March 2009 marks the 20^th anniversary of the invention of the Web.   Like all great inventions, it arises out of an unmet need that badly needed a solution.  Tim Berners-Lee foresaw the great potential that can be unlocked by connecting data across disparate operating systems.  You can see the full talk by Tim Berners-Lee as he explains it at:

Fast forward to 2004 when the term “Web 2.0” was first coined.  This term now generally has the connotation of instant “read-write” and increased connectivity on the Web as exemplified by applications like Facebook, MySpace and Twitter.

How will such technology impact upon the busy scientists’ workflow in terms of searching, compiling, organizing, sharing and analyzing peer reviewed journal articles?  A new crop of journal reference management applications have emerged within the last 18 months.  The term “journal reference management” is used here as opposed to the older term “bibliographic management” to emphasize the importance of managing and linking the bibliographic data with the PDFs.

The biggest frustration for the busy scientists is the difficulty of locating and managing the PDFs from a set of bibliographic data.  I have listed a number of recently released journal reference management applications that addresses to a certain degree this frustration.

Zotero
A research tool that helps you gather, organize, and analyze sources.
www.zotero.org

Labmeeting
Organize, search, and store your paper collection and lab protocols.
www.labmeeting.com

Pubget
Similar to Pubmed, except you get the PDFs right away.
www.pubget.com

Mendeley
Academic software for managing & sharing your research papers.
www.mendeley.com

At WizFolio, we started 2 years ago with a vision of creating a web based application that would manage bibliographic data and PDFs with the same ease that you would MP3 files.  Tightly coupled with the application is a citation tool that the user can customize on-the-fly with instantaneous preview.  We invite you to give WizFolio Web 2.0 a try at www.wizfolio.com and appreciate any feedback and comments that will make the application better. 

10 Reasons to use WizFolio Web 2.0

WizFolio simplifies journal reference management…almost as if it is magic.
	1.	You hate manual data entry. So do we. Manually entering all the bibliographic data for a reference is a waste of time. WizFolio lets you key in the minimal amount of information needed to identify a reference (e.g., partial title, name of author) and retrieves the matching bibliographic data for you. See Tutorial
	2.	Import references from Clipboard Copy references to WizFolio, and the full bibliographic data will be retrieved from Pubmed in a flash. Why hasn’t anyone thought of that? See Tutorial
	3.	Import bibliographic data directly from webpages WizAdd grabs bibliographic data, videos, patents and selected information from any webpage into your WizFolio account. A great productivity tool. See Tutorial
	4.	Locate PDFs faster than before After you click on “Locate PDF”, WizFolio will either download the PDF or bring you to the page closest to the PDF.
	5.	Obtain bibliographic data from PDF Upload your PDFs and WizFolio will attempt to locate the bibliographic data.
	6.	Cite as you write with WizCite Use the WizCite plug-in to manage your in-text citations and bibliographies in Word. With just one click, your desired citations can be inserted into Word. What’s more, besides being able to choose from 62 preloaded citation styles, you can customize your own citation style, review changes and save it for future use. Applying a citation style automatically changes all the citations in the Word document. See Tutorial
	7.	Share journal references with colleagues To share a folder with your colleagues, simply drag-and-drop their names into the folder.
	8.	Continue using your current collections Switching from other software to WizFolio is easy. Export your current collections to an .ris file and import directly into WizFolio. You can also export your WizFolio collections as an .ris file as a backup. See Tutorial
	9.	Say goodbye to endless updates Because WizFolio is a web-based application, there’s no need to update your software ever. We do it all for you.
	10.	What?! All this is free? Yes, the Basic Version is free.

The increasing importance of monoclonal antibody as a therapeutic modality is exemplified by Genentech’s $256 million worth of royalty in 2007 and a projected growth of 15% to 25% in 2008 as reported by the WSJ.  The royalty income is based mostly on a single patent generally known as the Cabilly II patent which have been the subjects of my previous blogs.  The Cabilly II patent relates to the basic methods for making monoclonal antibody using recombinant DNA technology.  As such, if you are importing, selling, or manufacturing monoclonal antibody drugs in the US, the chances are you will have to pay royalty to Genentech.

The latest development in this high stake game is that Genentech and MedImmune has reached a settlement with undisclosed terms.  This litigation is rather complicated and goes back to 2003.  MedImmune had licensed certain intellectual property rights from Genentech, but challenged the validity of one of the licensed patents from Genentech. The litigation revolves around the assertion that MedImmune did not breach its license agreement with Genentech by such a challenge.  For more detail discussion please see this article from law.com.

The Cabilly Controversy

Genentech’s Cabilly II Is Revoked

I have had a life long fascination with inventions and the inventive process.  How does the inventive process work?  In an excellent article titled “In the Air, Who says big ideas are rare?” by Malcolm Gladwell published in the May 12, 2008 issue of the New Yorker, gave some insight into the inventive process.  Gladwell eloquently argues that inventions and great ideas do not occur de novo but rather such inventions and ideas predicate on knowledge that have been previously accumulated.  He also paraphrases the famous sociologist Rober K. Merton:

“A scientific genius is not a person who does what no one else can do; he or she is someone who does what it takes many others to do. The genius is not a unique source of insight; he is merely an efficient source of insight.”

Gladwell’s article suggests the notion of “multiples” in which there are numerous thinkers out there with access to the same information.  The possibility of several thinkers simultaneously coming up with the same great idea is a more frequent occurrence than we think.  Gladwell’s original article illustrates such occurrences with many fascinating case histories.

The US Patent system is based on the first-to-invent concept.  Thus, if more than one inventor files for the same invention, the patent is awarded to the person who is able to demonstrate that he is the first to reduce the invention to practice.  For patent systems in the rest of the world the first-to-file principle is followed.  In this case, regardless of the number of “multiples”, the first inventor to file takes precedent.
When there are two US patent applications or when there is a pending US application and an issued US patent of less than a year old claiming the same invention, an “interference proceeding” may be held to determine which inventor should take precedent.  “Multiples” are not uncommon in medical device inventions.  A surgeon sees a problem and comes up with a solution (invention).  Another surgeon also sees the same problem and may come up with a similar or an identical solution. 
Interference particularly in the biotech industry can be a high stake game and may drag on for years.  I have written about the Cabilly patent in a previous blog and have recently followed the story with an update.

For years the relationship between doctors and the pharmaceutical industry has been under scrutiny.  The same magnifying glass is gradually being applied to surgeons and the medical device industry.  Within the last twelve months this type of scrutiny has intensified on the orthopedic community. This culminated in five leading US orthopedic companies being investigated.  The investigation resulted in the orthopedic companies agreeing to a Deferred Prosecution Agreement in September 2007 (see my Sep 2007 blog).  Although not admitting any liability, they agreed to pay a huge sum money and also agreed to be subject to oversight for 18 months by a US federally appointed monitor, pertaining to past consulting arrangements with healthcare professionals.  Zimmer alone paid the government $170 million.  One of the best attended symposiums at the recent annual meeting of the American Academy of Orthopedic Surgeons is the symposium on doctor-industry relation.  Certainly the situation is changing and advocate groups are getting more insistent and the industry is trying their best to comply with government’s initiative (see Associated Press’ report). 

For the medical device industry where ideas, innovation and identifying unmet medical needs, traditionally comes from surgeons and doctors.  There is a need to balance reform with judicious management of physician’s conflict of interest.  We need to be mindful not to throw out the baby with the bathe water.

Genentech the owner of the Cabilly patent announced on Monday February 25, 2008 that it has received notification from USPTO that the patentability of the claims in the Cabilly patent has been rejected.  This is a high stake game with millions of royalty payment at stake.

As discussed in my previous blogs, the Cabilly patent (also known as the Cabilly II patent for this particular case) covers the method of making monoclonal antibodies and antibody fragments.  Genentech in addition to using the technology to make it own drugs (Avastin, Herceptin and Rituxan) also license the technology to other companies.  Many billion dollar drugs such as Humira and Remicade for rheumatoid arthritis (Abbot and J&J) and Erbitux for colorectal cancer (Imclone) need the Cabilly patent for their manufacture.

This notification is in the form of a Final Office Action does not mean the end of the Cabilly patent.  Because of the huge amount of royalty is affected, Genentech will no doubt appeal the decision to the Board of Appeals of USPTO.  In the meantime the patent is deemed to be still valid pending the Appeal and this may take up to 2 to 3 years and Genentech can continue to enforce the patent and collect royalties.

Read my previous posts on Cabilly Patents
Cabilly I
Cabilly II

FDA is an agency within the United States Department of Health and Human Services and is mandated to regulate through its subdivisions Center for Devices and Radiological Health (CDHR) for medical devices and Center for Drug Evaluation and Research (CDER) for drugs with respect to safety and efficacy.  In addition to safety and efficacy, FDA regulates almost every facet of prescription drugs and use of medical devices, including testing, manufacturing, labeling, advertising and marketing.   The intent is to protect the public against fraudulent claims and to ensure safety of the consumers.  The intent of FDA is not to regulate the practice of medicine.  Within this context, a drug or medical device that has been approved by FDA for a specific use can at the discretion of the physician be legally used for conditions other than those approved by FDA.  Such practice is called the off-label use of an FDA approved product and the rules of the game are changing, at least for the companies. 

Companies have in the past have been prohibited to promote drugs or medical devices for uses that have not been specifically approved by FDA.  The leeway for companies to make such promotions may widen slightly.  The new guidelines (draft for public comments) would permit manufacturers and companies to distribute reprints from peer-reviewed journal articles.  Several categories of reprints are prohibited under this guideline including special supplements, letters to the editor, early-stage trials in healthy patients, and articles that are “inconsistent with the weight of credible evidence.”

This move by FDA is not without controversy.  As reported in WSJ Health Blog Randall Lutter, FDA deputy commissioner for policy stated that  ”Articles that discuss unapproved uses of FDA-approved drugs and devices can contribute to the practice of medicine and may even constitute a medically recognized standard of care,”.  Lutter maintained that “This guidance also safeguards against off-label promotion.”

Not everyone agrees with this latest intended move by FDA to what some deemed as facilitation of off-label use.  A particularly vocal opponent of this FDA initiative is Congressman Henry Waxman, a California Democrat.  He wrote a cautionary letter to the FDA citing danger of such a move as potentially short circuiting the FDA regulatory process and opens the door to abusive marketing.  He quoted Senator Estes Kefauver warning that if promotion of unapproved uses was allowed, “the expectation would be that the initial claim would tend to be quite limited, which, of course, would expedite approval of the new drug application.”  The implication here is that companies would then “promote” and “widen” the unapproved indications through the distribution of reprints from peer-reviewed journal articles touting the off-label use of such drug or device.  The controversy remains if this is after all necessarily a bad thing and not to the interest of the public.

Wall Street Journal has an excellent article on this issue.

There is a marked contrast between the US and Canadian health care systems.  Having worked in both systems, I have often compared them staying as in Days Inn as the only choice (for Canadians) as opposed to the US system where you have a choice of staying either at the Hilton and or the Budget Motel.  The freedom to choose comes at a price and some may say too much.  An opinion piece published in the prestigious New England Journal of Medicine on Feb 7, 2008 blaming the failure of market forces to deliver optimal health care is surely going raise this issue to the next level of debate in this election year.  This article is written by Robert Kuttner, a well known and well respected left-leaning liberal writer-commentator.  He is the co-founder and co-editor of The American Prospect,  “an authoritative magazine of liberal ideas,” according to its mission statement.

He crafted very cogent arguments for his point of view against a backdrop of the US health care system being an outlier against international practices.  Medicare statistics indicate that the average cost of health care for every person in the United States is $7,000 and this amounts to over $2.1 trillion.  He offered an alternative interpretation how the US health care system ended in the current extreme state of failure.  He stated that the pervasive commercialization of health care not only did not create an efficient market but has unintended consequences contributing to the massive market failure.   Kuttner claims that market forces for cost containment are generally targeted at maximizing shareholder values and the burden has fallen on the primary care physicians with increased case load, relying on tests rather than hands on diagnostic skill and referring to specialists when none is necessary.

Read more…

We are currently working in stealth mode on a journal article management plus academic networking software.  This has been previewed by a limited and trusted audience.  The initial reaction was why are you doing another one when there is already Endnotes and now Zotero out there.  I needed justification and inspiration as to why we are doing this as I am funding this project myself.

I am sure Steve Job was confronted with the same type of skepticism when he worked on iTune, iPod and iPhone.  Then I began to do more research on this including viewing all the videos of Steve Jobs posted on Youtube.  It was an interesting journey of discovery including re-reading Steve Jobs’ commencement address at Stanford which I read more than 2 years ago.   Here is the full text……

Stay Hungry. Stay Foolish

This is the text of the Commencement address by Steve Jobs, CEO of Apple Computer and of Pixar Animation Studios, delivered on June 12, 2005 at Stanford.

I am honored to be with you today at your commencement from one of the finest universities in the world. I never graduated from college. Truth be told, this is the closest I’ve ever gotten to a college graduation. Today I want to tell you three stories from my life. That’s it. No big deal. Just three stories.

The first story is about connecting the dots.

I dropped out of Reed College after the first 6 months, but then stayed around as a drop-in for another 18 months or so before I really quit. So why did I drop out?

It started before I was born. My biological mother was a young, unwed college graduate student, and she decided to put me up for adoption. She felt very strongly that I should be adopted by college graduates, so everything was all set for me to be adopted at birth by a lawyer and his wife. Except that when I popped out they decided at the last minute that they really wanted a girl. So my parents, who were on a waiting list, got a call in the middle of the night asking: “We have an unexpected baby boy; do you want him?” They said: “Of course.” My biological mother later found out that my mother had never graduated from college and that my father had never graduated from high school. She refused to sign the final adoption papers. She only relented a few months later when my parents promised that I would someday go to college.

And 17 years later I did go to college. But I naively chose a college that was almost as expensive as Stanford, and all of my working-class parents’ savings were being spent on my college tuition. After six months, I couldn’t see the value in it. I had no idea what I wanted to do with my life and no idea how college was going to help me figure it out. And here I was spending all of the money my parents had saved their entire life. So I decided to drop out and trust that it would all work out OK. It was pretty scary at the time, but looking back it was one of the best decisions I ever made. The minute I dropped out I could stop taking the required classes that didn’t interest me, and begin dropping in on the ones that looked interesting.

It wasn’t all romantic. I didn’t have a dorm room, so I slept on the floor in friends’ rooms, I returned coke bottles for the 5¢ deposits to buy food with, and I would walk the 7 miles across town every Sunday night to get one good meal a week at the Hare Krishna temple. I loved it. And much of what I stumbled into by following my curiosity and intuition turned out to be priceless later on. Let me give you one example:

Reed College at that time offered perhaps the best calligraphy instruction in the country. Throughout the campus every poster, every label on every drawer, was beautifully hand calligraphed. Because I had dropped out and didn’t have to take the normal classes, I decided to take a calligraphy class to learn how to do this. I learned about serif and san serif typefaces, about varying the amount of space between different letter combinations, about what makes great typography great. It was beautiful, historical, artistically subtle in a way that science can’t capture, and I found it fascinating.

None of this had even a hope of any practical application in my life. But ten years later, when we were designing the first Macintosh computer, it all came back to me. And we designed it all into the Mac. It was the first computer with beautiful typography. If I had never dropped in on that single course in college, the Mac would have never had multiple typefaces or proportionally spaced fonts. And since Windows just copied the Mac, its likely that no personal computer would have them. If I had never dropped out, I would have never dropped in on this calligraphy class, and personal computers might not have the wonderful typography that they do. Of course it was impossible to connect the dots looking forward when I was in college. But it was very, very clear looking backwards ten years later.

Again, you can’t connect the dots looking forward; you can only connect them looking backwards. So you have to trust that the dots will somehow connect in your future. You have to trust in something - your gut, destiny, life, karma, whatever. This approach has never let me down, and it has made all the difference in my life.

My second story is about love and loss.

I was lucky - I found what I loved to do early in life. Woz and I started Apple in my parents garage when I was 20. We worked hard, and in 10 years Apple had grown from just the two of us in a garage into a $2 billion company with over 4000 employees. We had just released our finest creation - the Macintosh - a year earlier, and I had just turned 30. And then I got fired. How can you get fired from a company you started? Well, as Apple grew we hired someone who I thought was very talented to run the company with me, and for the first year or so things went well. But then our visions of the future began to diverge and eventually we had a falling out. When we did, our Board of Directors sided with him. So at 30 I was out. And very publicly out. What had been the focus of my entire adult life was gone, and it was devastating.

I really didn’t know what to do for a few months. I felt that I had let the previous generation of entrepreneurs down - that I had dropped the baton as it was being passed to me. I met with David Packard and Bob Noyce and tried to apologize for screwing up so badly. I was a very public failure, and I even thought about running away from the valley. But something slowly began to dawn on me - I still loved what I did. The turn of events at Apple had not changed that one bit. I had been rejected, but I was still in love. And so I decided to start over.

I didn’t see it then, but it turned out that getting fired from Apple was the best thing that could have ever happened to me. The heaviness of being successful was replaced by the lightness of being a beginner again, less sure about everything. It freed me to enter one of the most creative periods of my life.

During the next five years, I started a company named NeXT, another company named Pixar, and fell in love with an amazing woman who would become my wife. Pixar went on to create the worlds first computer animated feature film, Toy Story, and is now the most successful animation studio in the world. In a remarkable turn of events, Apple bought NeXT, I returned to Apple, and the technology we developed at NeXT is at the heart of Apple’s current renaissance. And Laurene and I have a wonderful family together.

I’m pretty sure none of this would have happened if I hadn’t been fired from Apple. It was awful tasting medicine, but I guess the patient needed it. Sometimes life hits you in the head with a brick. Don’t lose faith. I’m convinced that the only thing that kept me going was that I loved what I did. You’ve got to find what you love. And that is as true for your work as it is for your lovers. Your work is going to fill a large part of your life, and the only way to be truly satisfied is to do what you believe is great work. And the only way to do great work is to love what you do. If you haven’t found it yet, keep looking. Don’t settle. As with all matters of the heart, you’ll know when you find it. And, like any great relationship, it just gets better and better as the years roll on. So keep looking until you find it. Don’t settle.

My third story is about death.

When I was 17, I read a quote that went something like: “If you live each day as if it was your last, someday you’ll most certainly be right.” It made an impression on me, and since then, for the past 33 years, I have looked in the mirror every morning and asked myself: “If today were the last day of my life, would I want to do what I am about to do today?” And whenever the answer has been “No” for too many days in a row, I know I need to change something.

Remembering that I’ll be dead soon is the most important tool I’ve ever encountered to help me make the big choices in life. Because almost everything - all external expectations, all pride, all fear of embarrassment or failure - these things just fall away in the face of death, leaving only what is truly important. Remembering that you are going to die is the best way I know to avoid the trap of thinking you have something to lose. You are already naked. There is no reason not to follow your heart.

About a year ago I was diagnosed with cancer. I had a scan at 7:30 in the morning, and it clearly showed a tumor on my pancreas. I didn’t even know what a pancreas was. The doctors told me this was almost certainly a type of cancer that is incurable, and that I should expect to live no longer than three to six months. My doctor advised me to go home and get my affairs in order, which is doctor’s code for prepare to die. It means to try to tell your kids everything you thought you’d have the next 10 years to tell them in just a few months. It means to make sure everything is buttoned up so that it will be as easy as possible for your family. It means to say your goodbyes.

I lived with that diagnosis all day. Later that evening I had a biopsy, where they stuck an endoscope down my throat, through my stomach and into my intestines, put a needle into my pancreas and got a few cells from the tumor. I was sedated, but my wife, who was there, told me that when they viewed the cells under a microscope the doctors started crying because it turned out to be a very rare form of pancreatic cancer that is curable with surgery. I had the surgery and I’m fine now.

This was the closest I’ve been to facing death, and I hope its the closest I get for a few more decades. Having lived through it, I can now say this to you with a bit more certainty than when death was a useful but purely intellectual concept:

No one wants to die. Even people who want to go to heaven don’t want to die to get there. And yet death is the destination we all share. No one has ever escaped it. And that is as it should be, because Death is very likely the single best invention of Life. It is Life’s change agent. It clears out the old to make way for the new. Right now the new is you, but someday not too long from now, you will gradually become the old and be cleared away. Sorry to be so dramatic, but it is quite true.

Your time is limited, so don’t waste it living someone else’s life. Don’t be trapped by dogma - which is living with the results of other people’s thinking. Don’t let the noise of others’ opinions drown out your own inner voice. And most important, have the courage to follow your heart and intuition. They somehow already know what you truly want to become. Everything else is secondary.

When I was young, there was an amazing publication called The Whole Earth Catalog, which was one of the bibles of my generation. It was created by a fellow named Stewart Brand not far from here in Menlo Park, and he brought it to life with his poetic touch. This was in the late 1960’s, before personal computers and desktop publishing, so it was all made with typewriters, scissors, and polaroid cameras. It was sort of like Google in paperback form, 35 years before Google came along: it was idealistic, and overflowing with neat tools and great notions.

Stewart and his team put out several issues of The Whole Earth Catalog, and then when it had run its course, they put out a final issue. It was the mid-1970s, and I was your age. On the back cover of their final issue was a photograph of an early morning country road, the kind you might find yourself hitchhiking on if you were so adventurous. Beneath it were the words: “Stay Hungry. Stay Foolish.” It was their farewell message as they signed off. Stay Hungry. Stay Foolish. And I have always wished that for myself. And now, as you graduate to begin anew, I wish that for you.

Stay Hungry. Stay Foolish.

Thank you all very much.

Each year Time Magazine in conjunction with CNN come up with a list of best inventions for various categories.  Because of the large number of categories and each invention is listed on separate page (I guess for more advertising opportunities), it is cumbersome to go through all of them.  I have condensed the best inventions on the Health category into a single page.  The best invention in my opinion for the health category is….

1. PowerFoot One, is the world’s first actively powered foot ankle prosthesis.  The inventor an MIT professor is himself a double amputee.  The secret to long battery life is to recapture energy during walking.
   Time Link       iWalk
2. Schizophrenic mouse.  Akira Sawa of John Hopkins has been studying how variants of a gene called DISC1 increase the risk of schizophrenia.  The Sawa Laboratory has developed a schizophrenic mouse model that will some day lead to better understanding and perhaps better treatment for this debilitating form of mental illness.  This research group is trying to match findings obtained in patients with schizophrenia with those from animal models using MRI and PET.
   Time Link       Sawa Laboratory
3. Blood Type Conversion System.  Group O blood is highly desirable for blood transfusion because the red blood cells do not have A antigen or B antigen on their cell surfaces.  As such it can be transfused to patients with Group A, Group B or Group AB blood type and of course also to patients with Group O.  Therefore Group O blood type is also known as universal donor blood.  Danish scientists have discovered two bacterial enzymes that will cleave the sugar molecules eliminating the A and B antigens and thus converting the blood essentially to Group O blood.
   Time Link       ZymeQuest
4. Do it Right.  In the heat of a CPR resuscitation one can over compress or under compress the chest.  Worst still because of the intensity of the situation at hand (pardon the pun), we tend to compress the chest at a higher rate than is usually recommended.  A group of final year engineering student from McMaster University came up with a simple and elegant solution to this problem.  Sensors embedded in neoprene glove detect the pressure exerted by the palm and also keep track of the rate of compression.  The data feed back to the machine is used to determine the type of verbal cues offered to the resuscitator such as “compress faster”.
   Time Link       CPRGolove
5. Prognosticating Cancer Recurrence.  Amsterdam-based Agendia molecular diagnostics was one of the first companies to be approved under FDA’s new In Vitro Diagnostic Multivariate Index Assay (IVDMIA) Guidelines for their diagnostic kit for breast cancer prognosis.  Agendia’s proprietary gene expression analysis can identify older breast cancer patients at low risk for metastatic disease.  This valuable information can be use clinically to decide which treatment regime to use for specific breast cancer patients.
   Time Link       Agendia

My favorite invention this year is the cprGlove.  Simple and elegant solution to an unmet need.