Stanley T. Crooke – Chairman of the Board & Chief Executive Officer Kristina Lemonidis – Director of Corporate Communication B. Lynne Parshall – Director, Chief Operating Officer & Chief Financial Officer

Joseph Schwartz – Leerink Swann Llc Mark Monane – Needham & Company Brent Kelly – Collins Stewart Llc Eric Schmidt – Cowen & Company Aaron Reames – Wachovia Capital Markets, LLC Carol Werther – Summer Street Research Partners Eun Yang – Jefferies & Company James Birchenough – Barclays Capital

Welcome to Isis Pharmaceuticals year-end financial results conference call. Today's call is being recorded. Leading the call today from Isis is Dr. Stan Crooke, Isis' Chairman and CEO. Dr. Crooke, please go ahead. Stanley T. Crooke: Good morning and thank you for joining us on today's conference call to discuss our year-end financial results. Joining us on today's call are Lynne Parshall, COO and CFO; Beth Hougen, Vice President of Finance, and Kristina Lemonidis, Director of Corporate Communication. Kris, will you read our forward-looking statements, please.

Sure. Thanks, Stan. Good morning. A reminder to everyone this webcast includes forward-looking statements regarding Isis’ business, the financial outlook for Isis as well as Regulus’ its majority-owned subsidiary and the therapeutic and commercial potential of Isis’ technology in products and development. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing, and commercializing drugs that are safe and effective for use of human therapeutics and in the endeavor of building a business around such products. Isis' forward-looking statements also involve assumptions that, if never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although, Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2007, and its most recent quarterly report on Form 10-Q, which are available on file with the SEC. Copies of these and other documents are available from the company. Stan back to you. Stanley T. Crooke: Thanks Kris. And the purpose of the call today is to report our financial performance for 2008 and to define our agenda for 2009. We had a great year in 2008 we continue to add corporate partners with the deal with Genzyme for mipomersen. We completed the sale of our diagnostic subsidiary Ibis to Abbott Molecular. From these and other transactions we have generated more than $650 million in new cash over the last 24 months. And of course in 2008, we continue to make progress in our pipeline moving mipomersen into broad Phase III programs to support our first planned NDA in 2010, with a planned launch in 2011, we report a positive data for several drugs in key clinical trials and made progress on all of the drugs in our pipeline. In addition, we put two new drugs into development. A unique aspect of our business is our satellite company strategy and the value of that strategy became even more apparent last year and our partner companies continued to mature. Most importantly they present a positive clinical data from studies on our drugs that we've partnered with them. Including the results of OGX-011 trials in patients with prostate cancer and a very exciting Phase II study evaluating ATL/TV1102 in patients with multiple sclerosis. Further, our satellite companies achieved important new partnerships our partners at ATL completed a partnership with Teva. Regulus completed its first partnership with GSK. And our partners at Alnylam continue to achieve new partnerships from which we had ISIS benefit. And of course the sale of Ibis, our first satellite company to Abbott was one of the highlights of the year. As a result of these activities, we've significantly strengthened our financial position. We start this year with more than $650 million in cash. We are pleased that we are in a relatively small group of successful and well-funded biotech companies that do not need to raise cash in these difficult economic times. Now, Lynne perhaps you can go over the financial details. B. Lynne Parshall: Thanks Stan. As usual I'll assume that you have read the details of the year and quarter end financials in our press release this morning. 2008 was a transformational year for us, with multiple successes in all aspects of our business, resulting in the strongest financial position in our history. Let me start by going over the highlights of our 2008 financial results. First, we exceeded our 2008 guidance of pro forma NOL of less than $15 million ending 2008 with a pro forma net income of $3.1 million and net operating income of $226,000. Second, we ended 2008 with nearly $500 million in cash. This is more than the $450 million we projected and does not include the $175 million that we received in January from the sale of Ibis. The considerable improvement in our financial results was driven primarily by significantly increased revenue from partnerships. In addition to creating a significant continuing revenue base, our partnerships have greatly improved our cash position. We have been cash flow positive for the last three years and we expect to be cash flow positive in 2009 also. Our projections for 2009 are for a pro forma net income of more than $140 million. We expect to end 2009 with more than $550 million in cash and we projected pro forma NOL in the low to mid-$20 million range, which is slightly higher than our 2008 NOL would have been with Ibis included. The accounting treatment for sale of Ibis to Abbott is somewhat complicated. So, I will spend just a few minutes walking you through the impact on our 2008 and 2009 financial statements. First and most importantly the sale of Ibis added a $175 million to our cash bringing the total to over $650 million at the beginning of the year. In addition, we expect continued financial benefit as a result of this transaction, because we received an earn-out that start with 5% on Ibis future sales on the terms we have previously described. We will record a gain on the sale of Ibis in the first quarter of 2009 of approximately $200 million. You will see this on our P&L below our operating results on a line called discontinued operations. This gain is a significant contributor to our projected net income for 2009. Because Abbott exercised this option in 2008, Ibis is considered an entity held for sale for the entire year of 2008. Therefore, we no longer include Ibis revenue or expenses in our operating results. In other words, in the 2008 financial results that we reported today, our operating results do not include Ibis financial results. Ibis' results are instead included on the line called net loss from discontinued operations. The good news is that the Abbott and Genzyme transactions contributed to very strong financial performance in 2008 and will also in 2009. The flip side is that for the first time in our history, we will have taxable income. To minimize our federal tax liability, we will use our NOL carry forward to offset a majority of our taxable income. However, due to the recent California tax law changes that were enacted with the 2008, 2009 California budget we are unable to use our NOL carry forward to offset taxable income for California. As a result, we expect to owe state tax and possibly some federal tax. But there are a number of unknowns still including the recently approved federal stimulus package, which means we don't know right now exactly what the number will be. Because our financial performance over the last several years has been so strong, many of you have asked us to provide additional color on our financial drivers going forward. So, I will do that now. I will start with revenue. Most of our revenue comes from licensing and partnerships and our revenue consists of three primary components. The first component is revenue from the amortization of upfront fees we've received from our partners. For example, we are amortizing $275 million of the upfront payments we received from Genzyme from the license fee and premium on its stock purchased into revenue of over four years through 2012. We are also recording revenue from the upfront fees we received from BMS and Ortho-McNeil and that Regulus received from GSK. The second component is revenue we earned for the research and development we performed for our partners and from ongoing licensing agreements. Typically, we entered into a collaboration agreement, we conduct research and development activities for our partners for sometime, which are partner funds. For example, we have ongoing R&D efforts related to our BMS and Ortho-McNeil collaborations. These first two components of revenue are relatively predictable and relatively consistent quarter-to-quarter and establish a strong base for our 2009 revenue. You can estimate this revenue base pretty accurately by annualizing our Q4 2008 revenue. Doing that the annualized revenue amount is approximately a $120 million. Although, less predictable the third component of our revenue provides meaningful upside to our base revenue. This component includes milestone payments, sub-licensing fees, money from transactions like contract manufacturing and money from new collaborations. In 2008, we received over $11 million from these sources. Already, this year we have received $1 million from Alnylam resulting from their Cubist transaction and $1 million from Achaogen when they filed an IND for ACHN-490. While we do not project the exact amount of revenue that we expect to come from this category, it has historically been a significant component of our revenue and we expect it to continue to be so in 2009. We believe it is likely that we will receive additional milestone in sub-licensing revenue this year. We also think it is likely that we will complete new corporate partner transactions this year. Obviously, we are in a very different position today than in the past. So, we are much more selective in the partnerships we are willing to engage in, but given the level of interest we think other new deals may be completed. Now let's move on to expenses. We expect operating expenses to be slightly higher in 2009 than in 2008 principally due to growth in the mipomersen clinical program and in Regulus. Mipomersen matured appreciably during 2008. We and Genzyme are currently evaluating mipomersen in four Phase III trials. The ongoing mipomersen studies significantly increased the number of patients exposed to the drug in support of future regulatory filings. Obviously. this expanded clinical effort will affect our expenses. Regulus will also continue to advance its microRNA technology. Regulus is in the process of building its core team augmenting the strengths of the team already assembled, we expect Regulus to approximately double in size in 2009 from 2008. We also expect modest expense growth in our other clinical programs as we advanced drugs into it through development. While we have initiated a new cancer program and research due to the efficiency of our antisense drug discovery platform that new program will represent only modest expense growth, while contributing to the three to five new drugs, we plan to add to our pipeline this year. Ahead of all this translate to the bottom line, over the last couple of years on a pro forma basis, we have reported three quarters of net income and three quarters of net operating income, ending 2008 with both pro forma net operating income and pro forma net income for the year. Right now, we are floating with sustainable profitability, we are not there yet, but it won’t take much a new deal, our mipomersen launch in 2011, a major milestone any of these things could be sufficient to tip us into profitability for the next several years or in the case of mipomersen launch into the future. We expect to end the year with more than $550 million in cash and we do not expect to seek additional financings. So, we are looking forward to another productive year in 2008. With that I will turn the call back to Stan to highlight what you might look forward to. Stanley T. Crooke: Well thanks Lynne. As Lynne said we've had an excellent year with progress in every element of our business. I will close now with a few comments focused on upcoming events in 2009. So far this year, we have already accomplished quite a few things. We completed the transaction with Abbott for the acquisition of Ibis. We have already advanced one of our pipeline drugs into Phase I clinical trials. Our SGLT2 inhibitor went in demand early this month and we expect other drugs to follow that this year. Furthermore, our satellite companies have started the year well. Achaogen initiated a Phase I trial on ACHN-490, their next generation aminoglycoside, a neoglycoside drug, designed to treat multi-drug resistant gram-negative bacterial infections. This drug derived from a technology that we created to identify small molecules defined structured RNA and then we licensed that technology to Achaogen. So, Achaogen added another drug to our pipeline and we earned a $1 million milestone. We also earned a $1 million sub-licensing fee from Alnylam recently announced deal with Cubist. Here are some of our upcoming highlights. We plan to report data from a Phase III study evaluating mipomersen in homozygous FH patients in the middle of the year. We also expect to report data from additional mipomersen studies in other patients populations late this year and early next year. We plan to report data from a Phase II study evaluating ISIS 113715, our novel insulin sensitizer in combination with sulfonylureas in patients with Type 2 diabetes in the first half of this year. We expect to complete Phase I study for our SGLT2 and our CRP drugs this year and of course completing the Phase I study sets both of these drugs out for Phase II studies. We expect news from our partners as well. For example, our partners at Altair, who plan to announce data from their Phase I studies with AIR465 (sic) [AIR645] and inhaled antisense drug to treat asthma. Remember that this is the first aerosol drug that we've taken in demand and so that will be important information and take a step toward expanding our opportunities through that route of administration. We are planning to begin clinical trials on three to five new drugs this year and we will add three to five new drugs into development this year as well. So, we've got a significant agenda. To add three to five new drugs to the pipeline each year is impressive, but perhaps equally exciting is the breadth and the diversity of diseases we will be treating. Our cardiovascular program is now approaching new targets in the management of lipid disorders. In addition to mipomersen and our PCSK9 inhibitor, we are focused on targets that ultra lipids other lipids such as triglycerides. Beyond lipid management, our cardiovascular program should add effect to a 11 inhibitor that affects the clotting cascade to development this year. And as I mentioned our CRP inhibitor will be completing Phase I trials. Our Phase II program for our CRP inhibitor will include not only cardiovascular disorders, but other inflammatory disorders. Certainly, our metabolic program is moving beyond Type 2 diabetes through the identification of peripherally acting anti-obesity agents. Our new CNS program has already created one development candidate our SOD1 inhibitor to treat patients with ALS, we plan for that drug in the clinical trials this year, we are looking forward to adding new drugs to treat severe neurodegenerative diseases out of that program in the near term. We also expect to add drugs from our cancer program. When you consider these drugs plus the drugs we already have in development, you can see that we have drugs to treat many types of diseases. These drugs are delivered by several routes of administration including aerosol and we are focused on indications that range from the very severe and acute to diseases as chronic as Type 2 diabetes and high cholesterol. Additionally, as always we continue to advance our technology, we are making great progress in learning how to exploit antisense mechanisms other than RNA SAGE, such as alternative splicing and hope to have a development candidate from our alternative splicing effort this year or next. Now, this is particularly important because with this mechanism, we cause a new protein to be made in effect we created an agonist instead of an inhibitor. We are also moving along throughout our goal of creating single strand antisense drugs that cause RNA target reduction via the siRNA mechanism. We think this could be a breakthrough that the siRNA field really needs. Finally, this year or early next year, we hope to introduce generation 2.5 antisense drugs, our new proprietary generation 2.5 chemistry should increase potency by 10 fold or more compared to the already very potent generation 2.2 drugs that are in the clinic. So, we will continue to expand the opportunities for antisense technology and enhance the performance of the drugs in our pipeline in a prudent stepwise station that enhances the value of the entire platform and extends our proprietary control much further into the future. We exceeded the financial and performance guidance that we provided for 2008 and I think that guidance was pretty aggressive to begin with. In 2009, will be cash flow positive and profitable and we will strive to sustain that as we approach the commercialization in mipomersen. In summary, this has been another great year for Isis, a year with impressive results in every aspect of our business and we expect 2009 to be as exciting as 2008 was. And with that I will now open the phone call up for questions. [Carny] if you can set us up for questions please.

Thank you. (Operator Instructions). And we will take our first question from Joseph Schwartz from Leerink Swann. Joseph Schwartz – Leerink Swann Llc: Great. Good morning. Thanks for taking the question. I was wondering if you can give us an update on severe high cholesterol study, how is side activation screening going, have you started to enroll payment yet? Stanley T. Crooke: Yes, its going very well as we don’t provide detailed information on enrollment that all of the trials with mipomersen are going well and enrolling. Joseph Schwartz – Leerink Swann Llc: So, I think I heard you say that late this year or early next year, you expect to report a [promotion] data in other high cholesterol populations, would this include, what was called the apheresis-eligible study and can you just explain to us it that just a nuance with the name change or has the strategy with those patients changed, can you take people off of that for instance, give us some color there so we can understand that. Thanks. Stanley T. Crooke: There hasn’t been any change in the basic design or the thrust of that trial Joe, its so I guess the right answer is it's just a name change. And I think we've said on the last cal or two that we have these four Phase III trials that we wanted to get up and running and they're getting up and running and they are enrolling nicely and we expect over the, from the middle of this year to 2010 and I don’t want to be a lot more specific than that to have sort of the rolling series of clinical trials that we will complete and we'll have those results. All geared toward having the data that we want to use to support our first filing. So, without being more specific about exactly what trial we will finish at exactly what date, I think we are feeling very good about where that program stands and that we are going to meet that guidance right on the numbers. Joseph Schwartz – Leerink Swann Llc: Thanks.

And we will take our next question from Mark Monane from Needham. Mark Monane – Needham & Company: Good morning and greetings from New York City. Couple of questions please. Thanks for the review for starting us off. When we look at the Phase III data, I know they haven’t come out, what kind of results do you think would be clinically relevant beyond statistically significant in these patients to make a difference in the real world? Stanley T. Crooke: : Mark Monane – Needham & Company: All right that was helpful. Now we saw some data on mipomersen that shows extremely long half-life of the drug. I know that in the current Phase III trials there is weekly dosing are some of the new trials that you are planning thinking about extending the dosing frequency in these patients. Stanley T. Crooke: No not yet. Our strategy there has not changed and that is that we want to do one thing well, which has developed the weekly dosing schedule have the weekly dosing schedule that’s simple and easy to use, get that to the market with as much safety data on that schedule as we can possibly do, once we get that done then we can start looking at other schedule, there are pluses and minuses to going to biweekly there are pluses and minuses to going monthly and those things really evaluate overtime, and those way I think of those things are just great opportunities for line extensions and life cycle management. Mark Monane – Needham & Company: Fair enough. A concrete question, the three trials that are start to see are Factor XI trial, the metabolic trial looking at peripheral diabetes and the SOD trial in ALS, is that correct? Stanley T. Crooke: So, we have the CRP trial that's underway. Mark Monane – Needham & Company: Right. Stanley T. Crooke: The SGLT2 trial that's underway, we hope to get the SOD1 trial clinical trials underway. The Factor XI is a drug that will enter development and run into clinical trials until next year. Mark Monane – Needham & Company: Okay, fine. And the peripheral diabetes, excuse me, obesity management drug? Stanley T. Crooke: We expect the drug to go into development this year, but it won't get into clinical trials this year. Mark Monane – Needham & Company: And then finally you've given us a lot of therapeutic options in terms of adjusting the target, there is any sense, there is siRNA and with your alliance with Alnylam there is the Regulus microRNA and then you talked today about the single stranded siRNA possibilities, how is the company thinking about the technology and marrying them to the different diseases that you are talking about in the different trials you are going to initiate. How do you know which one to use for which? Stanley T. Crooke: Well let's deal with microRNAs first. microRNAs are new targets. What's happening in our world is our world in terms of the science is floating and new types of RNAs that have important regulatory roles in the cell are being identified at a pace that's dizzying. microRNAs represents one class. So, our thoughts about microRNAs have not changed, [1iota] that's is their new targets and we use antisense drugs just like, we use for messenger RNAs to affect microRNAs, So, they're just new targets. The specific design of the antisense drug maybe slightly different from microRNA, but it's an antisense drug. With regard to the rest of antisense mechanisms throughout our history, we have studied all of the major mechanisms those were things what happens to the RNA after the drug binds. The mechanism that is proven to be the most productive is RNA SAGE. But we have been interested in other mechanisms like translation arrest and splicing for a long time. We are very, very interested in alternative splicing because alternative splicing is responsible for a large part of cellular diversity and we think it's accountable for a lot of different diseases. So, that mechanism we use when there is disease that we think can be improved by driving the production of a different protein and so that's alternative splicing. siRNA is an antisense mechanism. The strand involved in the double-strand RNA simply is a drug delivery device. The active molecule is an antisense agent. And so our focus in siRNA was to enable our partner Alnylam to approach traditional double-strand RNA, siRNA, and we have been looking at single-strand molecules that work through that risk mechanism. And the reason we're doing that is that we want to continue to evaluate new approaches that may change and improve some of the properties of our drugs long-term, with that mechanism I think we have a long way to go before we know if it provides benefit to relative to RNA SAGE. So, think of that as a long-term approach designed to continue to advance the technology that we've invented. I am afraid that was more complicated then it needed to be, but I hope that answered the question Mark. I put into sleep. Did I answer your question Mark?

And we'll take our next question from Brent Kelly from Collins Stewart. Brent Kelly – Collins Stewart Llc: Hi good morning. Stan can you comment on the regulatory strategy from mipomersen, homozygous seems pretty straightforward, but how are your conversations going with the FDA and in Europe with regard to using LBL surrogate end points for indications beyond homozygous? Stanley T. Crooke: Brent, I don't have anything to add to the comments that we have made previously. We’ve had good productive conversations that give us significant encouragement that the initial indication in Europe that we can achieve with LBL reduction will be boarder than simply severe patients. But I don't think I can go in to more detail than that and my preference is to wait until we and Genzyme discuss that in more detail. So, right suffice to say we are working hard at we feel very good about what where we are. Brent Kelly – Collins Stewart Llc: No is this something that we would learn in '09 in terms of Europe? Stanley T. Crooke: We are working at it. And we expect to yes. Brent Kelly – Collins Stewart Llc: Okay. Stanley T. Crooke: And but this Genzyme is driving this and so I don't want to speak to this its Genzyme's work and Genzyme should be speaking directly to this. Brent Kelly – Collins Stewart Llc: Okay. Thank you.

(Operator Instructions). And we will go next to Eric Schmidt from Cowen & Company. Eric Schmidt – Cowen & Company: Good morning. Stan or Lynne the press release mentioned your greater confidence in mipomersen safety profile with the added clinical experience. Can you just kind of provide us with an update on the rough numbers of patients that have now been exposed to the drug 3, 6 or say 12 months? Whatever metrics you want to use? Stanley T. Crooke: Well Eric I don’t want to, because the numbers change everyday obviously. Eric Schmidt – Cowen & Company: Yeah. Stanley T. Crooke: The longest exposure that we have with the drug is about two years now, and I think the total number of patients is approaching 500 or 600 somewhere in that range and all of the current studies has a dosing schedule of 26 weeks, and the opportunity to move, to rollover into an open label or extension study at one sort or another. So, we are certainly getting a lot more experience longer than 13 weeks as we speak with a lot of patients. Eric Schmidt – Cowen & Company: Any rough number of patients who may have completed 26 weeks? Stanley T. Crooke: I don’t have that and I would be uncomfortable giving it Eric because tomorrow it will be different. Eric Schmidt – Cowen & Company: Okay. Stanley T. Crooke: But if you just think about the fact that CS17 continues, which is the long-term open-label extension and that CS5, which is the homozygous FH trial has completed enrollment quite sometime ago. And the other trials are enrolling at a very rapid clip, you can see that we are adding people treated for longer than 13 weeks at a very fast pace. Eric Schmidt – Cowen & Company: Okay. That's helpful thanks on the outcome study that I think Genzyme has now indicated it will start next year. Can you provide us with any rough details on the size and scope of that trial size and timelines, I guess? Stanley T. Crooke: Our thinking about that has, that the total numbers and so on has not changed dramatically. And so we still subscribe to the view that it will be somewhere in the 5000 or there about patient range maybe to eight. And the discussions that we're having relate to do we use more patients shorter time or fewer patients longer time, and all of these things and they are still in discussion. So, these are really complicated studies we do especially with the subcutaneous drug and we are spending a lot of time planning, and I know it seems like long time to plan. But getting this right is much more important than getting it started this, at a particular moment. So, I just ask you to bare with us there is just a kind of planning going on to design that trial properly. Eric Schmidt – Cowen & Company: Okay. And on the financial guidance maybe more for Lynne you ended, you currently have little over $650 million in cash and the guidance calls for ending the year at $550 million. So, I guess I just want to be clear. Does that guidance not include any new partnerships or significant milestones or any other cash in flows? B. Lynne Parshall: What we typically do, when we do our guidance is to provide you with very conservative guidance and we always do better than our guidance, which is I think what you guys expect. So, we take the things that we expected to get, but which maybe contingent and handicap them significantly. So, those numbers do include a little bit of stuff that’s not guaranteed, but very, very little and when we look at it, it ends up being sort of if you get one of the things that you’ve handicapped, you get the whole amount because everything is discounted substantially. We are pretty conservative in our forecasting, so we feel very confident about the projection. Stanley T. Crooke: Yeah, I mean the short and simplest answer is that it doesn't contain a meaningful amount of uncommitted money. Eric Schmidt – Cowen & Company: Okay. Thank you very much.

And we'll take our next question from Aaron Reames from Wachovia. Aaron Reames – Wachovia Capital Markets, LLC: Thanks for taking my questions and congratulations on the year. Given the fact that you're maintaining your headcount. How much additional capacity does Isis have for validating targets advancing weak candidates into the clinic and does that provide any limitation on the type of transactions that you will be looking at. Should we think that these are predominately going to be target in weak candidate based or would they be potentially therapeutic focused? Stanley T. Crooke: We believe that we can, with the group of people that we have today. Add three to five new drugs a year, every year. I know that sounds like a very remarkable statement. But if you look at what we’ve done you can see that all we’re really talking about is doing what we have already been doing. And as you know, we want to keep the size of Isis in the same in the range that we are now. So, that then and our strategy is to license drugs at Phase II. So, the source of transactions that we're willing to consider are transactions that support moving into areas that we're not currently in that don’t require significant growth in our research organization. And transactions that are strategic enough to provide real value in therapeutic areas where we are working that give our, might get partners access to some drugs from some therapeutic areas. In addition to transactions that might include licensing our drugs, if you think about over the next year to 18 months, we will have proof-of-concept events with quite a range of drugs, each of those events will be, we will evaluate what the data look like and whether we feel the drug is ready to partner and each of those opportunities presents, the opportunity to generate a very large transaction, just similarly to what we do with mipomersen, whether we will have a mipomersen size transactions depends on the data. So, it's all of those, it's all of those things in addition of course our satellite companies continue to advance. Altair is doing great things with our aerosol drugs, ATL continues to move along OncoGenex moves along, Alnylam continues to do well, Regulus is moving along and each of those enterprises provide an opportunity to generate, earlier stage and later stage deals and each of those can contribute directly to the kinds of cash we generate and the kinds of P&L that we put together. So, it's quite the thing about having so much going on is that there were all sorts of options and opportunities, I don't know if I've helped you. I guess the answer is if you think about Isis core the transactions that we are willing to do are relevantly focused and more limited than we have in the past, but if you think of Isis plus all of our associated companies you can see all sorts of transactions contribute to our bottom line. Aaron Reames – Wachovia Capital Markets, LLC: Okay, that's helpful. And then on 3715, I know you have to see the data, but if we do get positive data would you expect then to expand the Phase II development program or would you, consider licensing after you just have a one Phase study, Phase II study. So, basically would you try to get longer duration exposure and some experience in combination with some other agents, how should we think about the step after 3715? Stanley T. Crooke: Well, the logical next step, whether we partner the drug or not, is to go to 26 weeks, 13 weeks is just not long enough for a Type 2 diabetes drug trial. And it's also logical that you would put the drug in combination with at least metformin and possibly other drugs. So, I think the logical next step, no matter who does it is that sort of work it won't be ready for Phase III when we finish this Phase II trial. Aaron Reames – Wachovia Capital Markets, LLC: Okay Stanley T. Crooke: Whether we have been partnered or not will depend on the quality of the data. If we think the data are encouraging, that we will get a better partnership done if we do a single or two additional Phase II trials that's what we do, if we think that data are even more supportive then we think that we are going to get a good deal with those data then we will do that it just depends on the data. Aaron Reames - Wachovia Capital Markets, LLC: Okay, thanks. And then just a last question I had is, I was wondering if you could expand on you had mentioned the new generation 2.5 chemistry, is that in fact the back backbone or is it a modification of the ling and phosphorothioate bridge and are any of those changes already incorporated into the SGLT2 compound or other compounds that are in the pipeline? Stanley T. Crooke: SGLT2 and CRP and SOD1 and the other drugs that we're putting into the clinic now are what we call 2.2. They're all the same chemistry, but have been optimized to take advantage of RNA SAGE and they are product of an ever more robust screening process. And those molecules we hope will give us about a three to five fold increase in potency over generation 2. So, if you think of mipomersen, minimum effective dose of 50 milligrams a week and the therapeutic dose that we are using, 200 milligrams a week, you could see that those drugs might be as potent as a dose that we might use at a 100 milligrams a week or somewhere in that range, maybe even less than that. Generation 2.5 is new chemistry and the generation 2.5 chemistry will be a novel sugar modification we are quite confident of that. And we will make that transition from the current chemistry to this new chemistry very cautiously because it represents a significant change we have been investing in this now for many years and we will spend the next year or 18 months more evaluating multiple members of these chemical classes in mice and monkey and lots of other species to be sure we make a good choice. When we make that choice, we expect that chemistry to give us at least a 10-fold increase in potency over the 2.2. So, we would hope that we might be in the range of somewhere around 10 milligrams to 20 milligrams a week or less. That then of course gives us a quantum set forward in the performance of the drugs and it now makes oral bioavailability and oral administration commercially feasible. So, that's the direction we are traveling, we think we are close enough to talk about it. This is the first time, we have said that sometime in the near future we will be bringing this chemistry forward that reflects the confidence that we are close and it reflects the progress that we've made over the last five or six years looking at this new advance. Did I answer your question Aaron. Aaron Reames - Wachovia Capital Markets, LLC: Yeah. Thank you for taking the questions and I appreciate the answers. Stanley T. Crooke: Okay.

And we will take our next question from Carol Werther from Summer Street. Carol Werther – Summer Street Research Partners: Hello. Stanley T. Crooke: Hi Carol. Carol Werther – Summer Street Research Partners: Stan, which of the trials have completed enrollment from mipomersen? Stanley T. Crooke: The homozygous FH trial. So, that’s what we call CS-5 that’s the first trial that’s the trial we started earliest it’s a 50-patient trial in patients with homozygous FH, in which mipomersen is added at 200 milligrams a week to maximum dose lipid-lowering therapy and the patients are evaluated after 26 weeks of treatment. Carol Werther – Summer Street Research Partners: Okay, great. And can you just Lynne could you just tell us about how much you expect to spend in CapEx? B. Lynne Parshall: Our capital expenditures historically are extremely low again since we're not doing any major renovations, it really represents, replacement of lab equipment and new lab equipment. This year actually we have a slightly larger capital expenditure because we are readying our second manufacturing suite to make launch supplies as mipomersen and so well historically our capital expenditures are on the order of several million dollars a year this year it will be in the $10 million to $15 million range. Carol Werther – Summer Street Research Partners: Okay great. And should we expect to see the some of the mipomersen data at Hart later this year, the homozygous? Stanley T. Crooke: We aren't prepared at this point to say more than, we expect to be able to give you information in the middle of the year. Carol Werther – Summer Street Research Partners: Okay, great. Thank you.

And we will take our next question from Eun Yang from Jefferies. Eun Yang – Jefferies & Company: Thanks very much. On the mipomersen clinical development for the first $125 million Isis is going to spend for the development, but after that you guys are sharing 50:50 with the Genzyme, based on your spending assumption for mipomersen clinical development do you think the 50:50 share could take place later this year or sometime early next year? Stanley T. Crooke: No. We actually think that the drug will be on, everything changes when the drug becomes commercialized. So, if you're looking for the first event in those two events, we think the commercialization will take place. Eun Yang – Jefferies & Company: Okay. And the next question you might have disclosed in the past. Is there a milestone associated with the successor with this homozygous study data expected later year from Genzyme? Stanley T. Crooke: There is a milestone for NDA filing and I believe that that milestone is $50 million. Eun Yang – Jefferies & Company: 50. Stanley T. Crooke: 50. Eun Yang – Jefferies & Company: Okay. Thanks very much. Stanley T. Crooke: You bet.

And we'll go next to Jim Birchenough from Barclays Capital. James Birchenough – Barclays Capital: Yeah. Hi guys. A couple of questions, just one for Lynne, your guidance for year end cash of $550 million and at the same time you are guiding to cash flow positive I am just wondering if there is a use of cash that we are missing that takes us down from 650 to 550 over the course of the year? B. Lynne Parshall: Yeah. The cash flow positive Jim is not from operations, it is representative of the $175 million that we got at the beginning of the year from Abbott. James Birchenough – Barclays Capital: Okay got it. B. Lynne Parshall: Yes. James Birchenough – Barclays Capital: Okay, that's clear. And then just on the homozygous FH trial, do you have any sense right now of what percent of patients are going on to the open label extension? Stanley T. Crooke: Yes I do, but I am not going to tell you. James Birchenough – Barclays Capital: I have to try. And Stan just a bigger picture at the point at you filed mipomersen with FDA, it would be the first systemic antisense drug the FDA would be looking at. I am wondering if you've had any discussions with them about them needing to see other antisense data. Are they interested in safety data from other programs, so they can get comfortable with the technology or do you said but just going to look at mipomersen itself? Stanley T. Crooke: Well as you know, we've had ongoing dialog with the FDA about this technology for 20 years, we've helped developed many of the processes that are used to evaluate these drugs. And mipomersen will actually not be the first systemic drug to be submitted to the FDA for approval. So, our sense is that the FDA is reasonably, parts of the FDA are reasonably conversant with these drugs, the manufacturing, analytical all those sort of background things, we think are in very good shape at the FDA they understand what we do and how we do it and as a general rule like what we do. So, the things that can often cause problems with drugs especially new classes of drugs, we are not very concerned about. And so I guess our thinking is that the focus of the FDA will be pretty specific on mipomersen from a safety and efficacy point of view, they will of course have background information on the performance of lots of other drugs that that in contrast to small molecules, where you don't learn anything that information will help inform them, but I think the safety and efficacy will be focused right on mipomersen and whether it adds value to patients with severe cardiovascular risk factors. James Birchenough – Barclays Capital: Great. And just one final question, I know in the past there has been some enthusiasm about oncology targets like Survivin and Clusterin, haven't heard a lot about any of those programs moving into pivotal programs or when we might see data, could you maybe update where your partners are at with the oncology side of the business? Stanley T. Crooke: Well, one of the most exciting reports from us and our partners last year was OncoGenex is a randomized Phase II trial, in which they showed and when you added OGX-011 to docetaxel in first line treatment of prostate cancer you got a dramatic improvement in survival. That’s really quite exciting, and I think that again I think those data need to be reviewed and detailed and it needs to be reproduced, but if they are reproduced I think it will represent really quite an exiting break-through in prostate cancer. So, we are quite encouraged by that and OncoGenex is ready to begin Phase III trials. With regard to Survivin, Lilly is completing important trials and we hope that Lilly will be discussing some of the results with Survivin, we are certainly very encouraged by what we are hearing. So, we are very confident now, that with second generation antisense drugs, we are getting good concentrations of drug in human cancers reducing target I think the demonstrations of that with Clusterin, Survivin and others is very compelling, and if we have the right target, target reduction then leads to the biological effects that we hope that will have an effect on cancer. So, we are quite we are reinvigorated about the notion of these drugs for cancer treatment and that’s why we have reinitiated our cancer program. James Birchenough – Barclays Capital: Thanks. Stanley T. Crooke: Very, very encouraged Jim. James Birchenough – Barclays Capital: Thanks Stan. Stanley T. Crooke: I think with that we are at about an hour, and we are to bring the question and answer period to a close. So, [Carny] if you can do that. Thanks everyone for your interest, and we will keep you posted as we progress this year.

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