 15.1     |  |   | (2.6     | ) |  | (17 | )%
|Contractual services                    |  |      | 12.6 |      |   | 19.2     |  |   | (6.6     | ) |  | (34 | )%
|Depreciation and amortization           |  |      | 5.5  |      |   | 5.9      |  |   | (0.4     | ) |  | (7  | )%
|Overhead                                |  |      | 9.3  |      |   | 10.1     |  |   | (0.8     | ) |  | (8  | )%
|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   
|Total research and development expenses |  | $    | 64.5 |      | $ | 81.6     |  |   |          |   |  |     |   
|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   



The decrease in
research and development expenses for the year ended December 31, 2003 was primarily due to implementation of corporate restructuring plans in late 2002 and mid 2003, intended to reduce overall costs and focus resources on prioritizing, selecting
and advancing our most promising product candidates. We anticipate that research and development expenses, particularly in connection with our preclinical and clinical candidates, will



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increase approximately 5% in 2004 over the 2003 amounts, as we continue to advance our pipeline of protein, antibody, and
small molecule therapeutics, and as expenses increase in preparation for, and in connection with, the expected commercialization of 454s technology.



Currently, our potential pharmaceutical products require significant research and development efforts and preclinical testing, and will require extensive
clinical trials prior to submitting an application to regulatory agencies for their commercial use. Although we are conducting human studies with respect to CG53135, we may not be successful in developing or commercializing CG53135 or other
products. Our product candidates are subject to the risks of failure inherent in the development and commercialization of pharmaceutical products and we cannot currently reliably estimate when, if ever, our product candidates will generate revenue
and cash flows.



Completion of research and
development, preclinical testing and clinical trials may take many years. Estimates of completion periods for any of our major research and development projects are highly speculative and variable, depending on the nature of the disease indication,
how common it is among the general populace, and the results of the research. For example, preclinical testing and clinical trials can often go on for an indeterminate period of time since the results of tests are continually monitored, with each
test considered complete only when sufficient data has been accumulated to assess whether the next phases are warranted or whether the effort should be abandoned. Typically, Phase I clinical trials are expected to last between 12 and 24
months, Phase II clinical trials are expected to last between 24 and 36 months and Phase III clinical trials are expected to last between 24 and 60 months. The most significant time and costs associated with clinical development are the Phase III
trials as they tend to be the longest and most comprehensive studies conducted during the drug development process.



In addition, many factors may delay the commencement and speed of completion of preclinical testing and clinical trials, including the number of patients
participating in the trial, the duration of patient follow-up required, the number of clinical sites at which the trials are conducted, and the length of time required to locate and enroll suitable patient subjects. The successful completion of our
development programs and the successful development of our product candidates are highly uncertain and are subject to numerous challenges and risks. Therefore, we cannot presently estimate anticipated completion dates for any of our projects. See
also Risks Related to Our Business.



Due to the
variability in the length of time necessary to develop a product candidate, the uncertainties related to the cost of projects and our ability to obtain governmental approval for commercialization, accurate and meaningful estimates of the ultimate
costs to bring our product candidates to market are not available. If our major research and development projects are delayed, then we can expect to incur additional costs in conducting our preclinical testing and clinical trials and a longer period
of time before we become profitable from our operating activities, as described more fully in the Risk Factors section under the headings We have a history of operating losses and expect to incur losses in the future and We may
need to raise additional funding, which may not be available on favorable terms, if at all. Accordingly, the timing of the potential market approvals for our existing product candidate, CG53135, and future product development candidates, may
have a significant impact on our capital requirements.



General and administrative expenses. General and administrative expenses for the year ended December 31, 2003 decreased primarily due to the implementation of corporate restructuring plans. Additionally, lower intellectual
property expenses are indicative of the shift in our focus from early-stage discovery efforts to the advancement of our therapeutic development efforts. General and administrative expenses are expected to increase slightly in 2004.



Restructuring and related charges. Restructuring and related
charges of approximately $2.9 million were incurred in the second quarter of 2003 as a part of our June 2003 corporate restructuring plan which was intended to focus resources on continuing to advance our pipeline of therapeutics into preclinical
and clinical development. In connection with the 2003 restructuring plan, we incurred $1.8 million related to employee separation costs, $1.0 million of operating lease obligations and $0.1 million of asset impairment costs. The employee separation
costs were recorded under Statement of Financial Accounting Standards No. 146, Accounting for Costs Associated with Exit or Disposal Activities (SFAS 146) and included amounts to be paid for severance and related benefits,
the services for which had been performed in full as of the end of 2003. The cash requirements under the June 2003 restructuring plan were $2.7 million, of which $1.4 million were paid prior to December 31, 2003. The remaining cash requirements of
$1.3 million will be paid through the end of 2008. The components of our 2002 restructuring charges are set forth on page 16.



Interest income. Interest income for the year ended December 31, 2003 decreased primarily due to lower yields in our investment portfolio
and a decrease in cash and investment balances during 2003. We earned an average yield of 2.3% in 2003 as compared to 2.7% in 2002. During 2004, we anticipate that interest income will increase as compared to 2003, as a result of the receipt of net
proceeds of approximately $97.0 million from our 4% convertible subordinated notes due 2011, which we issued on February 17, 2004, offset by the utilization of cash and



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investment balances in the normal course of operations. In 2004, we expect the yields in our investment portfolio to be
consistent with 2003. However, in the event that in 2004 we use a portion of the net proceeds of the debt offering due 2011 to repay our existing debt due 2007, our anticipation of an increase in interest income for 2004 will differ accordingly.



Interest expense. We expect a significant
increase in interest expense during 2004, attributable to interest to be paid semi-annually to the holders of our $100.0 million of 4% convertible subordinated notes due 2011, which we issued on February 17, 2004.



Income tax benefit. For the year ended December 31, 2003, the
income tax benefit decrease was a result of the decline in various expenses which qualified for the annual research and development credit as a result of the corporate restructuring plan, primarily personnel costs, supplies and reagents, and
intellectual property expenses. We recorded the income tax benefit as a result of Connecticut legislation, which allowed companies to obtain cash refunds from the State of Connecticut at a rate of 65% of their annual research and development expense
credit, in exchange for forgoing the credit carryforward. In addition, due to 454s focus on revenues to be realized in the short term, 454 elected not to request a cash refund for 2003, but instead elected to continue to carry forward the
credit.



Minority interest in subsidiary loss.
Minority interest in subsidiary loss for the year ended December 31, 2003 (which is the portion of 454s loss attributable to shareholders of 454 other than us) increased primarily due to 454s additional efforts to advance its technology.
During 2004, losses attributed to the minority ownership in 454 are expected to remain fairly constant as compared to 2003, as 454 continues to make progress towards commercializing and developing new technologies.



The following table sets forth a comparison of the components of our net loss for the
years ended December 31, 2002 and 2001 (in millions):



|                                     |  |      |      |      |   |          |  |   |          |   |  |     |   
|------------------------------------ |  | ---- | ---- | ---- | - | -------- |  | - | -------- | - |  | --- | --
|                                     |  | 2002 |      | 2001 |   | $ Change |  |   | % Change |  
|Collaboration revenue                |  | $    | 18.2 |      | $ | 23.5     |  | $ | (5.3     | ) |  | (23 | )%
|Research and development expenses    |  |      | 81.6 |      |   | 65.9     |  |   | 15.7     |   |  | 24  | % 
|General and administrative expenses  |  |      | 22.9 |      |   | 18.8     |  |   | 4.1      |   |  | 22  | % 
|Restructuring and related charges    |  |      | 11.0 |      |   |         |  |   | 11.0     |   |  | N/A |   
|Interest income                      |  |      | 11.7 |      |   | 23.8     |  |   | (12.1    | ) |  | (51 | )%
|Interest expense                     |  |      | 10.2 |      |   | 10.6     |  |   | (0.4     | ) |  | (4  | )%
|Income tax benefit                   |  |      | 1.5  |      |   | 3.6      |  |   | (2.1     | ) |  | (58 | )%
|Minority interest in subsidiary loss |  |      | 3.9  |      |   | 1.5      |  |   | 2.4      |   |  | 160 | % 
|Net loss                             |  |      | 90.4 |      |   | 42.9     |  |   | 47.5     |   |  | 110 | % 



Collaboration
revenue. The decrease in collaboration revenue for the year ended December 31, 2002 reflected a change in our business strategy which is to establish strategic research and development alliances with companies for the co-development and
co-commercialization of therapeutics from our development pipeline, rather than focusing on short-term revenue generating service-based collaborations. The decline in collaboration revenue can also be attributed to the completion in 2001 of various
short-term service-based collaborations including GlaxoSmithKline, Inc. and Millennium Pharmaceuticals, Inc. (formerly COR Therapeutics, Inc.). The decrease in collaboration revenue was also a result of the progression of the Bayer alliance during
2002 from the set-up phase to the production phase, offset by additional revenue recognized from the Abgenix strategic alliance.



Research and development expenses.



The following table sets forth a comparison of research and development expenses by segment, for the years ended December 31, 2002 and 2001 (in millions):



|                                   |  |      |      |      |   |          |  |          |  |     |  
|---------------------------------- |  | ---- | ---- | ---- | - | -------- |  | -------- |  | --- | -
|                                   |  | 2002 |      | 2001 |   | $ Change |  | % Change | 
|Research and development expenses: |  |      |      |      |   |          |  |          |  |     |  
|CuraGen                            |  | $    | 73.3 |      | $ | 62.3     |  | 11.0     |  | 18  | %
|454                                |  |      | 8.3  |      |   | 3.6      |  | 4.7      |  | 131 | %
|                                   |  |      |      |      |   |          |  |          |  |     |  
|Total                              |  | $    | 81.6 |      | $ | 65.9     |  |          |  |     |  
|                                   |  |      |      |      |   |          |  |          |  |     |  



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Research and development expenses consisted primarily of salary and benefits, supplies and reagents,
contractual services, and facility costs. We budget and monitor our research and development costs by type or category, and below is a summary that reconciles our total research and development expenses for the years ended December 31, 2002 and 2001
into the major categories mentioned above (in millions):



|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   
|--------------------------------------- |  | ---- | ---- | ---- | - | -------- |  | - | -------- | - |  | --- | --
|                                        |  | 2002 |      | 2001 |   | $ Change |  |   | % Change |  
|Salary and benefits                     |  | $    | 31.3 |      | $ | 24.5     |  | $ | 6.8      |   |  | 28  | % 
|Supplies and reagents                   |  |      | 15.1 |      |   | 17.2     |  |   | (2.1     | ) |  | (12 | )%
|Contractual services                    |  |      | 19.2 |      |   | 13.0     |  |   | 6.2      |   |  | 48  | % 
|Depreciation and amortization           |  |      | 5.9  |      |   | 4.7      |  |   | 1.2      |   |  | 26  | % 
|Overhead                                |  |      | 10.1 |      |   | 6.5      |  |   | 3.6      |   |  | 55  | % 
|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   
|Total research and development expenses |  | $    | 81.6 |      | $ | 65.9     |  |   |          |   |  |     |   
|                                        |  |      |      |      |   |          |  |   |          |   |  |     |   



The increase in
research and development expenses for the year ended December 31, 2002 was primarily attributable to increased internal research efforts and our obligations to fulfill research requirements under existing collaborations and strategic alliances,
which included payments for contractual services, increased equipment depreciation expense and additional personnel costs.



General and administrative expenses. General and administrative expenses for the year ended December 31, 2002 increased primarily due to
legal expenses in support of the development of our intellectual property portfolio and additional personnel costs.



Restructuring and related charges. Restructuring and related charges of approximately $11.0 million were incurred in 2002 as a part of our
restructuring plan which was intended to reduce costs and focus resources on prioritizing, selecting and rapidly advancing our most promising drug candidates. In connection with this restructuring plan, we incurred $1.8 million related to employee
separation costs and $1.1 million of asset impairment costs related to equipment no longer in service. The employee separation costs were recorded under SFAS 146 and included amounts to be paid for severance and related benefits, the services for
which had been performed in full as of the end of 2002. The cash requirements under the restructuring plan were $1.9 million, of which $1.2 million were paid prior to December 31, 2002, and the remaining cash requirements of $0.7 million were paid
by the end of 2003.



Also included in restructuring and related
charges was an asset impairment of $8.1 million, consisting of costs previously incurred in conjunction with the planned construction of a campus facility, including a new corporate headquarters and protein production facility in Branford,
Connecticut. Plans to construct these facilities have been deferred indefinitely, pending improvements in the external financing environment, which would afford us the ability to finance the future construction costs.



Interest income. Interest income for the year ended December
31, 2002 decreased primarily due to lower yields in our investment portfolio and a decrease in cash and investment balances during 2002. We earned an average yield of 2.7% in 2002 as compared to 4.0% in 2001.



Minority interest in subsidiary loss. Minority interest in
subsidiary loss for the year ended December 31, 2002 (which is the portion of 454s loss attributable to shareholders of 454 other than us) increased primarily due to 454s additional personnel costs, increased purchases of laboratory
supplies, increased equipment depreciation expense and payments for consulting and contractual services as a result of the continued development of their technology platform.



Liquidity and Capital Resources



Since our inception, we have financed our operations and met our capital expenditure requirements primarily through public equity offerings, private
placements of equity securities, convertible subordinated debt offerings, revenues received under our collaborative research agreements and government grants, capital leases and exercises of stock options. As of December 31, 2003, we had recognized
$106.0 million of cumulative sponsored research revenues from collaborative research agreements and government grants. At December 31, 2003, our gross investment in lab and office equipment, computers, land and leasehold improvements was $47.4
million, and equipment with a gross book value of $2.3 million secured our capital lease facilities. Since inception, we have not had any off-balance sheet arrangements. To date, inflation has not had a material effect on our business.



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Cash and investments. The following table depicts the components of our operating,
investing and financing activities for the year ended December 31, 2003, using the direct cash flow method (in millions):



|                                                                               |  |   |       |  
|------------------------------------------------------------------------------ |  | - | ----- | -
|Cash received from collaborators                                               |  | $ | 7.3   |  
|Cash paid to suppliers and employees                                           |  |   | (69.9 | )
|Restructuring and related charges paid                                         |  |   | (2.1  | )
|Interest income received                                                       |  |   | 8.9   |  
|Interest expense paid                                                          |  |   | (9.1  | )
|Income tax benefit received                                                    |  |   | 2.7   |  
|                                                                               |  |   |       |  
|Net cash and investments used in operating activities                          |  |   | (62.2 | )
|                                                                               |  |   |       |  
|Cash paid to acquire property and equipment, net of sales proceeds             |  |   | (6.9  | )
|Cash paid to acquire intangible assets                                         |  |   | (3.6  | )
|                                                                               |  |   |       |  
|Net cash and investments used in investing activities                          |  |   | (10.5 | )
|                                                                               |  |   |       |  
|Cash paid for principal portion of capital leases                              |  |   | (1.6  | )
|Cash received from outside investors, net of stock issuance costs              |  |   | 3.5   |  
|Cash received from employee stock option exercises and restricted stock grants |  |   | 1.4   |  
|                                                                               |  |   |       |  
|Net cash and investments provided by financing activities                      |  |   | 3.3   |  
|                                                                               |  |   |       |  
|Unrealized loss on marketable securities                                       |  |   | (1.8  | )
|                                                                               |  |   |       |  
|Net decrease in cash and investments                                           |  |   | (71.2 | )
|Cash and investments, beginning of period                                      |  |   | 414.8 |  
|                                                                               |  |   |       |  
|Cash and investments, end of period                                            |  | $ | 343.6 |  
|                                                                               |  |   |       |  



The decrease in cash
and investments for 2003 was primarily a result of additional operating losses in support of our research and development activities and acquisitions of additional property and equipment and intangible assets, offset by proceeds received in
454s equity financing from several existing minority shareholders.



In accordance with our investment policy, we are utilizing the following investment objectives for cash and investments: (1) investment decisions are made with the expectation of minimum risk of principal loss, even
with a modest penalty in yield; (2) appropriate cash balances and related short-term funds are maintained for immediate liquidity needs, and appropriate liquidity is available for medium-term cash needs; and (3) maximum after-tax yield is achieved.



Future Liquidity



Sources of Liquidity. During 2004, we expect to continue to fund our
operations through a combination of the following sources: cash and investment balances; interest income; collaboration revenue; and potential public securities offerings and/or private strategic-driven common stock offerings.



Uses of Liquidity. Throughout 2004, we plan to continue making
substantial investments in our emerging preclinical and clinical drug pipeline. In that regard, we foresee the following as significant uses of liquidity: personnel costs; supplies and reagents; clinical trial related costs such as contractual
services and manufacturing costs; interest expense related to payments made to the holders of our convertible subordinated debt issued in February 2000 and February 2004; and capital expenditures. These costs will be incurred primarily in connection
with the following preclinical and clinical efforts: ongoing clinical trial costs and anticipated Phase II manufacturing costs on our protein therapeutic CG53135 in the area of oral mucositis; costs related to our manufacturing agreement with
Abgenix for CR002; toxicology costs to support our planned submission of an IND for CR002; preclinical and clinical costs in connection with the use of our protein therapeutic CG53135 to treat alternative clinical indications; and legal expenses in
support of the continued protection of our intellectual property portfolio. We anticipate that we will also incur significant capital expenditures in 2004, primarily for the expansion of our existing protein production laboratory facilities, in
addition to the purchase of equipment and leasehold improvements at both our and 454s research facilities and administrative offices.



9



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Contractual Obligations



The following table represents our consolidated contractual obligations as of December 31, 2003:



|                                                  |  |                                      |         |      |   |        |  |      |        |      |   |        |  |            |         |  |   |     |  |   |   
|------------------------------------------------- |  | ------------------------------------ | ------- | ---- | - | ------ |  | ---- | ------ | ---- | - | ------ |  | ---------- | ------- |  | - | --- |  | - | --
|                                                  |  | Payments Due Year Ended December 31,
|                                                  |  | Total                                |         | 2004 |   | 2005   |  | 2006 |        | 2007 |   | 2008   |  | Thereafter
|Long-term debt obligations (1) (5)                |  | $                                    | 150,000 |      | $ |       |  | $    |       |      | $ |       |  | $          | 150,000 |  | $ |    |  | $ |  
|Interest on convertible subordinated debt (1) (5) |  |                                      | 31,500  |      |   | 9,000  |  |      | 9,000  |      |   | 9,000  |  |            | 4,500   |  |   |    |  |   |  
|Capital leases (2)                                |  |                                      | 208     |      |   | 208    |  |      |       |      |   |       |  |            |        |  |   |    |  |   |  
|Operating leases (2)                              |  |                                      | 7,340   |      |   | 2,236  |  |      | 1,949  |      |   | 1,586  |  |            | 1,221   |  |   | 300 |  |   | 48
|Purchase commitments (3)                          |  |                                      | 3,581   |      |   | 3,581  |  |      |       |      |   |       |  |            |        |  |   |    |  |   |  
|Other long-term liabilities (4)                   |  |                                      | 1,500   |      |   |       |  |      | 500    |      |   | 500    |  |            | 500     |  |   |    |  |   |  
|                                                  |  |                                      |         |      |   |        |  |      |        |      |   |        |  |            |         |  |   |     |  |   |   
|Total                                             |  | $                                    | 194,129 |      | $ | 15,025 |  | $    | 11,449 |      | $ | 11,086 |  | $          | 156,221 |  | $ | 300 |  | $ | 48
|                                                  |  |                                      |         |      |   |        |  |      |        |      |   |        |  |            |         |  |   |     |  |   |   

---

|(1) | Refer to Note 7 and Note 13 to our consolidated financial statements for additional discussion.
|--- | -----------------------------------------------------------------------------------------------

|(2) | Refer to Note 3 to our consolidated financial statements for additional discussion.
|--- | -----------------------------------------------------------------------------------

|(3) | Includes commitments for capital expenditures and contractual services, but excludes amounts included on our balance sheet as liabilities and certain purchase obligations as
discussed below.
|--- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

|(4) | Refer to Note 11 to our consolidated financial statements for additional discussion.
|--- | ------------------------------------------------------------------------------------

|(5) | On February 17, 2004, we completed an offering of $100.0 million of 4% convertible subordinated notes due 2011 and received net proceeds of approximately $97.0 million. In February
2004, we also repurchased $20.0 million of our existing 6% convertible subordinated debentures due 2007. We will pay cash interest of $2.0 million on the notes on February 15 and August 15 of each year, beginning on August 15, 2004. Refer to Note 13
to our consolidated financial statements for additional discussion.
|--- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------



The expected timing of payment of the obligations discussed above is estimated based on current information. Timing of payments and actual amounts paid may be different depending on the time of receipt of goods or
services or changes to agreed-upon amounts for some obligations.



Purchase obligations for supplies and reagents are not included in the table above, as our purchase orders typically represent authorizations to purchase rather than binding agreements. For the purposes of this table, contractual
obligations for purchase of goods or services are defined as agreements that are enforceable and legally binding on us and that specify all significant terms, including: fixed or minimum quantities to be purchased; fixed, minimum or variable price
provisions; and the approximate timing of the transaction. Our purchase orders are based on our current operating needs and are fulfilled by our vendors within short time periods. We do not have significant agreements for the purchase of supplies
and reagents specifying minimum quantities or set prices. Additionally, we have entered into agreements for contractual services primarily relating to the manufacturing costs of our protein therapeutic CG53135, and our fully-human monoclonal
antibody CR002, and have included these amounts in purchase commitments above.



On February 17, 2004, we completed an offering for $100.0 million of 4% convertible subordinated notes due February 15, 2011, and received net proceeds of approximately $97.0 million. Depending on market and other
conditions, from time to time, we may repurchase a portion of the existing notes in open market purchases, in privately negotiated transactions, or otherwise. In addition, we also may use net proceeds for working capital, general corporate purposes
and potentially for future acquisitions of complementary businesses or technologies. The amounts and timing of our actual expenditures will depend upon numerous factors, including the amount and extent of our acquisitions, our product development
activities, our investments in technology and the amount of cash generated by our operations. Actual expenditures may vary substantially from our estimates. Our failure to use such funds effectively could have a material adverse effect on our
business, results of operations and financial condition. In February 2004, we repurchased $20.0 million of our 6% convertible subordinated debentures due 2007, for total consideration of $20.0 million, plus accrued interest of $0.05 million to the
date of repurchase.



We believe that our existing cash and
investment balances and other sources of liquidity will be sufficient to meet our requirements for the next twenty-four months. Our operating and capital expenditures are considered to be crucial to our future success, and by continuing to make
strategic investments in our preclinical and clinical drug pipeline, we believe that we are building substantial value for our shareholders. The adequacy of our available funds to meet our future operating and capital requirements, including the
repayment of our remaining $130.0 million of 6% convertible subordinated debentures due February 2, 2007 and our $100.0 million of 4% convertible subordinated notes due February 15, 2011, will depend on many factors. These factors include: the
number, breadth and progress of our research, product development and clinical programs; the costs and timing of obtaining regulatory approvals for any of our products; potential future acquisitions of complementary businesses or technologies;
in-licensing of pharmaceutical products; and costs incurred in enforcing and defending our patent claims and other intellectual property rights.



10



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While we will continue to explore alternative sources for financing our business activities, including
the possibility of public securities offerings and/or private strategic-driven common stock offerings, we cannot be certain that in the future these sources of liquidity will be available when needed or that our actual cash requirements will not be
greater than anticipated. In appropriate strategic situations, we may seek financial assistance from other sources, including contributions by others to joint ventures and other collaborative or licensing arrangements for the development and testing
of products under development. However, should we be unable to obtain future financing either through the methods described above or through other means, we may be unable to meet the critical objective of our long-term business plan, which is to
successfully develop and market pharmaceutical products.



We
received federal grants during 1999 and earlier years, for specific purposes that are subject to review and audit by the grantor agencies. Such audits could lead to requests for reimbursement by the grantor agency for any expenditures disallowed
under the terms of the grant. Additionally, any noncompliance with the terms of the grant could lead to loss of current or future awards.



During 1995 to 1998, we also received two grants from Connecticut Innovations, Inc. (CII) in the amounts of $0.5 million and $0.2 million. The
term of the $0.5 million grant is January 4, 1995 to December 31, 2004, and the term of the $0.2 million grant is February 1, 1995 to January 31, 2005. We could be required to repay 100% of these amounts if during the terms of the respective grants
(i) we breach and fail to cure a material covenant, (ii) a we fail to cure any of our material representations or warranties that become untrue, (iii) we become bankrupt or insolvent or liquidate our assets, or (iv) we are required to repay the
federal grants to which the CII grants relate. In addition, we could be required to repay up to 200% of the amounts of the CII grants if we cease to have a Connecticut presence, during the terms of the respective grants.



Income Taxes



For income tax purposes, we do not file consolidated income tax returns with 454. We and 454 have tax net operating loss
carryforwards available to reduce future federal and Connecticut taxable income and research and development tax credit carryforwards available to offset future federal and Connecticut income taxes as detailed below. Utilization of the net operating
loss and tax credit carryforwards may be limited due to changes within each companys ownership, as defined within Section 382 of the Internal Revenue Code.



|                                                  |  |         |         |           |              |             |   |           |  |             
|------------------------------------------------- |  | ------- | ------- | --------- | ------------ | ----------- | - | --------- |  | ------------
|Net Operating Loss Carryforwards                  |  | Federal |         | Expire In |              | Connecticut |   | Expire In
|CuraGen                                           |  | $       | 321,603 |           | 2007 to 2023 |             | $ | 286,604   |  | 2004 to 2023
|454                                               |  | $       | 28,517  |           | 2020 to 2023 |             | $ | 28,203    |  | 2020 to 2023
|                                                  |  |         |         |          
|Research and Development Tax Credit
Carryforwards |  | Federal |         | Expire In |              | Connecticut |   | Expire In
|CuraGen                                           |  | $       | 12,619  |           | 2008 to 2023 |             | $ | 9,737     |  | 2013 to 2018
|454                                               |  | $       | 1,146   |           | 2020 to 2023 |             | $ | 1,219     |  | 2016 to 2018



Minority Interest in Subsidiary



As of December 31, 2003, minority interest in
subsidiary was $8.2 million. Minority interest in subsidiary is related to 454 and reflects the minority shareholders capitalization, less a gain recognition of $3.9 million as a result of our contribution of technology to 454 in 2000, and
less the minority shareholders portion of losses incurred to date. The loss attributed to the minority ownership in 454 is expected to remain fairly constant during 2004, as 454 continues to make progress towards commercializing and developing
new technologies.



Recently Enacted Pronouncements



In January 2003, the Financial Accounting Standards Board (FASB)
issued FASB Interpretation (FIN) No. 46, Consolidation of Variable Interest Entitiesan Interpretation of Accounting Research Bulletin No. 51. FIN No. 46 clarifies rules for consolidation of special purpose entities. The
provisions of FIN No. 46 became effective for financial statements issued after January 31, 2003 and the adoption of FIN No. 46 did not have a material effect on our financial statements. In December 2003, the FASB issued FIN No. 46(R) which
clarifies rules for consolidation of special purpose entities. We have evaluated the provisions of this interpretation, and we do not believe it will have an impact on our financial statements.



11



---

In April 2003, the FASB issued Statement of Financial Accounting Standards No. 149, Amendment of
Statement 133 on Derivative Instruments and Hedging Activities, (SFAS 149) which amends and clarifies financial accounting and reporting for derivative instruments, including certain derivative instruments embedded in other
contracts (collectively referred to as derivatives) and for hedging activities under FASB Statement No. 133, Accounting for Derivative Instruments and Hedging Activities. The provisions of SFAS 149 are effective for financial statements
issued after June 30, 2003, and the adoption of SFAS 149 did not have a material effect on our financial statements.



In May 2003, the FASB issued Statement of Financial Accounting Standards No. 150, Accounting for Certain Financial Instruments with Characteristics
of Both Liabilities and Equity (SFAS 150) which requires that an issuer classify a financial instrument that is within its scope as a liability, or an asset in some circumstances, where those instruments were previously classified
as equity. The provisions of SFAS 150 are effective for financial statements issued after May 15, 2003, and the adoption of SFAS 150 did not have a material effect on our financial statements.



In December 2003, the FASB issued Statement of Financial Accounting Standards
No. 132R (SFAS 132R), Employers Disclosures about Pensions and Other Post-retirement Benefits. SFAS 132R amends the disclosure requirements of SFAS 132 to require additional disclosures about assets, obligations, cash
flow and net periodic benefit cost. The statement was effective in 2003 and did not have an impact on our financial statements.



12



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RISK FACTORS



Risks Related to Our Business



Because our business strategy is still largely untested, we do not know whether we will be able to commercialize any of our products or to what extent we will
generate revenue or become profitable.



We do not know
whether we can implement our business strategy successfully because we are in the early stages of development. Initially, we set out to find as many genes and their related functions as possible and are now using that information to develop our own
therapeutic products. This strategy is largely untested. Other companies first target particular diseases and try to find cures for them, have a limited number of genes and proteins of potential therapeutic interest, or rely on other more proven
strategies. If our strategy does not result in the development of products that we can commercialize, we will be unable to generate revenue. We have not completed development of any product based on our genomics research. Although our first
potential product has entered clinical trials, we cannot be certain that this or any future products will receive marketing approval. If we are unable to commercialize products, we may not be able to recover our investment in our product development
efforts.



Because clinical trials for our products will be expensive and
protracted and their outcome is uncertain, we must invest substantial amounts of time and money that may not yield viable products.



Conducting clinical trials is a lengthy, time-consuming and expensive process. Before obtaining regulatory approvals for the commercial sale of any
product, we must demonstrate through laboratory, animal and human studies that such product is both effective and safe for use in humans. We will incur substantial expense for, and devote a significant amount of time to, these studies.



Completion of clinical trials may take many years. The length of time
required varies substantially according to the type, complexity, novelty and intended use of the product candidate. The FDA monitors the progress of each phase of testing, and may require the modification, suspension, or termination of a trial if it
is determined to present excessive risks to patients. Our rate of commencement and completion of clinical trials may be delayed by many factors, including:



| |  | our inability to manufacture sufficient quantities of materials for use in clinical trials;
| | - | -------------------------------------------------------------------------------------------



| |  | variability in the number and types of patients available for each study, as well as the difficulty in enrolling patients in each study;
| | - | ----------------------------------------------------------------------------------------------------------------------------------------



| |  | difficulty in maintaining contact with patients after treatment, resulting in incomplete data;
| | - | ----------------------------------------------------------------------------------------------



| |  | unforeseen safety issues or side effects;
| | - | -----------------------------------------



| |  | poor or unanticipated effectiveness of products during the clinical trials;
| | - | ---------------------------------------------------------------------------



| |  | institutional review board delays at institutions assisting us with our clinical trials; and
| | - | --------------------------------------------------------------------------------------------



| |  | government or regulatory delays.
| | - | --------------------------------



Studies that we conduct, or studies which third parties conduct on our behalf, may not demonstrate sufficient effectiveness and safety to obtain the
requisite regulatory approvals for these or any other potential products. Regulatory authorities may not permit us to undertake any additional clinical trials. The clinical trial process may be accompanied by substantial delay and expense and there
can be no assurance that the data generated in these studies ultimately will be sufficient for marketing approval by the FDA.



We have only one product in clinical development and our other products are in preclinical development. None of these products may demonstrate sufficient
effectiveness or safety to obtain the requisite regulatory approvals required for initiation or continuation of clinical studies or obtaining marketing approval.



13



---

Because we have limited experience in developing, commercializing and marketing products, we may be unsuccessful in
our efforts to do so.



Currently, we are developing
several potential pharmaceutical products, and such products will require significant research and development and preclinical testing, and will require extensive clinical testing prior to our submitting any regulatory application for their
commercial use. Although we are conducting human studies with respect to one product, we have limited experience with these activities and may not be successful in developing or commercializing these or other products. These activities, if
undertaken without the collaboration of others, will require the expenditure of significant funds. Such potential pharmaceutical products will be subject to the risks of failure inherent in the development of pharmaceutical products based on new
technologies. Before we can commercialize a product, we must rigorously test the product in the laboratory and complete extensive human studies. Even if we complete such studies, our ability to develop and commercialize products will depend on our
ability to:



| |  | complete laboratory testing and human studies;
| | - | ----------------------------------------------



| |  | obtain and maintain necessary intellectual property rights to our products;
| | - | ---------------------------------------------------------------------------



| |  | obtain and maintain necessary regulatory approvals related to the efficacy and safety of our products;
| | - | ------------------------------------------------------------------------------------------------------



| |  | enter into arrangements with third parties to manufacture our products on our behalf; and
| | - | -----------------------------------------------------------------------------------------



| |  | deploy sales and marketing resources effectively or enter into arrangements with third parties to provide these functions.
| | - | --------------------------------------------------------------------------------------------------------------------------



As a result of these possibilities, we may not be able to develop through our
research and development activities any commercially viable products. We cannot be certain that expenses for testing and study will yield profitable products or even products approved for marketing by the FDA. If we are not successful in identifying
products that we can develop commercially, we may be unable to recover the large investment we have made in research, development and manufacturing. In addition, should we choose to develop pharmaceutical products internally, we will have to make
significant investments in pharmaceutical product development, marketing, sales and regulatory compliance resources, and we will have to establish or contract for the manufacture of products under the current good manufacturing practices
(cGMPs) of the FDA. Any potential products developed by our licensees will be subject to the same risks.



We do not have any marketed products. If we develop products that can be marketed, we intend to market the products either independently or together with
collaborators or strategic partners. If we decide to market any products independently, we will incur significant additional expenditures and commit significant additional management resources to establish a sales force. For any products that we
market together with partners, we will rely, in whole or in part, on the marketing capabilities of those parties. We may also contract with third parties to market certain of our products. Ultimately, we and our partners may not be successful in
marketing our products.



We depend on a limited number of suppliers and
depend on them to manufacture and supply critical components of our development and clinical programs.



Currently, we contract with third-party manufacturers or develop products with partners and use the partners manufacturing capabilities. As we use
others to manufacture our products, we depend on those parties to comply with cGMPs, and other regulatory requirements and to deliver materials on a timely basis. These parties may not perform adequately. Any failures by these third parties may
delay our development of products or the submission of these products for regulatory approval.



We depend on third-party research organizations to design and conduct our laboratory testing and human studies. If we are unable to obtain any necessary testing services on acceptable terms, we may not complete our
product development efforts in a timely manner. As we rely on third parties for laboratory testing and human studies, we may lose some control over these activities and become too dependent upon these parties. These third parties may not complete
testing activities on schedule or when we request.



Because neither we nor
any of our collaborative partners have received marketing approval for any product resulting from our research and development efforts, and may never be able to obtain any such approval, we may not be able to generate any product revenue.



All the products being developed by our collaborative
partners also will require additional research and development, extensive preclinical studies and clinical trials and regulatory approval prior to any commercial sales.



14



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In some cases, the length of time that it takes for our collaborative partners to achieve various regulatory approval
milestones may affect the payments that we are eligible to receive under our collaboration agreements. We and our collaborative partners may need to address a number of technical challenges successfully in order to complete development of our
products. Moreover, these products may not be effective in treating any disease or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining regulatory approval or prevent or limit
commercial use.



We may be unable to manufacture or obtain sufficient
quantities of our products and ensure their proper performance and quality.



Biopharmaceuticals must be produced under the cGMPs of the FDA. We do not have facilities capable of manufacturing drug products under cGMPs and must outsource any such production. We are devoting resources to
establishing our own manufacturing capabilities to support development and preclinical activities and are contracting with third-party vendors for the manufacture of materials for use in humans. We may be unable to contract successfully for cGMPs
manufacture of any products and may be unable to obtain required quantities of our products economically. We may not be able to obtain capacity to produce a sufficient amount of commercial product to meet our commercial and clinical development
needs. Failure to meet the demand for product may adversely affect our ability to continue to market the product.



Compliance with government regulation is critical to our business and failure to satisfy regulatory requirements could impair our business.



Prior to the marketing of any new drug developed by us, or by our
collaborators, that new drug must undergo an extensive regulatory review process in the United States and other countries. This regulatory process, which includes preclinical and clinical studies, as well as post-marketing surveillance to establish
a compounds safety and efficacy, can take many years and require the expenditure of substantial resources. Data obtained from such studies are susceptible to varying interpretations that could delay, limit or prevent regulatory approval. Even
if the FDA approves our products, we will still need to obtain institutional review board approval, which may involve additional delays. The rate of completion of clinical trials depends upon, among other factors, the enrollment of patients. Patient
enrollment is a function of many factors, including:



| |  | timing and restriction of institutional review board approval;
| | - | --------------------------------------------------------------



| |  | the size of the patient population;
| | - | -----------------------------------



| |  | proximity of patients to clinical sites;
| | - | ----------------------------------------



| |  | eligibility criteria for the study;
| | - | -----------------------------------



| |  | time commitment of a patient to the study; and
| | - | ----------------------------------------------



| |  | existence of competitive clinical trials.
| | - | -----------------------------------------



We have not had any of our product candidates receive approval for commercialization in the United States or elsewhere. Neither we nor our collaborators
may be able to conduct clinical testing or obtain the necessary approvals from the FDA or other regulatory authorities for any products. Failure by us or our collaborators to obtain required governmental approvals will delay or preclude our
collaborators or us from marketing drugs developed with us or limit the commercial use of such products and could have a material adverse effect on our business, financial condition and results of operations. Even where a product is exempted from
FDA clearance or approval, the FDA may impose restrictions as to the types of customers to which we can market and sell our products. Such restrictions may materially and adversely affect our business, financial condition and results of operations.



In addition, the FDA may condition marketing approval on the
conduct of specific post-marketing studies to further evaluate safety and efficacy. Rigorous and extensive FDA regulation of pharmaceutical products continues after approval, particularly with respect to compliance with cGMPs reporting of adverse
effects, advertising, promotion and marketing. Discovery of previously unknown problems or failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the
market as well as possible civil or criminal sanctions, any of which could materially adversely affect our business.



We must obtain regulatory approval by governmental agencies in other countries prior to commercialization of our products in those countries. Foreign
regulatory systems may be just as rigorous, costly and uncertain as in the United States.



15



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We rely significantly on our collaborative partners, and our business could be harmed if we are unable to maintain
strategic alliances.



As part of our business strategy, we
have strategic research and development alliances with companies to gain access to specific technologies. These alliances with other pharmaceutical and biotechnology companies may provide us with access to unique technologies, access to capital,
near-term revenues, milestone and/or royalty payments, and potential profit sharing arrangements. In return, we provide access to unique technologies, expertise in genomics, and information on the molecular basis of disease, drug targets, and drug
candidates. To date, we have entered into significant strategic alliances with Abgenix and Bayer, in addition to numerous smaller agreements to facilitate these efforts. In these strategic alliances, either party can terminate the agreement at any
time the alliance permits them to or if either party materially breaches the contract. We may not be able to maintain or expand existing alliances or establish any additional alliances. If any of our existing collaborators were to breach, terminate
or not renew their agreements with us or otherwise fail to conduct activities successfully and in a timely manner, the preclinical or clinical development or commercialization of product candidates or research programs may be delayed or terminated.



We depend on attracting and retaining key employees.



We are highly dependent on the principal members of our management and
scientific staff, including Jonathan M. Rothberg, Ph.D., our Chief Executive Officer, President and Chairman of the Board; David M. Wurzer, Executive Vice President and Chief Financial Officer; Christopher K. McLeod, Executive Vice President;
Timothy M. Shannon, M.D., Executive Vice President and Chief Medical Officer; and Richard F. Begley, Ph.D., President and Chief Executive Officer of 454. The loss of services of any of these personnel could materially adversely affect our business,
financial condition and results of operations. We entered into employment agreements with all of the principal members of our management and scientific staff that bind them to a specific term of employment. We maintain key person life insurance on
the life of Dr. Rothberg in the amount of $2.0 million. Our future success also will depend in part on the continued services of our key scientific and management personnel and our ability to attract, hire and retain additional personnel. There is
intense competition for such qualified personnel and there can be no assurance that we will be able to continue to attract and retain such personnel. Failure to attract and retain key personnel could materially, adversely affect our business,
financial condition and results of operations.



We depend on academic
collaborators, consultants and scientific advisors.



We
have relationships with collaborators and consultants at academic and other institutions who conduct research at our request. These collaborators and consultants are not our employees. Substantially all of our collaborators and consultants are
employed by employers other than us and may have commitments to, or consulting or advisory contracts with, other entities that may limit their availability to us. As a result, we have limited control over their activities and, except as otherwise
required by our collaboration and consulting agreements, can expect only limited amounts of their time to be dedicated to our activities. Our ability to discover genes and biological pathways involved in human disease and commercialize products
based on those discoveries may depend in part on continued collaborations with researchers at academic and other institutions. We may not be able to negotiate additional acceptable collaborations with collaborators or consultants at academic and
other institutions.



Our academic collaborators, consultants
and scientific advisors may have relationships with other commercial entities, some of which could compete with us. Our academic collaborators, consultants and scientific advisors sign agreements which provide for confidentiality of our proprietary
information and of the results of studies. We may not be able to maintain the confidentiality of our technology and other confidential information in connection with every academic collaboration or advisory arrangement, and any unauthorized
dissemination of our confidential information could materially adversely affect our business, financial condition and results of operations. Further, any such collaborator, consultant or advisor may enter into an employment agreement or consulting
arrangement with one of our competitors.



Competition in our field is
intense and likely to increase.



We face, and will
continue to face, intense competition from one or more of the following entities:



| |  | biotechnology companies;
| | - | ------------------------



| |  | pharmaceutical companies;
| | - | -------------------------



| |  | academic and research institutions; and
| | - | ---------------------------------------



| |  | government agencies.
| | - | --------------------



16



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We also are subject to significant competition from organizations that are pursuing approaches,
technologies and products that are the same as, or similar to, our technology and products. Many of the organizations competing with us have greater capital resources, research and development staffs and facilities and marketing capabilities. In
addition, research in the field of genomics, protein therapeutics, and fully-human antibodies generally is highly competitive. Our competitors include:



| |  | Human Genome Sciences, Inc.;
| | - | ----------------------------



| |  | Genentech, Inc.;
| | - | ----------------



| |  | ZymoGenetics, Inc.;
| | - | -------------------



| |  | Amgen, Inc.;
| | - | ------------



| |  | Incyte Pharmaceuticals, Inc.;
| | - | -----------------------------



| |  | major biotechnology and pharmaceutical companies; and
| | - | -----------------------------------------------------



| |  | universities and other non-profit research organizations.
| | - | ---------------------------------------------------------



A number of organizations are attempting to rapidly identify and patent genes and gene fragments sequenced at random, typically without specific knowledge
of the function of such genes or gene fragments. If our competitors discover or characterize important genes or gene fragments before we do, it could adversely affect our ability to commercialize our products. We expect that competition in genomics
research, protein therapeutics, and therapeutic antibodies will intensify as technical advances are made and become more widely known. In addition, a number of competitors are producing proteins from genes and claiming both the proteins as potential
therapeutics as well as claiming antibodies against these proteins. In many cases generic antibody claims are being issued by the United States Patent and Trademark Office (USPTO) even though competitors have not actually made antibodies
against the protein of interest, or do not have cellular, animal, or human data to support the use of these antibodies as therapeutics. These claims on proteins as therapeutics and these claims covering all antibodies against the proteins and
methods of use in broad human indications are being filed at a rapid rate, and some number of these claims have issued and may continue to issue. In addition, purified proteins, therapeutic data, and antibodies, including polyclonal antibodies,
mouse monoclonal antibodies and, in some cases, fully-human monoclonal antibodies, are being generated against a large number of targets within the human genome. All of these activities may make it difficult to commercialize products, or, if
licenses are made available, may make the royalty burden on these products so high as to prevent commercial success.



We may engage in acquisitions that are unsuccessful.



In the future, we may engage in acquisitions in order to exploit technology or market opportunities. We are not experienced in acquiring and integrating
new businesses. If we acquire another company, we may not be able to integrate the acquired business successfully into our existing business in a timely and non-disruptive manner or at all. Furthermore, an acquisition may not produce the revenues,
earnings or business synergies that we anticipate. If we fail to integrate the acquired business effectively or if key employees of that business leave, the anticipated benefits of the acquisition would be jeopardized. The time, capital management
and other resources spent on an acquisition that fails to meet our expectations could cause our business and financial condition to be materially and adversely affected. In addition, acquisitions can involve material non-recurring charges and
amortization of significant amounts of non-cash acquisition costs that could adversely affect our results of operations.



If our patent applications do not result in issued patents, then our competitors may obtain rights to commercialize our discoveries.



Our business and competitive position depends on our ability to protect our
products, processes and technologies. We continually file patent applications for our proprietary methods, novel uses of genes, and our development products. As of the date of this report, we had approximately 790 patent applications pending
covering novel genes and gene transcripts, as well as our products, processes and technologies with the USPTO, and had filed numerous corresponding international and foreign patent applications. As of the date of this report, we had been issued
approximately 50 patents with respect to aspects of our gene portfolio, products, processes and technologies.



17



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Our commercial success also depends in part on obtaining patent protection on genes and proteins for
which we or our collaborators discover utility and on products, methods and services based on such discoveries. We have applied for patent protection on novel genes and proteins, novel mutants of known genes and their uses, partial sequences of
novel proteins and their gene sequences and uses, and novel uses for previously identified genes discovered by third parties. We have applied for patents on antibodies against the proteins we have discovered, as well as seek or have our partners
seek patent protection on the antibodies we produce against these proteins. We have sought and intend to continue to seek patent protection for novel uses for genes and proteins and therapeutic antibodies that may have been patented by third
parties. In such cases, we would need a license from the holder of the patent with respect to such gene or protein in order to make, use or sell such gene or protein for such use. We may not be able to acquire such licenses on commercially
reasonable terms, if at all. Our patent application filings that result from the identification of genes associated with the cause or effect of a particular disease generally seek to protect the genes and the proteins encoded by such genes as well
as antibodies raised against these gene products. We also seek patent protection for our therapeutic, diagnostic and drug screening methods and products.



In 2001, the USPTO issued new guidelines for patent applications reflecting the USPTOs current policy regarding statutory written description and
utility requirements for patentability. The implementation of these new guidelines may cause the USPTO initially to reject some of our pending new gene and protein patent applications. There is no guarantee that the USPTO will approve them. We
strive especially to gain issued patents for our commercially important genes and proteins.



The patent positions of pharmaceutical, biopharmaceutical and biotechnology companies, including us, are generally uncertain and involve complex legal and factual questions. Our patent applications may not protect our
products, processes and technologies because of the following reasons:



| |  | there is no guarantee that any of our pending patent applications will result in additional issued patents;
| | - | -----------------------------------------------------------------------------------------------------------



| |  | we may develop additional proprietary technologies that are not patentable;
| | - | ---------------------------------------------------------------------------



| |  | there is no guarantee that any patents issued to us or our collaborative customers will provide a basis for commercially viable products;
| | - | -----------------------------------------------------------------------------------------------------------------------------------------



| |  | there is no guarantee that any patents issued to us or our collaborative customers will provide us with any competitive advantages;
| | - | -----------------------------------------------------------------------------------------------------------------------------------



| |  | there is no guarantee that any patents issued to us or our collaborative customers will not be challenged or circumvented or invalidated by third parties; and
| | - | --------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | there is no guarantee that any patents issued to others will not have an adverse effect on our ability to do business.
| | - | ----------------------------------------------------------------------------------------------------------------------



In addition, patent law relating to the scope of claims in the technology
fields in which we operate is still evolving. The degree of future protection for our proprietary rights is uncertain. Furthermore, there can be no assurance that others will not independently develop similar or alternative technologies, duplicate
any of our technologies, or, if patents are issued to us, design around the patented technologies developed by us. In addition, we could incur substantial costs in litigation if we are required to defend ourselves in patent suits brought by third
parties or if we initiate such suits.



The issuance of patents may not
provide us with sufficient protection.



We may not be able
to obtain further patents for our products, processes and technologies, or, if we are able to obtain further patents, these patents may not provide us with substantial protection or be commercially beneficial. The issuance of a patent is not
conclusive as to its validity or enforceability, nor does it provide the patent holder with freedom to operate without infringing the patent rights of others. A patent could be challenged by litigation and, if the outcome of such litigation were
adverse to the patent holder, competitors could be free to use the subject matter covered by the patent, or the patent holder may license the technology to others in settlement of such litigation. The invalidation of key patents owned by or licensed
to us or non-approval of pending patent applications could increase competition, and materially adversely affect our business, financial condition and results of operations. In addition, any application or exploitation of our technology could
infringe patents or proprietary rights



18



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of others and any licenses that we might need as a result of such infringement might not be available to us on
commercially reasonable terms, if at all. Third parties have indicated to us that they believe we may be required to obtain a license in order to perform certain processes that we use in the conduct of our business or in order to market potential
drugs we have in development.



We cannot predict whether our or
our competitors pending patent applications will result in the issuance of valid patents. Litigation, which could result in substantial cost to us, also may be necessary to enforce our patent and proprietary rights and/or to determine the
scope and validity of others proprietary rights. We may participate in interference proceedings that may in the future be declared by the USPTO to determine priority of invention, which could result in substantial cost to us. The outcome of
any such litigation or interference proceeding might not be favorable to us, and we might not be able to obtain licenses to technology that we require or that, if obtainable, we could license such technology at a reasonable cost.



The public availability of genomic sequence information or other sequence
information prior to the time we apply for patent protection on a corresponding full-length or partial gene could adversely affect our ability to obtain patent protection with respect to such gene or gene sequences. In addition, certain other groups
are attempting to rapidly identify and characterize genes through the use of gene expression analysis and other technologies. To the extent any patents issue to other parties on such partial or full-length genes or uses for such genes, the risk
increases that the sale of potential products, including therapeutics, or processes developed by us or our collaborators may give rise to claims of patent infringement. Others may have filed and in the future are likely to file patent applications
covering genes or gene products or antibodies against the gene products that are similar or identical to our products. Any such patent application may have priority over our patent applications. Any legal action against us or our collaborators
claiming damages and seeking to enjoin commercial activities relating to the affected products and processes could, in addition to subjecting us to potential liability for damages, require us or our collaborators to obtain a license in order to
continue to manufacture or market the affected products and processes or could enjoin us from continuing to manufacture or market the affected products and processes. There can be no assurance that we or our collaborators would prevail in any such
action or that any license required under any such patent would be made available on commercially acceptable terms, if at all. We believe that there may be significant litigation in the industry regarding patent and other intellectual property
rights. If we become involved in such litigation, it could consume a substantial portion of our managerial and financial resources.



There is substantial uncertainty concerning the extent to which supportive data will be required for issuance of patents for human therapeutics. If data
additional to that available to us is required, our ability to obtain patent protection could be delayed or otherwise adversely affected. Although the USPTO issued new utility guidelines in July 1995 that address the requirements for demonstrating
utility for biotechnology inventions, particularly for inventions relating to human therapeutics, there can be no assurance that the USPTO examiners will follow such guidelines or that the USPTOs position will not change with respect to what
is required to establish utility for gene sequences and products and methods based on such sequences.



We cannot be certain that our security measures will protect our proprietary technologies.



We also rely upon trade secret protection for some of our confidential and proprietary information that is not subject matter for which patent protection
is being sought. We have developed a database of proprietary gene expression patterns and biological pathways which we update on an ongoing basis and which can be accessed over the Internet. We have taken security measures to protect our proprietary
technologies, processes, information systems and data and continue to explore ways to enhance such security. Such measures, however, may not provide adequate protection for our trade secrets or other proprietary information. While we require
employees, academic collaborators and consultants to enter into confidentiality and/or non-disclosure agreements where appropriate, any of the following could still occur:



| |  | proprietary information could be disclosed;
| | - | -------------------------------------------



| |  | others may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose such technology; or
| | - | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | we may not be able to meaningfully protect our trade secrets.
| | - | -------------------------------------------------------------



We depend upon our ability to license technologies.



We may have to acquire or license certain components of our technologies or products from third parties. We may not be able to acquire from third parties
or develop new technologies, either alone or with others. Failure to license or otherwise acquire necessary technologies could materially adversely affect our business, financial condition and results of operations.



19



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The 454 Life Sciences technology platform is in development and the early stages of commercialization.



The technology platform of 454, our majority-owned subsidiary (see
Business  454 Life Sciences Corporation), is still in development and 454 has not had significant sales of its services or products. 454 may not be able to continue to successfully develop or commercialize the 454 technology
platform. The success of commercialization of the 454 technology platform depends on many factors, including:



| |  | the acceptance of 454s technology in the market place;
| | - | -------------------------------------------------------



| |  | technical performance of 454s platform in relation to existing technologies;
| | - | -----------------------------------------------------------------------------



| |  | 454s ability to obtain key components for the manufacture of the 454 instrument and reagents from suppliers; and
| | - | -----------------------------------------------------------------------------------------------------------------



| |  | 454s ability to obtain licenses to resell reagents for use in the 454 instrument, if required.
| | - | -----------------------------------------------------------------------------------------------



454 is subject to competition from organizations that have developed or are developing technologies and products to service 454s
potential customers.



Many of the organizations competing
with 454 potentially have greater capital resources, research and development staffs and facilities and marketing capabilities. 454s potential competitors include:



| |  | Applied Biosystems;
| | - | -------------------



| |  | Amersham Biosciences;
| | - | ---------------------



| |  | Affymetrix;
| | - | -----------



| |  | Perlegen; and
| | - | -------------



| |  | other companies recently formed or soon to be funded to develop whole genome sequencing technologies.
| | - | -----------------------------------------------------------------------------------------------------



We believe that the future success of 454 will depend in large part on our ability to maintain a competitive position in
instruments for the high throughput nucleic acid sequencing field. Before we recover development expenses for our products or technologies, such products or technologies may become obsolete as a result of technological developments by us or others.
Our products could also be made obsolete by new technologies which are less expensive or more effective. We may not be able to make the enhancements to our technology necessary to compete successfully with newly emerging technologies. A market for
the high throughput nucleic acid sequencing field may not be sufficient to generate revenues significant enough for 454 to achieve profitability.



We could be liable for any failure to comply with hazardous product regulations.



Our research and development activities involve the controlled use of hazardous materials and chemicals. We are subject to
federal, state and local laws and regulations governing the use, storage, handling and disposal of such materials and certain waste products. Although we believe that our safety procedures for handling and disposing of such materials comply with the
standards prescribed by federal, state and local laws and regulations, the risk of accidental contamination or injury from these materials cannot be completely eliminated. In the event of such an accident, we could be held liable for any damages
that result and any liability could exceed our resources.



Risks Related to Our Financial Results



We have a history of
operating losses and expect to incur losses in the future.



We have incurred losses since inception, principally as a result of research and development and general and administrative expenses in support of our operations. We anticipate incurring additional losses over the next several years as we
focus our resources on prioritizing, selecting and advancing our most promising drug candidates. We may never be profitable or achieve significant revenues. For example, we experienced net losses of $74.5 million in 2003, $90.4 million in 2002 and
$42.9 million in 2001, and as of December 31, 2003 had an accumulated deficit of $289.5 million.



20



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Our quarterly operating results have fluctuated greatly and may continue to do so.



Our operating results have fluctuated on a quarterly basis. We expect that
losses will continue to fluctuate from quarter to quarter and that these fluctuations may be substantial. Our results of operations are difficult to predict and may fluctuate significantly from period to period, which may cause our stock price to
decline and result in losses to investors. Some of the factors that could cause our operating results to fluctuate include:



| |  | changes in the demand for our services;
| | - | ---------------------------------------



| |  | the nature, pricing and timing of products and services provided to our collaborators;
| | - | --------------------------------------------------------------------------------------



| |  | our ability to compete effectively in our therapeutic discovery and development efforts against competitors that have greater financial or other resources or drug candidates that
are in further stages of development;
| | - | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | acquisition, licensing and other costs related to the expansion of our operations;
| | - | ----------------------------------------------------------------------------------



| |  | losses and expenses related to our investments;
| | - | -----------------------------------------------



| |  | regulatory developments or changes in public perceptions relating to the use of genetic information and the diagnosis and treatment of disease based on genetic information;
| | - | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | regulatory actions and changes related to the development of drugs;
| | - | -------------------------------------------------------------------



| |  | changes in intellectual property laws that affect our patent rights;
| | - | --------------------------------------------------------------------



| |  | payments of milestones, license fees or research payments under the terms of our external alliances and collaborations and our ability to monitor and enforce such payments; and
| | - | --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | the timing of intellectual property licenses that we may enter.
| | - | ---------------------------------------------------------------



We believe that quarterly comparisons of our financial results are not necessarily meaningful and should not be relied upon as an indication of future
performance. In addition, fluctuations in quarterly results could affect the market price of our common stock in a manner unrelated to our long-term operating performance.



The market price of our common stock is highly volatile.



The market price of our common stock has fluctuated widely and may continue to do so. For example, during fiscal year 2003,
the closing sale price of our stock ranged from a high of $7.70 per share to a low of $3.17 per share. Many factors could cause the market price of our common stock to rise and fall. These factors include:



| |  | variations in our quarterly operating results;
| | - | ----------------------------------------------



| |  | announcements of technological innovations, clinical results, or new products by us or our competitors;
| | - | -------------------------------------------------------------------------------------------------------



| |  | introduction of new products or new pricing policies by us or our competitors;
| | - | ------------------------------------------------------------------------------



| |  | acquisitions or strategic alliances by us or others in our industry;
| | - | --------------------------------------------------------------------



| |  | announcement by the government or other agencies regarding the economic health of the United States and the rest of the world;
| | - | ------------------------------------------------------------------------------------------------------------------------------



| |  | the hiring or departure of key personnel;
| | - | -----------------------------------------



| |  | changes in market valuations of companies within the biotechnology industry; and
| | - | --------------------------------------------------------------------------------



| |  | changes in estimates of our performance or recommendations by financial analysts.
| | - | ---------------------------------------------------------------------------------



21



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We have a large amount of debt and our debt service obligations may prevent us from taking actions that we would
otherwise consider to be in our best interests.



As of
March 1, 2004, we had total consolidated debt of $231.5 million; and for the year ended December 31, 2003, we had a deficiency of earnings available to cover fixed charges of $80.6 million. A variety of uncertainties and contingencies will affect
our future performance, many of which are beyond our control. We may not generate sufficient cash flow in the future to enable us to meet our anticipated fixed charges, including our debt service requirements with respect to our notes that we sold
in February 2000 and February 2004. At March 1, 2004, $230.0 million of those notes remained outstanding. The following table shows, as of March 1, 2004, the remaining aggregate amount of our interest payments due in each of the years listed (in
millions):



|           |  |                   |     
|---------- |  | ----------------- | ----
|Year       |  | AggregateInterest
|2004       |  | $                 | 5.9 
|2005       |  |                   | 11.8
|2006       |  |                   | 11.8
|2007       |  |                   | 7.9 
|2008       |  |                   | 4.0 
|Thereafter |  |                   | 10.0



Our substantial
leverage could have significant negative consequences for our future operations, including:



| |  | increasing our vulnerability to general adverse economic and industry conditions;
| | - | ---------------------------------------------------------------------------------



| |  | limiting our ability to obtain additional financing;
| | - | ----------------------------------------------------



| |  | requiring the dedication of a substantial portion of our expected cash flow to service our indebtedness, thereby reducing the amount of our expected cash flow available for other
purposes, including working capital and capital expenditures;
| | - | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | limiting our flexibility in planning for, or reacting to, changes in our business and the industry in which we compete; or
| | - | --------------------------------------------------------------------------------------------------------------------------



| |  | placing us at a possible competitive disadvantage compared to less leveraged competitors and competitors that have better access to capital resources.
| | - | ------------------------------------------------------------------------------------------------------------------------------------------------------



Our debt investments are impacted by the financial viability of the underlying companies.



We have a diversified portfolio of investments of which
$196.6 million at December 31, 2003 were invested in U.S. Treasuries and debt investments that are sponsored by the U.S. Government. Our corporate fixed-rate debt investments comply with our policy of investing in only investment-grade debt
instruments. The ability for the debt to be repaid upon maturity or to have a viable resale market is dependent, in part, on the financial success of the underlying company. Should the underlying company suffer significant financial difficulty, the
debt instrument could either be downgraded or, in the worst case, our investment could be worthless. This would result in our losing the cash value of the investment and incurring a charge to our statement of operations.



We may need to raise additional funding, which may not be available on favorable terms, if
at all.



We believe that we have sufficient capital to
satisfy our capital needs for at least the next twenty-four months. However, our future funding requirements will depend on many factors and we anticipate that, at some future point, we will need to raise additional capital to fund our business plan
and research and development efforts on a going-forward basis. To the extent that we need to obtain additional funding, the amount of additional capital we would need to raise would depend on many factors, including:



| |  | the number, breadth and progress of our research, product development and clinical programs;
| | - | --------------------------------------------------------------------------------------------



| |  | our ability to establish and maintain additional collaborations;
| | - | ----------------------------------------------------------------



22



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| |  | the progress of our collaborators;
| | - | ----------------------------------



| |  | our costs incurred in enforcing and defending our patent claims and other intellectual property rights; and
| | - | -----------------------------------------------------------------------------------------------------------



| |  | the costs and timing of obtaining regulatory approvals for any of our products.
| | - | -------------------------------------------------------------------------------



We expect that we would raise any additional capital we require through public or private equity offerings, debt financings
or additional collaborations and licensing arrangements. We cannot be certain that in the future these sources of liquidity will be available when needed or that our actual cash requirements will not be greater than anticipated. In appropriate
strategic situations, we may seek financial assistance from other sources, including contributions by others to joint ventures and other collaborative or licensing arrangements for the development and testing of products under development. If we
raise additional capital by issuing equity securities, the issuance of such securities would result in ownership dilution to our shareholders. If we raise additional funds through collaborations and licensing arrangements, we may be required to
relinquish rights to certain of our technologies or product candidates, or to grant licenses on unfavorable terms. The relinquishing of rights or granting of licenses on unfavorable terms could materially adversely affect our business, financial
condition and results of operations. If adequate funds are not available, our business, financial condition and results of operations would be materially adversely affected. However, should we be unable to obtain future financing either through the
methods described above or through other means, we may be unable to meet the critical objective of our long-term business plan, which is to successfully develop and market pharmaceutical products. If we require additional capital at a time when
investment in biotechnology companies such as ours, or in the marketplace in general, is limited due to the then prevailing market or other conditions, we may not be able to raise such funds at the time that we desire or any time thereafter.



Risks Related to Our Convertible Debt and Our Common Stock
into which Our Debt is Convertible



We have significant leverage as a
result of the sales of our debt in 2000 and 2004.



In
February 2000, in connection with the sale of our 6% convertible subordinated debentures due in 2007, we incurred $150.0 million of indebtedness. In February 2004, we repurchased $20.0 million of these debentures, for total consideration of $20.0
million, plus accrued interest of $0.05 million to the date of repurchase. As a result of the remaining indebtedness of $130.0 million, our interest payment obligations amount to $7.8 million per year.



In February 2004, in connection with the sale of our 4% convertible
subordinated notes due in 2011, we incurred an additional $100.0 million of indebtedness. As a result of this indebtedness, our interest payment obligations amount to $4.0 million per year. The degree to which we are leveraged could adversely affect
our ability to obtain further financing for working capital, acquisitions or other purposes and could make us more vulnerable to industry downturns and competitive pressures. Our ability to meet our debt service obligations will depend upon our
future performance, which may be subject to the financial, business and other factors affecting our operations, many of which are beyond our control.



These notes, due in 2007 and 2011, are effectively subordinated to all of our secured indebtedness and all indebtedness of our subsidiaries. These notes
are our general unsecured obligations and are not guaranteed by any of our subsidiaries. Accordingly, these notes are effectively subordinated to all of our current and future secured indebtedness to the extent of the assets securing the
indebtedness. Furthermore, our right to receive any distribution of assets of any subsidiary upon that subsidiarys liquidation, reorganization or otherwise, is subject to the prior claims of creditors of that subsidiary, except to the extent
we also are recognized as a creditor of that subsidiary. As a result, these notes are effectively subordinated to the claims of such creditors.



There are no restrictive covenants in our indentures relating to our ability to incur future indebtedness.



The indentures governing our notes due in 2007 and 2011 do not contain any
financial or operating covenants or restrictions on the payment of dividends, the incurrence of indebtedness, transactions with affiliates, incurrence of liens or the issuance or repurchase of securities by us or any of our subsidiaries. We may
therefore incur additional debt, including secured indebtedness senior to these notes. As part of our growth strategy, we potentially may use proceeds from the 2004 offering to finance future acquisitions of complementary businesses or technologies,
which may cause us or our subsidiaries to incur significant indebtedness to which these notes would be subordinate.



These notes, due in 2007 and 2011, are obligations exclusively of CuraGen Corporation. Our subsidiaries are separate and distinct legal entities. Our
subsidiaries have no obligation to pay any amounts due on these notes or to



23



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provide us with funds for our payment obligations, whether by dividends, distributions, loans or other payments. In
addition, any payment of dividends, distributions, loans or advances by our subsidiaries to us could be subject to statutory or contractual restrictions. Payments to us by our subsidiaries will also be contingent upon our subsidiaries earnings
and business considerations.



Our debt service obligations may adversely
affect our cash flow.



A higher level of indebtedness
increases the risk that we may default on our debt obligations. We cannot be certain that we will be able to generate sufficient cash flow to pay the interest on our debt or that future working capital, borrowings or equity financing will be
available to pay or refinance such debt. If we are unable to generate sufficient cash flow to pay the interest on our debt, we may have to delay or curtail our research and development programs.



The level of our indebtedness among other things, could:



| |  | make it difficult for us to make payments on our notes;
| | - | -------------------------------------------------------



| |  | make it difficult for us to obtain any necessary financing in the future for working capital, capital expenditures, debt service requirements or other purposes;
| | - | ----------------------------------------------------------------------------------------------------------------------------------------------------------------



| |  | limit our flexibility in planning for, or reacting to, changes in our business and the industry in which we compete; and
| | - | ------------------------------------------------------------------------------------------------------------------------



| |  | make us more vulnerable in the event of a downturn in our business.
| | - | -------------------------------------------------------------------



Our ability to repurchase notes, if required, with cash upon a change in control or fundamental change may be limited.



In certain circumstances involving a change in control, we may be required
to repurchase some or all of the notes due 2007. In certain circumstances involving a fundamental change, we may be required to repurchase some or all of the notes due 2011. We cannot be certain that we will have sufficient financial resources at
such time or would be able to arrange financing to pay the repurchase price of the notes. Our ability to repurchase the notes in such event may be limited by law, by the indenture and by such indebtedness and agreements as may be entered into,
replaced, supplemented or amended from time to time.



Securities we issue to
fund our operations could cause dilution to our shareholders ownership.



The conversion of our notes into shares of common stock will dilute the ownership interest of our current shareholders. We may decide to raise additional funds through a public or private debt or equity financing to
fund our operations. If we raise funds by issuing equity securities, the percentage ownership of current shareholders, including the ownership that holders of the notes would have upon conversion, will be reduced, and the new equity securities may
have rights prior to those of the common stock issuance upon conversion of the notes. We may not obtain sufficient financing on terms that are favorable to existing shareholders and us.



Item 7a.Quantitative and Qualitative Disclosures About Market Risk



Currently, we maintain approximately 12% of our cash and investments in
financial instruments with original maturity dates of less than three months, 21% in financial instruments with original maturity dates of greater than three months and less than one year, and the remaining 67% in financial instruments with original
maturity dates of greater than one year and less than five years. These financial instruments are subject to interest rate risk and will decline in value if interest rates increase. We estimate that a change of 100 basis points in interest rates
would result in a $3.0 million decrease or increase in the fair value of our cash and investments.



Our outstanding long-term liabilities as of December 31, 2003 consisted of our 6% convertible subordinated debentures due February 2, 2007 and an accrued
long-term liability for the remaining future minimum payments under a license agreement (see Note 11 to our consolidated financial statements). As the debentures bear interest at a fixed rate, our results of operations would not be affected by
interest rate changes. Although future borrowings may bear interest at a floating rate, and would therefore be affected by interest rate changes, at this point we do not anticipate any significant future borrowings (except for the issuance on
February 17, 2004 of $100.0 million of 4% convertible subordinated notes due 2011, which is more fully described in Note 13 to our consolidated financial statements), and therefore do not believe that a change of 100 basis points in interest rates
would have a material effect on our financial condition.



24



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Accordingly, we do not believe that there is any material market risk exposure with respect to derivative
or other financial instruments that would require disclosure under this item.



As of December 31, 2003, the market value of our $150.0 million 6% convertible subordinated debentures due 2007, based on quoted market prices, was estimated at $133.0 million.



25



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SIGNATURES



Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by
the undersigned thereunto duly authorized.



|                     |  |                     |  |                                      
|-------------------- |  | ------------------- |  | -------------------------------------
|Dated: June 16, 2004 |  | CuraGen Corporation
|                     |  |                    
|                     |  | By:                 |  | /s/ David M. Wurzer                  
|                     |  |                     |  | David M. Wurzer                      
|                     |  |                     |  | Executive Vice President,            
|                     |  |                     |  | Chief Financial Officer and Treasurer



26