Patent Docs

GSK's Sherry Knowles Responds to Post on BIO Session

    By Donald Zuhn --

On Wednesday, we posted a report on a BIO Super Session entitled "A Model Patent Office for the Future -- Promoting and Protecting Investments in Innovation" (see "Docs at BIO: Panel Offers Suggestions for Fixing the USPTO").  At that session, a panel consisting of Sherry Knowles (at right), Vice President of Corporate Intellectual Property at GlaxoSmithKline Biopharmaceuticals, Inc.; Q. Todd Dickinson, Executive Director for the American Intellectual Property Law Association (AIPLA); John Duffy, Professor of Law at George Washington University Law School; and Jeff Kushan, a Partner at Sidley Austin LLP, provided a long range view of what the model patent office of the future can and should look like to drive innovation and economic growth, and promote investment in IP-intensive industries.  Today, Ms. Knowles sent us a message to let us know that she believed the report did not accurately represent the gist of her comments at the BIO session.  The text of Ms. Knowles' message is provided below:

Don:

Your article inaccurately represented the gist of my comments at BIO.  To be accurate, my position is that the success of the pharmaceutical and biotech industries are directly linked to the success of the US Patent Office.  I said it is not just up to Congress, the courts or the new Commissioner to fix the Patent Office issues, it is up to all of us as stakeholders to play an active role to make sure the PTO's problems are solved.  I concluded the session by saying we should all put the past frustrations and rhetoric behind us and fully support the new PTO Commissioner with a new spirit of cooperation.

Gene Quinn's articles in IPwatchdog.com on the new attitude of Dep. Commissioner Focarino are refreshing and show the PTO is trying to go in the right direction.  We want to work closely with the new administration to accomplish these goals.

The comment about the potential "train wreck" referred to the statistics showing a decreasing allowance rate and decreasing filing rate (which leads to a smaller PTO budget) in combination with an increasing backlog of applications.  This is a matter all of us must proactively propose solutions for.

I am of the opinion that the PTO fee sheet can be used to incentivize behavior and is a better means to regulate filings, submissions and claim presentation than absolute restrictions.  A structure can be implemented that provides relief for small entities and patent applicants for whom this presents a hardship.

I would appreciate it if you post this response.

Sherry Knowles

Our goal in reporting on the BIO session was to provide a fair summary of all of the panelists' comments for Patent Docs readers unable to attend the session.  To the extent that the report did not accomplish this goal, the publication of Ms. Knowles' e-mail should help clarify her intended message.  In addition, as regular readers are well aware, we have previously expressed the opinion that the patent community owes a debt of gratitude to GSK for leading the challenge (along with Dr. Tafas) against the continuation and claims rules (and, as a result, for perhaps playing a role in the USPTO's decision to put the IDS, Markush, and appeals rules packages on hold).  Thus, in publishing our prior report, there was no intent to diminish these important efforts (see links below).

• "Federal Circuit Hears Oral Argument on Tafas Appeal," December 8, 2008
• "GSK Files Brief in Tafas v. Dudas Appeal," September 25, 2008
• "USPTO Posts Comments on New Rules for Alternative Claiming," April 23, 2008
• "No April Fool's Joke -- Tafas and GSK Win on Summary Judgment," April 1, 2008
• "Managing Intellectual Property Releases MIP 50," July 28, 2008
• "U.S. Senate Mailbox Filling with Letters against Passage of Patent 'Reform' Bill," January 18, 2008
• "Enjoined New Rules and Patent Reform Finally Appearing on Biotech Industry's Radar," December 20, 2007
• "Tafas v. Dudas; SmithKline Beecham Corp. v. Dudas (E.D. Va. 2007)," October 31, 2007
• "AIPLA Supports GSK's Lawsuit Against the Patent Office's New Rules," October 25, 2007
• "GSK Brings Out the Big Guns Opposing the New Continuation and Claims Rules," October 24, 2007
• "Hooray! - (Finally) the Big Dogs Have Joined the Hunt," October 11, 2007

Docs at BIO: Lilly Counsel Discusses Patent Issues Regarding Personalized Medicine

    By Donald Zuhn --

In a Breakout Session entitled "The Emerging Promise of Personalized Medicine," a panel consisting of Cindy Collins, Group Vice President at Beckman Coulter, Inc.; Brian Barrett, Associate General Patent Counsel at Eli Lilly & Company; Dr. Courtney Harper, Associate Director for Toxicology at the Office of In Vitro Diagnostic Device Evaluation and Safety of the Food and Drug Administration; and Sheldon Bradshaw, a partner and regulatory attorney at Hunton & Williams, LLP, addressed the business, scientific, and legal challenges for the commercialization of personalized medicine on Tuesday at BIO 2009.  Mr. Barrett's presentation would likely have been of most interest to Patent Docs readers, as his focus at Lilly is on patent procurement.  In Mr. Barrett's portion of the presentation, entitled "Unpredictable Patent Protection and Inadequate Data Protection:  Key Obstacles to Developing Personalized Medicine," he listed a number of patent obstacles for personalized medicine and then briefly touched on data exclusivity with regard to proposed follow-on biologics legislation.

With regard to patent-related obstacles for personalized medicine, Mr. Barrett discussed the recent Association for Molecular Pathology v. U.S. Patent and Trademark Office gene patenting case, and noted that the Supreme Court has not had an opportunity to address the patentability of "isolated DNA."  He also noted that the landmark Diamond v. Chakrabarty decision involved human intervention rather than isolation.  Mr. Barrett also discussed the impact of Laboratory Corp. v. Metabolite Laboratories, Inc. (LabCorp), In re Bilski, and the pending appeal in Prometheus v. Mayo on medical diagnostics.  He next addressed the possible impact of the Supreme Court's decision in KSR International Co. v. Teleflex Inc. on optimization (i.e., tailoring) of therapeutics to individual patients, and then touched on a number of decisions impacting nucleic acid patentability, including In re Fisher, In re Kubin, and Ariad v. Eli Lilly & Co.  Patent Docs readers are no doubt quite familar with the above cases.  Mr. Barrett concluded the patent obstacles portion of his talk by briefly discussing anticipation by experimental use, inherent anticipation, inequitable conduct, compliance with the best mode requirement, inducing infringement, and injunctions in view of eBay Inc. v. MercExchange, L.L.C.

On the topic of data exclusivity, Mr. Barrett highlighted the exclusivity periods in the two pending House follow-on biologics bills (the Waxman and Eshoo bills), and noted that because data protection and patent protection were not additive, the Waxman bill would provide insufficient protection for innovator drug companies.  He stated that innovators, who learn a lot about a therapeutic "deep into" Phase II clinical trials, would be well past the 5.5 years of data protection afforded under the Waxman bill by the time such knowledge had been gathered.  When asked during the question and answer portion of the session whether there was a compromise level of data exclusivity that innovators could live with (i.e., something lower than the maximum 14.5 years provided under the Eshoo bill), Mr. Barrett responded that the Eshoo period "was the compromise" since the data protection period is "currently unlimited" (in the absence of a follow-on biologics regulatory pathway).  Perhaps not surprisingly, Mr. Barrett's response was identical to the one BIO President and CEO Jim Greenwood gave Patent Docs at the BIO IPCC conference in March.

For additional information regarding many of the obstacles discussed in Mr. Barrett's presentation, please see:
• "Association for Molecular Pathology v. U.S. Patent and Trademark Office," May 17, 2009
• "Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. (Fed. Cir. 2009)," April 6, 2009
• "In re Kubin (Fed. Cir. 2009)," April 5, 2009
• "Second Follow-on Biologics Bill Is Introduced in House," March 18, 2009
• "Waxman Introduces Follow-on Biologics Bill," March 11, 2009
• "Applying In re Bilski to Diagnostic Method Claims," February 5, 2009
• "Personalized Medicine: A Patent Office Perspective," December 11, 2008
• "KSR Int'l Co. v. Teleflex Inc. (2007)," April 30, 2007
• "In re Fisher (Fed. Cir. 2005)," November 9, 2006

Meet the Docs at BIO 2009

The Biotechnology Industry Organization (BIO) is holding its annual BIO International Convention this week at the Georgia World Congress Center in Atlanta.  Founded in 1993, BIO is a nonprofit association seeking supportive biotechnology policies on behalf of more than 1,200 biotechnology companies, state and international affiliates, and related organizations, as well as providing business development services for many emerging biotech companies.

As part of the Convention, more than 2,200 biotech companies, organizations, and institutions are expected to participate in the BIO Exhibition.  Patent Docs Donald Zuhn, Kevin Noonan, Sherri Oslick, Mark Chael, and Andrew Williams will also be attending BIO as part of the MBHB contingent.  Patent Docs readers who may be attending BIO this week are encouraged to stop by booth #4343 to meet the Docs and talk a little biotech patent law.

IPO Releases List of Top 300 Patent Holders for 2008 - Updated

"Biotech/Pharma" Top 43

    By Donald Zuhn --

The Intellectual Property Owners Association (IPO) released its 26th annual list of the top 300 organizations receiving U.S. patents.  Patent Docs Readers may recall that the U.S. Patent & Trademark Office stopped releasing its annual list of top patent recipients in 2006 in order to "discourag[e] any perception that we believe more is better."

The IPO stated that while it does not intend for the report to "encourage or discourage patenting," it would continue to publish its annual list of top recipients because "the number of patents granted is one of the few objective measures of the patent system as a whole and the patenting activities of individual industries and companies."  The IPO compiled its list by counting the number of utility patents granted during 2008 on which an organization or its subsidiary was listed as the owner on the face of the patent.  However, the IPO attributed patents that were granted to two or more organizations jointly to the organization listed first on the patent.  The IPO noted that 157,772 patents were issued in 2008, which was an increase from the 153,283 patents that issued in 2007 (but still lower than the 173,771 patents that issued in 2006).  The top fifteen companies on the IPO Top 300 are listed below.

 

UPDATE:  The IPO has revised its list to indicate that Hitachi finished 3rd with 2,197 patents in 2008.

As with the 2007 and 2008 rankings, we used the IPO's list of top patent holders to compile a list of the top "biotech and pharma" companies and organizations receiving U.S. patents in 2008.  While our list of companies and organizations numbered 51 for 2006 and 47 for 2007, we were only able to compile a list of 43 biotech and pharma companies and organizations for 2008.  Each organization's IPO top 300 ranking for 2008 is indicated in the "'08 IPO Rank" column; the IPO top 300 ranking for 2007 (if available) is indicated in the "'07 IPO Rank" column.  Please note that some of the companies and organizations listed below may be involved in non-biotech or non-pharma work, and therefore, that a portion of the patents granted to these companies may be directed to other than biotech and pharma-related inventions.  In addition, our list is a little inclusive in that we included medical device companies.

UPDATE:  The IPO has revised its list to indicate that Dow Chemical Co. finished 206th with 82 patents in 2008.  In our Biotech/Pharma Top 47 for 2007, Dow Chemical Co. finished 33rd (and 229th overall) with 76 patents.

Interestingly, the so-called Coalition for Patent Fairness, which has lobbied for substantial patent "reforms" that would arguably weaken patent rights in the U.S., placed a significant number of its corporate partners on the IPO's top 300 list.  Of the fourteen corporate partners listed on the group's website, twelve made the top 300 (only Autodesk and Palm did not), and five of these companies placed in the top 25.

For additional information regarding this topic, please see:
• "IPO Releases List of Top 300 Patent Holders," May 22, 2008
• "IPO Posts List of Top 300 Patent Holders," April 20, 2007

Author of Nature Article Provides Rebuttal; Patent Docs Provides Surrebuttal

On Wednesday, we reported on an article, entitled "The dangers of diagnostic monopolies," that appeared in the March 26th edition of Nature (see "Genetic Diagnostic Testing: The 'Anti-Commons' Revisited?").  Today, we received an e-mail from one of the authors of the article, Robert Cook-Deegan (at right), providing some additional comments regarding the article:

This is a very thoughtful take on our article.  I disagree with much of it, but not for the reasons you might predict.  I think if you read through the case studies that underlie this summary commentary in today's Nature, you'll find the reason for specifying the "problems" as we did.

My main point here:  the problems we specify are identified as such by the companies, health professionals who order the tests, and those who get tested -- everyone says they want to avoid them, and the companies say their informal policies are to, for example, permit unfettered basic and clinical research, and to ensure that everyone gets a second opinion and has their test paid for by their insurance or health plan.  If you're prepared to defend patent rights when they cause these problems -- and sometimes they do -- then that's where we can have productive disagreement.

Two other key points where patents in this area differ -- and here I really do urge you to read the case studies and see if you agree.  The word "monopoly" is not a scare word when it describes the reality.  The companies in these case studies -- Athena, Myriad, and Clinical Data/PGxHealth -- do have effective monopolies for testing for some of the conditions (and not others, the point of comparisons); that is their business plan.  It is completely legal, and as the case studies make plain, it's not a slam dunk for either the pro-patent camp or the anti-patent camp (and believe me, we'll get shot at from the other side too).  The tests have been on the market for over ten years in many cases, and in no case has someone "worked around" the key patents when those center on DNA sequences for the consensus sequence or the most common mutations associated with disease.  Myriad has been in effect the sole provider in the US.  (One little aside -- the reason BRCA testing options in Europe are different are because Myriad's patent position has been much weaker there -- so I didn't quite follow your train of argument on that point.)  So it is simply misleading to say such patents do not lead to monopoly effects.  Sometimes they do; and sometimes they don't (other cases also covered in the case studies -- see comparison to colon).  When they do, the problems we note can arise.

The peculiar dynamics of genetic testing  explain why patents on one or a few common mutations can dominate testing for an entire condition caused by many different genes or different mutations in the same gene.  An example:  if you have long-QT syndrome, you don't know which mutation or even which gene might be causing it.  You send your sample for testing to find that out.  Until recently, PGxHealth had a monopoly for such testing by having exclusive rights to Utah patents for some of the most common mutations associated with long-QT.  It was the only place you could send samples to get tested for those and other mutations.  BioReference Labs Inc. has now secured countervailing exclusive rights on other mutations, so that monopoly probably won't continue.  It seems to be an instance of mutually blocking patents -- because neither lab can know in advance whether they are infringing the others' patents until they find out which mutations that particular patient has.  Until BRLI acquired contervailing exclusive rights, no one else was offering testing because PGxHealth had the exclusive rights to common mutations.  Through exclusive rights on the common mutations, PGxHealth has gotten all the business for those mutations as well as patients with long-QT caused by unpatented variants and mutations in undiscovered genes.  This is not necessarily bad (arguments on both sides), and it is unlikely to be catastrophic -- the companies can cross-license or find some other accommodation.  But the situation until recently is fairly and accurately described as a monopoly, and a monopoly not only on the patented inventions but extending to other causes of the same clinical condition.  So I don't agree there is an inherent contradiction in our logic; monopolies can indeed form (but they can also prove unstable in the face of countervailing exclusive rights).

The point about the necessity of the patent incentive is particular to this use of patents, not patents in general.  We do not make these arguments in therapeutics, vaccines, or instruments.  The evidence that a patent incentive is not needed comes from reference labs and academic labs that already offer a test when the exclusively licensed test hits the market.  In that case, it is tautological that the patent incentive was not needed.  The role of patents in that case is to shut down competitors.  That is, of course, a common use of patents and a reason they exist and how they often work; but it is nonetheless evidence that the patent was not needed to create the product or service.  This is not Pfizer keeping Lilly and Merck from making Viagra or Lipitor.  These are commercial labs eliminating testing by reference labs and academic health centers.  We are careful not to judge whether that is a good or bad thing -- there are plenty of arguments on both sides -- but the social benefit of patents in those cases is not that they create tests that would otherwise never come to be.

I do think you're on thin ice and won't be very persuasive if you rest your case on "just live with it" arguments about access to health goods and services.  Here I stick to my guns.  If we can specify problems that could be solved by weakening monopoly rights a little at the margin when they conflict with patient access, then we should do so.  At root, this rests on a premise that patents are instrumental rights balancing net social benefit, not an inherent right, and so constraining them is fair game when doing so promotes social benefit.

But thanks for being first out of the gate in rekindling a debate on this.  Really.  This is great.  And thanks for keeping it civil.

Kevin Noonan (at right), of course, provides a response:

I don't doubt that there are circumstances and situations where the problems you outline in your commentary could occur.  My critique stems from my understanding that the evidence strongly suggests that the problems do not (at present) exist.

As you mention, I have not reviewed the underlying case studies, and we will blog on the HHS White Paper in a future post.  But turning to what I do understand, there are good reasons to believe that the "problems" you outline are not problems at present.  For example, if companies permit basic and clinical research, or ensure that "everyone" gets a second opinion, then the informality of the policies does not trump the consequences -- exactly what you propose be done under threat of patent unenforceability.  If there is an example of a company that has sued a university researcher engaged in basic research, or has refused a patient from getting a second opinion, by all means identify it and let's talk about how to solve the problem.  Revising patent law isn't the only option -- good corporate citizenship seems to be working effectively to prevent the types of predation your commentary warns against.

My reaction to using the term "monopoly" is several-fold.  First, even if not intended, it has a negative connotation.  If that is your opinion, fine, but I will react to it based on its use in anti-patent polemic.  It is also inaccurate because patents by definition have only a limited right -- to exclude others from making, using, selling, offering to sell or importing the patented article or method in the U.S. during the term of the patent.  It does not prevent someone from designing around the patent, and the patent by definition discloses the identity of the gene involved in disease pathology.  All this information is fair game for a competitor to look for other, unpatented ways to achieve the same diagnosis.  You are right that the exclusivity is important for diagnostic companies' business plans -- as I mentioned in my piece, the cost of validating these tests so that they can be reliably used with actual human patients is typically much higher than the cost of the original genetic observation, and without patent exclusivity no one would take the risk on that type of investment.  The fact that no one has "worked around" the patents you cite is, as you much recognize, a very small sample for interrogating a very big question:  it is possible that the earliest genetic diagnostic tests are just robust enough to be hard to design around.  But these tests are ten years old -- how long until they are "off patent" and then fair game for competitors to use for free in perpetuity?

The situation you described between PGxHealth and Bioreference Labs is precisely that which the patent system envisions -- the development of blocking patents between competitors that require cross-licensing.  But as you admit, any "monopoly" is both unstable and short-lived -- the quid pro quo of having the companies disclose their inventions so they can be practiced freely after the patents expire.  The alternatives -- and they are potentially myriad -- are instances where the underlying basis for the diagnostic assay is undisclosed as a trade secret.  In that case (which weakening the patent system would encourage) there would be no disclosure and thus no end to the (non-patent based) monopoly.

I don't intend to rely on "just live with it" arguments.  I merely contend that you identify a host of theoretical or potential problems that, even if they existed would, at their worst, be inherently time-limited and associated with positive benefits for the public.  These benefits include disclosure of the underlying disease-associated polymorphisms, development of the genetic information into robust diagnostic tests, and incentives for others to design-around the patented tests.  I disagree that your proposals would weaken patents at the margins -- the proposals in your commentary would impose your concepts of morality and public benefit -- patient rights -- for mine, or others.  There are certainly instances where that may be appropriate; the Federal government has "march-in" rights for any test developed with Federal grant money, as well as an inherent right to license any patent to any third party for its own use (with compensation through the Court of Claims).  These rights have not been lightly exercised, for good reason, but they exist for instances when they are necessary.  But I think there is little need to impinge on patent rights that underlie investment in genetic diagnostics to solve problems -- such as patient access and insurance coverage -- better addressed by other routes.

Thanks for your response.

Genetic Diagnostic Testing: The "Anti-Commons" Revisited?

    By Kevin E. Noonan --

"Monopoly" is a loaded buzzword when it comes to patents.  It is imprecise, indeed incorrect, but it can be effective in appealing to prejudices that emphasize a negative view of patent rights.  It also effectively telegraphs the writer's own prejudices, so that when it is used in the title of a putatively academic article it can be particularly jarring.

Such an article appears on-line today in the March 26th edition of Nature, in a commentary by Robert Cook-Deegan (lower left), Subhashimi Chandrasekharan, and Mishra Angrist (lower right) of the Institute for Genome Science and Policy at Duke University.  Entitled "The dangers of diagnostic monopolies," it is reminiscent of nothing so much as Eisenberg and Heller's "The Tragedy of the Anti-Commons" in 1998, positing potential problems in the (then) uncertain future of gene patenting, in the context of little support for the espoused position.

The authors of today's Nature commentary admit, in the first paragraph, that the recent report from the Health and Human Services Secretary's Advisory Committee on Genetics, Health and Society disclosed little to no "irreparable" harm to genetic diagnostics from patenting, but assert that "neither have [patents] proven greatly advantageous."  At best, the authors' own research "detect[ed] no pervasive effects of patenting that consistently help or hinder clinical access to genetic testing."  This is consistent with the overwhelming majority of studies showing that the anti-commons aren't tragic after all.  Nonetheless, the authors contend that there are "some" problems that "could be addressed" to benefit everyone -- "patients, researchers, health professionals and companies alike."

The authors' primary concerns are (here we go again) "monopoly situations" -- i.e., when patents are exclusively licensed to one provider.  Why this is a concern is unclear, since they report that "prices of patented and exclusively licensed tests are not dramatically or consistently higher than those of tests without a [wait for it] monopoly."  Moreover, the patent incentive is "usually not necessary."  But the authors go on to state that the effects of patents ("monopolies," of course) on test quality are "equivocal."  And the relationship between quality issues relating to Myriad's BRCA test could not "be ascribed only to the monopoly" (although they assert without support that "[t]est quality is a general problem but monopolies can exacerbate it").  It would be reasonable to conclude from the information discussed in the article to this point that patents are, if anything, neutral with regard to genetic diagnostic tests.

Even benefits associated with sole providers (exclusive patent licensees), such as establishing standards of care, are described as being suspect.  The authors answer the question: "Is a standard of care set by a single provider desirable?" by noting that European companies "take various [alternative] approaches" before performing BRCA tests.  If BRCA tests are reliable, however, what is the benefit of alternative testing?  The authors do not say, merely that "[i]f [if] alternatives are valuable, exclusive licenses limit their availability."  If available alternatives are not patented by the exclusively-licensed single provider, it is unclear how exclusive licenses for BRCA tests could limit availability for those (other, distinct, unpatented) tests.

The authors also bemoan the "fact" that exclusive licenses (actually, the patents underlying them) are difficult to design around.  There is a flaw in the logic behind this assertion, however.  Noting that "[m]ost genetic disorders are heterogeneous -- different genes and mutations lead to clinically similar syndromes," the authors state that "[a]n exclusive license to one or a few common genes or mutations can drive testing to one provider."  On the contrary, the existence of such heterogeneity suggests that it should be difficult for one patentee to cover the entire field, and that continued research on such diseases and the heterogeneous genetic bases thereof should provide a variety of tests controlled by a variety of patentees (much like the co-existence of varieties of pharmaceuticals that address the same underlying pathology).

The authors do raise a legitimate issue -- whether full-genome sequencing efforts will encounter a "patent thicket" comprising patent holders owning rights to specific genetic polymorphisms.  These concerns are real but not realistic, in view of the technical obstacles for the technology (not performing the sequencing but accurately interpreting the data to provide a useful genetic diagnostic test) and the developing legal obstacles to diagnostic testing in general, in view of the Federal Circuit's decisions in Classen Immunodiagnostics, Inc. v. Biogen Idec, In re Bilski, and Justice Breyer's patent musings in the Laboratory Corp. v. Metabolite Labs., Inc. case.  They also ignore the reality that most of the patents existing today will have expired before any of these issues are likely to have been sufficiently resolved to make genomic sequence-based diagnosis a commonly-available diagnostic tool.

The authors eventually arrive at their message -- that "patient rights" should "trump" patent rights for genetic diagnostic tests.  Indeed, the authors identify six "obstructive practices" that should "negate gene patent enforcement," consistent with their goal of whose rights should be trumped.  These include exclusive rights-holders whose policies do not permit:

• Basic and clinical research, including genetic testing in clinical trials or health-services research;
• Performing a test in a form that it does not offer (such as prenatal or preimplantation diagnosis);
• Testing in a territory where the company does not offer a test but has exclusive rights;
• Getting second opinions or verification testing;
• Testing those not covered by its payment agreements with insurers and health plans; and
• Research and development to make testing more comprehensive, more accurate or less expensive.

Opponents of patents frequently raise the issue of "patient rights," typically conflating issues such as reproductive rights or genetic privacy with patent issues, and simplistically framing the issue as one of individual "rights."  These authors do not make these mistakes, but they do seem to forget the realities of the U.S. healthcare system.  The "patient rights" they believe should trump patent rights are solely economic ones (since even the accessibility issues devolve to economics).  But in America, the one right patients don't have when it comes to medical treatment or diagnosis is an economic one.  Healthcare in this country depends intimately on what each individual patient can afford, or if they have benefits through their employer, what their employer provides.  The patent system didn't create this situation and weakening patenting won't solve it.

What weakening the patent system will do is make it less likely that the fundamental research done at universities (where researchers are indeed not motivated by patent concerns) will be translated into useful genetic diagnostic tests.  There is enormous expense required to convert the genetic observations made in a laboratory into a validated diagnostic test that physicians can rely upon in making diagnostic and therapeutic decisions.  This is as it should be -- such tests should be thoroughly vetted before patients are asked to make critical decisions about their health in reliance upon them.  Without the exclusivity provided by patents, there would be little incentive for investors to take the risk that the result of such expenditures will be a robust, reliable genetic diagnostic test.  Restricting patent rights in ways that reduce patent exclusivity can be expected only to reduce these incentives.  This outcome would impinge on a more fundamental patient right than the ones discussed by the authors -- the right to quality and reliable clinical care based on innovation in the genetic bases of human disease.  While the sentiment underlying the authors' commentary may be admirable, they have identified the wrong villain.  In that, of course, (at least lately) they have no monopoly.

President Obama Reaffirms Faith in Science

    By Kevin E. Noonan --

In all the understandable excitement surrounding President Obama's lifting of the Bush Administration's ban on federal funding for embryonic stem cell research, his broader message may have gotten lost.  Overturning the stem cell ban is just a part of a return to the tradition, the guiding principle in Western societies since the end of the Dark Ages, to use the scientific method and its results to understand the world and make rational decisions on policy based on science instead of ideology. 

This tradition was suppressed during the Bush years.  The evidence for this conclusion is rampant:  there have been several books published describing the undue influence of ideology (Seth Shulman's Undermining Science: Suppression and Distortion in the Bush Administration, University of California Press, 2006; Chris Mooney, The Republican War on Science, Basic Books, 2006), as well as dozens of editorials (collected by the Union of Concerned Scientists here).  The Union has also collected its Periodic Table of these abuses).  While the Bush administration's antipathy to the evidence of global warming is well known, there are several other important issues where ideology trumped science, such as abortion and its psychological and medical effects; various specific environmental policies involving endangered species; and political litmus and loyalty tests for scientists appointed to advisory and other federal panels.

President Obama has been on record for some time as being opposed to this philosophy.  In a radio address in December, announcing members of his scientific and technology advisory team, he said:

[T]oday, more than ever before, science holds the key to our survival as a planet and our security and prosperity as a nation.  It is time we once again put science at the top of our agenda and worked to restore America's place as the world leader in science and technology.  Because the truth is that promoting science isn't just about providing resources -- it's about protecting free and open inquiry.  It's about ensuring that facts and evidence are never twisted or obscured by politics or ideology.  It's about listening to what our scientists have to say, even when it's inconvenient -- especially when it's inconvenient.  Because the highest purpose of science is the search for knowledge, truth and a greater understanding of the world around us.  That will be my goal as President of the United States.

A distinct change from the immediate past.

In his remarks on Monday, President Obama reiterated some of these sentiments:

This Order is an important step in advancing the cause of science in America.  But let's be clear:  promoting science isn't just about providing resources -- it is also about protecting free and open inquiry.  It is about letting scientists like those here today do their jobs, free from manipulation or coercion, and listening to what they tell us, even when it's inconvenient -- especially when it's inconvenient.  It is about ensuring that scientific data is never distorted or concealed to serve a political agenda -- and that we make scientific decisions based on facts, not ideology. 

By doing this, we will ensure America's continued global leadership in scientific discoveries and technological breakthroughs.  That is essential not only for our economic prosperity, but for the progress of all humanity.

That is why today, I am also signing a Presidential Memorandum directing the head of the White House Office of Science and Technology Policy to develop a strategy for restoring scientific integrity to government decision making.  To ensure that in this new Administration, we base our public policies on the soundest science; that we appoint scientific advisors based on their credentials and experience, not their politics or ideology; and that we are open and honest with the American people about the science behind our decisions.  That is how we will harness the power of science to achieve our goals -- to preserve our environment and protect our national security; to create the jobs of the future, and live longer, healthier lives.

Amen.

For additional information regarding this or other related topics, please see:
• "President Obama to Life Stem Cell Limits on Monday," March 8, 2009

President Obama to Lift Stem Cell Limits on Monday

    By Donald Zuhn --

The New York Times reported late last week that President Obama will satisfy one of his campaign pledges on Monday when he reverses limits imposed by the Bush administration on embryonic stem cell research.  In August of 2001, the Bush administration ordered that federal research be limited to lines of cells that were already in existence at the time.  President Obama is expected to allow federal research on not only stem cell lines already in existence, but stem cell lines that have yet to be created.  In addition, the President will be asking the National Institutes of Health to come up with new stem cell research guidelines within 120 days of the announcement.

Accompanying the President for the announcement, which is scheduled to take place at 11:45 am (Eastern) in the White House, will be a number of Democratic and Republican legislators who support the reversal.  Among the lawmakers who have been invited to attend the announcement are Senators Dianne Feinstein (D-CA), Tom Harkin (D-IA), Orrin Hatch (R-UT), Edward Kennedy (D-MA), and Arlen Specter (R-PA), and Representatives Michael Castle (R-DE) and Diana DeGette (D-CO).  According to the Times, President Obama will also take the opportunity to speak about a return to "sound science" during his administration, fulfilling a campaign promise to separate politics and science.

In an additional report in today's edition of the Times, officials in the Obama administration noted that the President would be looking -- but perhaps not expressly asking -- for some cooperation from Congress with respect to its own stem cell ban.  In particular, the President would like Congress to overturn the Dickey-Wicker amendment, first passed in 1996, which prohibits the use of tax dollars to create human embryos or to conduct research in which embryos are destroyed, discarded, or knowingly subjected to risk of injury.

Congress has already begun work on the stem cell issue with the introduction last month of three bills in the House (H.R. 872 and H.R. 873) and Senate (S. 487).  The bills would amend the Public Health Service Act to require the Secretary of Health and Human Services to conduct and support research that utilizes human embryonic stem cells, regardless of the date on which the stem cells were derived from a human embryo.  The two House bills, which were sponsored by Rep. DeGette and co-sponsored by Rep. Castle, Tammy Baldwin (D-WI), Mary Bono Mack (R-CA), Lois Capps (D-CA), Russ Carnahan (D-MO), Charles Dent (R-PA), Gene Green (D-TX), Mark Kirk (R-IL), James Langevin (D-RI), Ed Perlmutter (D-CO), and Fred Upton (R-MI), differ in that H.R. 872 also directs the National Institutes of Health to issue guidelines for such stem cell research.  The Senate bill, which was sponsored by Sen. Harkin and co-sponsored by Sen. Feinstein, Hatch, Kennedy, Specter, Harry Reid (D-NV), and Jeanne Shaheen (D-NH), is similar to H.R. 873.  Similar bills were passed by both the House and Senate in 2007, only to be vetoed by then-President Bush.  At a press conference to announce the introduction of the Senate bill, Sen. Specter said the legislation was needed so that "this important policy change . . . does not ping-pong back and forth with each successive President."

New Administration Will Act Quickly to Jump-Start Stem Cell Research

    By Donald Zuhn --

Last week, we reviewed prior Patent Docs reports discussing some aspects of President-elect Barack Obama's technology platform, including his positions on patent issues and follow-on biologics (see "A Second Look at President-elect Obama's Technology Platform").  We also reported on the response by some in the patent community to last week's election (see "Reaction to Historic Presidential Election").  While the results of presidential election -- and shake-up in Congress -- will almost certainly have a significant impact on U.S. patent policy and the creation of a follow-on biologics regulatory pathway, the election results will also impact biotech and pharma research.  No area of the biotech industry is likely to see swifter and more pronounced change than that portion of the industry which is focused on stem cell research.

On Monday, the Washington Post confirmed what many of the President-elect's supporters already knew:  an Obama Administration will be good for stem cell research (see "Stem cell supporters await their Obama moment").  According to the Post, John Podesta, the co-chair of the President-elect's transition team and President Clinton’s Chief of Staff from 1998 to 2001, stated that the President-elect plans to quickly reverse President Bush's 2001 directive limiting federal funding of human embryonic stem cell research.  Geron Corp. CEO David Greenwood and Parkinson's Action Network CEO Amy Comstock Rick expect that as a result of the policy reversal, the industry will see a surge in funding.  The Post notes, however, that for the next few months the industry will have to deal with the Bush Administration's status quo, since President Bush is expected to make no changes in his current stem cell policy.  Addressing the current stem cell climate, White House Press Secretary Dana Perino asserted that "scientists from all over the world, and especially here in our country, have shown their innovation and their abilities to do embryonic stem cell research and make huge leaps in achievement without destroying embryos."

While things look far better for stem cell researchers from a policy standpoint, the Associated Press reported today that stem cell researchers will be facing a new obstacle in 2009:  a lack of funding resulting from the current financial crisis (see "Obama election no panacea for stem cell industry").  The true impact of the financial crisis on stem cell research is hard to gauge, however, since the AP report notes that federal funding restrictions have led to much duplicative spending (as one example, the article cites Harvard's Stem Cell Institute, which purchases one set of equipment for use in federally funded research and another set of equipment for use in non-federally funded research).  In addition, a reversal of the Bush Administration's stem cell policy might lure back stem cell research that moved to China or Singapore.  Any reemergence of the U.S. stem cell industry, however, will depend on an influx of investment dollars, as funding in this country has declined by 65% since 1999.  According to the AP report, one possible group of investors may be drugmakers, who are looking for ways to deal with the loss of patent protection on approximately $24 billion worth of drugs in 2009.

Human embryonic stem cells image: Ryddragyn, Wikipedia Commons

Patents Online Announces New Patent Search Engine

    By Donald Zuhn --

Patents Online, LLC, the company behind FreePatentsOnline, today announced the release of a companion online service, SumoBrain.  The service, which was launched this summer, offers an alternative to patent search pay services by providing free cross-collection searching, portfolios, saved search capabilities, alerts, bulk PDF download capabilities, and collaboration tools.  According to the company's release, SumoBrain was initially conceived as a subscription service, but Patents Online decided to make the service completely free.  Patents Online CEO Erik Reeves noted that the FreePatentsOnline database, from which SumoBrain will draw its search results, currently includes 8,812,656 patents.  SumoBrain permits full-text searching of U.S. patents (1976-present), published U.S. applications (2001-present), European patents and published European applications (1991-present), PCT publications (1978-present), and English abstracts of Japanese patent applications (1996-present).  PDFs can be obtained for U.S. patents (1790-present), published U.S. applications (2001-present), European patents and published European applications (1978-present), and PCT publications (1978-present).

National Medal of Technology and Innovation Winners Announced

    By Donald Zuhn --

The U.S. Patent and Trademark Office announced today that U.S. Secretary of Commerce Carlos Gutierrez joined President Bush last week in identifying the winners of the 2007 National Medal of Technology and Innovation.  The award, previously known as the National Medal of Technology, is the highest honor that the President can bestow on American innovators for technological achievement, and is administered by the Patent Office.  The 2007 laureates will receive their medals in a ceremony at the White House on September 29.

Among the 2007 recipients of the National Medal is Dr. Roscoe O. Brady (at left), a Senior Investigator at the National Institutes of Health.  According to the Department of Commerce release, Dr. Brady's discovery of the enzymatic defects in hereditary metabolic disorders such as Gaucher disease, Niemann-Pick disease, Fabry disease, and Tay-Sachs disease, led to the development of a highly effective enzyme replacement therapy to treat patients with many hereditary enzyme-deficiency disorders.

Also receiving the National Medal will be Dr. Adam Heller  (at right), a Research Professor and Professor Emeritus at the University of Texas at Austin College of Engineering.  According to the Department of Commerce release, Dr. Heller's contributions to electrochemistry and bioelectrochemistry led to the development of products that have improved the quality of life of millions, particularly in the area of human health and well-being.  Dr. Heller is a named inventor on nearly 100 U.S. patents.

Four other individuals and two corporations will receive medals in September.

TauRx Therapeutics and University of Aberdeen Present Data on Potential Alzheimer's Drug

    By Christopher P. Singer --

In a July 29, 2008 presentation at the Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) in Chicago, scientists involved in a collaboration between the University of Aberdeen and TauRx Therapeutics discussed data demonstrating that their candidate drug, rember, appears to slow the progress of the Alzheimer's disease.  According to a press release from the University of Aberdeen as well as TauRx's website, rember is a small molecule Tau Aggregation Inhibitor that targets the tangles (aggregates of abnormal fibres of tau protein) that form in nerve cells in the brains of Alzheimer's patients.

The data presented by the scientists indicated that patients receiving the therapeutic experienced an 81% reduction in cognitive decline over one year, and did not experience a significant decline in their mental function over the course of 19 months.  Brain imaging data performed by TauRx was said to suggest that the drug had the most significant effect in the regions of the brain thought to be critical for memory function and where the tangle density is typically high.

Dr. Claude Wischik, TauRx's Executive Chairman, and a Professor at the University of Aberdeen, characterized the Phase 2 clinical results as representing the first real hope that it may be possible to arrest progression of Alzheimer's disease.  Following up on this promising clinical data, TauRx is planning to begin a Phase 3 trial next year.  If the Phase 3 trial confirms the Phase 2 findings, the drug could be available by 2012.

FDA Includes Genotyping Advisory in Black Box Warning

    By Kevin E. Noonan --

One of the promises of the genomics revolution of the late 20th Century is the advent of personalized medicine.  The belief was (and is) that the unfolding understanding of genetic variation stemming from sequence analysis of genes known or discovered to be involved in an individual's response to a drug would permit physicians to identify which patients should (and more importantly) should not receive a particular drug.  In addition to these benefits for individuals, the prospect of understanding how genetic variation affected drug responses was also believed to provide a way to screen populations of drug trial participants, to avoid clinical trial failures for pharmaceutical lead compounds because the trial population contained individuals whose genetic makeup was inappropriate for the drug.

Like a great deal of the biotechnology revolution, these prospects have not generally come to fruition.  There have been some applications of the personalized medicine paradigm (excessive toxicity of Camptosar® (irinotecan) for colon carcinoma is associated with the *28 variant of UGT1A1 enzyme, for example), but by and large most patients and their physicians do not test their genotype before taking (or prescribing) a drug.  This makes those instances where the genetic component is taken into account more noteworthy; the latest example involves GlaxoSmithKline's drug abacavir (structure at right), a reverse transcriptase inhibitor drug used widely for infection with the human immunodeficiency virus and its sequellae, acquired immune deficiency syndrome.  It is sold as Ziagen®, and is also a component in two other AIDS medications, Trizivir® (abacavir sulfate/lamivudine/zidovudine) and Epzicom® (abacavir sulfate/lamivudine).

The reason for genotype testing is simple:  the Food and Drug Administration has determined that administering the drug to people having the 'wrong' genotype can be life-threatening.  The problem is a severe allergic reaction in people with a particular variant gene in the human immunohistocompatibility complex.  This variant, HLA-B*5701, is associated with more than a 15-fold increase in the incidence of a hypersensitivity reaction (from 4% to 61%) when these patients are administered the drug, and prescreening for the variant reduces the incidence of hypersensitivity reactions from 7.8% to 3.4%.  Symptoms of the reaction range from the merely annoying (rash, nausea) to the severe (fever, breathing difficulties).

The FDA posted the following notice on its website earlier today:

FDA informed healthcare professionals that serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701.  FDA reviewed data from two studies that support a recommendation for pre-therapy screening for the presence of the HLA-B*5701 allele and the selection of alternative therapy in positive subjects.  Genetic tests for HLA-B*5701 are available and all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications.  Development of clinically suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients negative for HLA-B*5701.

The association of this genetic variant with the hypersensitivity reaction was first reported in February by a multinational group including GSK researchers, in an article in the New England Journal of Medicine (see "HLA-B*5701 Screening for Hypersensitivity to Abacavir").

The drug currently bears this warning:

                                     WARNINGS

Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate).  Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis).  Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected.  Permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.  Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.

Reintroduction of ZIAGEN or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions.  Such reactions can occur within hours (see WARNINGS and PRECAUTIONS: INFORMATION FOR PATIENTS).

Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including ZIAGEN and other antiretrovirals (see WARNINGS).

The good news for GSK is that the percentage of the population bearing this variant is small -- about 5%.  The company also benefits from having a way of preventing this small percentage of patients from being harmed by the drug.  This may offset the negative consequences stemming from the FDA's intention to include the genotype advisory in a "black box" label for the drug, which alerts physicians to potentially significant side-effects but also can inhibit physicians from prescribing the drug in the first place.  Having a way to determine whether a particular patient falls outside the proscribed patient population should be sufficiently reassuring to physicians that prescriptions should not plummet as a consequence of the new labeling.

Docs at BIO: Steve Burrill's State of the Biotechnology Industry Report 2008

    By Kevin E. Noonan --

Steven Burrill, President and CEO of Burrill & Co., unveiled his company's "State of the Biotechnology Industry" report on Wednesday at BIO 2008 in San Diego.  Mr. Burrill (below) described developments globally that he anticipates will occur by 2020 and how those changes will impact the industry.

Mr. Burrill's vision is described on the company website as being "furutistic," but he contends these are just extensions of technology and social trends existing in the present day.  For example, he believes that medicine will change focus from passively waiting for disease or disability to appear for doctors to treat, to an extensive (and invasive) medical monitoring system, where medical sensors and diagnostics will become part of the daily routine.  Rather than having "family doctors," primary medical care in 2020 will be provided by "wellness centers" staffed by nurse practitioners relying on both diagnostic technology and personal medicine.  Individuals will carry a card, or have implanted a chip, detailing their personal genetic variations relevant to disease predispositions and drug susceptibilities/sensitivities, and their diagnosis will be determined while they shop in the rest of the store.  Serious diseases (heart disease, cancer) will be treated in specialized medical centers by specialist medical doctors and their staff.  And on a daily basis the emphasis will be on medical monitoring and surveillance with regard to drug treatment compliance and "lifestyle" choices such as smoking, alcohol consumption and diet.

Mr. Burrill responded to challenges to his vision by noting that the technology for a good deal of his schema already exists, and that current economic conditions favor trending in this direction.  He also noted that the current healthcare system will experience extreme financial stressors by as early as 2013, the date where the amount of Medicare revenues from payroll taxes will be exceeded by expect expenditures, and that a great deal of the current and expected costs on the healthcare system are either outright waste or are devoted to aspects of the system (such as administrative and reimbursement costs) that are not directly related to delivering care.  Importantly for his audience, he also mentioned that while the majority of Americans believe that drug costs account for 60% of overall healthcare costs in the U.S., the actual number is just 12%, and that this misconception has significant political consequences for the industry (including his acknowledgement that strong trend for generic drugs can be expected to continue if not accelerate).

The other trend Mr. Burrill described is the ascendancy of India and China as centers of research and development in the biotech/pharma industry.  Compelled by a growing middle class population and its attendant demands for a "more and better" life, these governments will continue the present trend of supporting development of "home grown" biotech and pharma industries.  Finally, he projected that agricultural biotechnology will play an increased role in addressing the world food crisis, but also used the AgBio industry as an example of how the social and political aspects of introducing biotechnology solutions must be addressed for the industry to remain successful.

The complete report can be purchased from Burrill & Co. ($430 + tax); sales at BIO 2008 include a CD-ROM of Mr. Burrill's presentation slides.

Will Biotechnology Solve the World Food Crisis?

    By Kevin E. Noonan --

The current crises in energy and food have followed eerily similar paths.  The founding of OPEC and the exponential rise in crude oil prices during and after the 1973 Arab-Israeli conflict produced a short-lived emphasis in the U.S. with fuel efficiency and smaller automobiles.  These were predominantly imported from Japan and U.S. automakers were unable to compete despite government efforts to encourage conservation, such as mandated fuel efficiency standards, "gas guzzler" taxes, and the 55 mph speed limit.  But during the 1980's and 1990's, as the relative cost of gasoline in the U.S. fell, U.S. automakers and consumers returned to bigger automobiles, particularly SUVs, as safety and room for suburban soccer moms and their broods were more important considerations than fuel efficiency.  Indeed, the small trend towards more fuel-efficient cars since the turn of the century was motivated more by the threat from greenhouse gases and global warming than fuel costs per se.  Until recently.

Similarly, the last time world food supplies were threatened by world population growth was the 1960's, and the response was "The Green Revolution," a combination of technology transfer and agricultural subsidies by individual Western governments, including our own and institutions like the World Bank.  These efforts were so successful that by the 1980's an American government official scoffed at the idea that poor and developing nations should be concerned with local agriculture when they could just "buy American."

But today the world food supply is dwindling as an increasing number of the increasing populations in countries like China and India are becoming prosperous enough to pursue a greater percentage of the food supply.  This has led to food riots in some countries and calls for increased government cooperation and subsidies for food.  As reported in a May 18th article in The New York Times, the world may soon reap what it has sown over the past twenty years, as a result of severe neglect of the infrastructure research and development efforts in countries around the world (see "World's Poor Pay Price as Crop Research Is Cut").  The Times article documents how research institutions like the International Rice Research Institute in the Philippines and the International Maize and Wheat Improvement Center in Mexico, remnants of the Green Revolution efforts, have suffered years of underfunding and neglect.  Ironically, these institutes and others have made scientific developments in insect resistance and increased yields that could address some of the causes of reductions in food supply, but don't have the funds to transfer the technology to the farmers, mostly impoverished, that most need it.  One example discussed in the article is the brown plant hopper, a rice pest that threatens rice harvests throughout Asia.  Scientists at the Rice Institute "have identified 14 genetic traits that could help rice plants survive" infestation by this pest, but there are no funds to support the work of transferring these traits into the most common rice varieties.  Staffing has been drastically cut (from 5 entymologists supervising 200 employees to 1 entymologist with a staff of 8) and the physical plant of the institute neglected.  A similar situation exists in the Maize and Wheat Institute in Mexico, where scientists have developed drought-tolerant corn that could be used in Africa and disease-resistant wheat that could be grown in parts of Asia.  But without funding, these new varieties cannot be sent to the places that most need them.

And while Western governments are awakening to the problem, they have not reversed a decades-long trend to reduce agricultural aid.  As cited in the article, the U.S. under the Bush Administration has slashed 75% of the monies this country gives to global efforts (and the researchers manning those efforts) to improve crops grown in poor countries.  What makes the situation worse is the penny-wise/pound foolish nature of American policies, since at the same time the Administration has asked Congress for an "extra" $770 million in food aid for poor countries.  The Times sets forth a series of informative graphs showing the decline in agricultural aid over the past 20 years (click on graphs to enlarge).

Agricultural support from the World Bank, for example, has dropped from $7.7 billion in 1980 to 2 billion in 2004 (although this trend may be reversed under the new President, Robert B. Zoellick, who has proposed doubling agricultural lending to Africa).  On the whole, the article states that Western countries have reduced agricultural aid from $6 billion in 1980 to $2.8 billion in 2006; U.S. support in that time frame has fallen from $2.3 billion to $624 million according to the Times.

The frightening reality is that the food supply is always finely balanced between agriculture and nature i.e., pests and diseases that affect yield, much like the constant battle between disease-causing microorganisms and antibiotics.  Traditional plant breeding programs, because they can take several generations or growing seasons to establish useful traits are more vulnerable to variations in support and effort and operate best when the research is sufficient to stay abreast if not ahead of diseases, pest, environmental changes, and other yield reducing phenomenon.  This is precisely what the world has not done over the past 25 years, and one of the reasons why worldwide agriculture is lagging behind population growth for the first time in more than a generation.  As Robert S. Ziegler, director general of the Rice Institute is quoted in the article as saying, "[c]utting back on agricultural research today is pure folly."

This is where biotechnology might provide an antidote.  One of the advantages of biotechnology as compared with traditional agricultural research is that it can be more easily targeted and new traits more rapidly introduced, as a consequence inter alia of being able to assess genotype as well as phenotype.  The biotechnology approach also has the benefit of being part of private enterprise, which can avoid the bureaucratic and political inertia associated with government-run programs.  The fruits of agricultural biotechnology can also have a plurality of applications, so that applying the technology to profit-making ventures can subsidize technology transfer to countries without the ability to afford it.  (In some ways this is already happening in the pharmaceutical industry, where drug pricing is much lower even in developing countries like Brazil as a result of government policies that force Western drug companies to provide lower drug prices.  Ultimately, the differential costs are borne by Western consumers more able to pay the full price.)  Under these circumstances, initiatives like the ones announced by Monsanto last week, pledging to provide pest-, disease-, and drought-resistant varieties of important crop species may become an important solution to the world food problems.

Only the naïve would not recognize the potential for abuses under a system where a significant component of global food technology is in private hands.  But the reality is that biotechnology provides the only known solution with the potential to alleviate the results of decades of neglect of more traditional agricultural research in a time frame short enough to make a difference between starvation and survival for the world's poorest inhabitants.  It would be unconscionable to forego the potential of biotechnology in these efforts.

For additional information on this topic, please see:

• "Monsanto Moves to Address World Food Shortages," June 4, 2008

Espresso: New Technology Search Engine

    By Donald Zuhn --

Dr. Michael Wisz, the Chief Technical Officer of Emerjent, Inc., recently contacted Patent Docs to inform us about Espresso, a new web-based search application that Emerjent is touting as "the premier emerging technology information search engine."  The search engine, which requires a free registration to access, can be found here.

According to Emerjent's website, Espresso differs from search engines such as Google and Yahoo because it relies on more focused searches of document collections that are "essential to tracking emerging technologies, especially those in biotechnology, chemistry, biology, and medicine."  These collections include all issued U.S. patents and published U.S. patent applications; peer-reviewed research papers; NIH, NSF, and SBIR/STTR research grants; grant solicitation announcements; news stories from 1000 "trusted technology sources," and market and web search data.  Emerjent notes that "[m]any of these documents are not even accessible from today's web search engines."  Emerjent also notes that because Espresso's collection of documents is smaller, it can go beyond typical indexing to extract information about people, companies, and universities, and then map connections between these entities.

Monsanto Moves to Address World Food Shortages

    By Kevin E. Noonan --

American opinion has finally turned in support of the idea that global warming, and ecological concerns in general, are relevant and important to themselves and their children (despite years of opposition, both formal and informal, from the current Administration and its fellow-travelers from energy corporations and the right wing).  In what could turn out to be a fortuitous combination of good public relations and good corporate citizenship, Monsanto today announced its intentions to be part of the solution to ecological problems rather than part of the problem.  As reported by Andrew Pollack in The New York Times ("Monsanto Seeks Big Increase in Crop Yields"), Monsanto chief executive Hugh Grant "pledged" to work to develop seeds that would increase corn, soybean, and cotton yields by 100% by 2030 and would reduce the amount of water, land, and energy needed to grow them by 30%.  Monsanto made the announcement at a meeting in Rome where world leaders were discussing the current crises of rising food costs and increases in food shortages.  While the Times (predictably) noted that Monsanto would stand to benefit from the effort in increased acceptance of its genetically-modified food, not even the Times could gainsay the benefits to the world population by the efforts.

Monsanto evinced its eagerness for collaboration in noting that the company had consulted with "farmers, political leaders, academics and advocacy groups" in identifying the necessary technological steps required to increase food production in the face of rising world population and harsher growing environments, as well as competing needs for vegetation such as biofuels.  Monsanto's position that biotechnology provides both an approach and an opportunity to address these issues was supported by U.S. Undersecretary of Agriculture Edward T. Schafer; the United Nations and World Bank have less sanguine views, reflected in a recent review of agricultural technology.  And some experts, such as Dr. James E. Specht, a "soybean genetic expert" at the University of Nebraska believes that the "hype-to-reality ratio [of Monsanto's plans] is essentially infinity."  Monsanto countered by citing new technology, specifically marker-assisted selection which it contended could "double" the rate of improvements produced by breeding.  The approach also has the advantage on the world stage of not involving foreign gene introduction into crops, thereby avoiding the "Frankenfood" label that has inhibited acceptance of Monsanto's existing genetically-engineered crops in Europe and elsewhere.  And Monsanto admits that, to achieve its lofty goals it envisions producing genetically-engineered cotton and corn varieties that could grow with reduced water and fertilizer requirements, a key need for a drier future.

Another aspect of Monsanto's new "warm and fuzzy" approach is a commitment by the company to share its technology with farmers in distressed areas, presumably at greatly reduced or no cost.  The Times article specifically mentions initiatives in Africa where Monsanto will forego royalties from farmers using to-be-developed drought-resistant corn.  Moreover, Monsanto is donating $10 million over the next five years to public programs directed to improvements in wheat and rice yields, two crops that have recently experienced sharp increases in price and decreases in supply.  It is expected that this work would be performed by universities and government agencies, since these crops are not within Monsanto's current corporate focus.

These actions are in sharp contrast with Monsanto's track record for its principle generically-engineered Roundup Ready® crops, which are resistant to Monsanto's Roundup® herbicide.  Monsanto has made headlines over the past year or so in winning several patent infringement and breach of contract lawsuits against individual farmers in the U.S., based on replanting of seed produced from genetically-engineered plants (see links below).  And Monsanto's foray into genetic engineering approaches to drought-resistant and other crop varieties capable of thriving under harsher environmental conditions expected in the near future has been criticized by non-governmental organizations like the Erosion, Technology and Concentration (ETC) Group, who are generally opposed to patenting technology (see "ETC Group Opposes 'Climate Ready' Gene Patent 'Grab'").

Even if Monsanto's plans are in no way related to such criticisms, its actions are consistent with the company's appreciation of a continuing trend:  it can be just as important to win the political and public relations battle as the legal ones in technology areas that impact human health and well-being.  Western pharmaceutical companies have learned that the establishment of the WTO has not led to the hoped-for respect for their patent rights around the world; indeed, through the Doha declaration and actions of individual countries in the developing world in implementing the WTO treaty, pharmaceutical companies are in no better shape (and in some ways it is much worse) with respect to protecting their patented technologies that they were beforehand (see "Indian Generic Drug Maker Seeks to Invalidate Cancer Drug Patent").  Even in the U.S., drug companies risk adverse governmental action when their concern with return-on-investment for their investors is perceived as being contrary to the common good.  Monsanto has proactively thrown down the gauntlet to governments and NGOs more comfortable with criticizing than working with them, by boldly proposing to work with such groups to attempt to solve, or stave off, the coming food crisis.  Let's see which groups will be more interested in their own political agendas than finding a solution to the problem.

For additional information regarding this and other related topics, please see:

• "Monsanto and Syngenta Settle All Litigation Between the Companies," May 30, 2008
• "ETC Group Opposes 'Climate Ready' Gene Patent 'Grab,'" May 19, 2008
• "Monsanto Co. v. David (Fed. Cir. 2008)," February 6, 2008
• "Monsanto Co. v. Bayer Bioscience N.V. (Fed. Cir. 2008)," January 28, 2008
• "Supreme Court Fails to Grant Certiorari in Monsanto Co. v. McFarling," January 7, 2008
• "Monsanto Co. v. Syngenta Seeds, Inc. (Fed. Cir 2007)," October 7, 2007
• "Monsanto Co. v. McFarling (Fed. Cir. 2007)," June 4, 2007
• "Syngenta Seeds, Inc. v. Monsanto Co. (Fed. Cir. 2007)," May 7, 2007

IPO Releases List of Top 300 Patent Holders

"Biotech/Pharma" Top 47

    By Donald Zuhn --

The Intellectual Property Owners Association (IPO) released its 25th annual list of the top 300 organizations receiving U.S. patents.  Readers may recall that the U.S. Patent & Trademark Office stopped releasing its annual list of top patent recipients in 2006 in order to "discourag[e] any perception that we believe more is better."

The IPO stated that while it does not intend for the report to "encourage or discourage patenting," it would continue to publish its annual list of top recipients because "the number of patents granted is one of the few objective measures of the patent system as a whole and the patenting activities of individual industries and companies."  The IPO compiled its list by counting the number of utility patents granted during 2007 on which an organization or its subsidiary was listed as the owner on the face of the patent.  However, the IPO attributed patents that were granted to two or more organizations jointly to the organization listed first on the patent.  The IPO noted that 153,283 patents were issued in 2007, which was a decline from the 173,771 patents that were issued in 2006.

As in 2007, we have used the IPO's list of the top 300 patent holders to compile a list of the top "biotech and pharma" companies and organizations receiving U.S. patents in 2007 (this year, we were only able to fill out a list of 47 biotech/pharma companies and organizations).  Each organization's IPO top 300 ranking is indicated in the "IPO Rank" column.  Please note that some of the companies and organizations listed below may be involved in non-biotech or non-pharma work, and therefore, that a portion of the patents granted to these companies may be directed to other than biotech and pharma-related inventions.  In addition, our list is a little inclusive in that we included medical device companies.

For additional information on this topic, please see:

• "IPO Posts List of Top 300 Patent Holders," April 20, 2007

ETC Group Opposes "Climate Ready" Gene Patent "Grab"

    By Donald Zuhn --

Last week, both The Washington Post and Nature News reported on the efforts of biotech companies to secure patents directed to gene-altered crops that are designed to withstand the effects of global warming.  The impetus behind both articles was a 30-page report entitled "Patenting the 'Climate Genes' . . . and Capturing the Climate Agenda," which was released by the Erosion, Technology and Concentration (ETC) Group, an activist organization based in Ottawa, Ontario, on May 13th.  (Patent Docs readers are no doubt familiar with the ETC Group, as we have reported on a few of the Group's other initiatives; see links below.)

According to the ETC Group, biotech and agrochemical companies such as BASF, Monsanto, Bayer, Syngenta, and Dupon have been "stockpiling hundreds of monopoly patents on genes in plants," and that the companies intend to market genetically engineered crops containing such genes (i.e., "climate ready" plants) as being able to withstand environmental stresses such as drought, heat, cold, floods, and saline soils.  The ETC Group contends that the above companies have thus far filed 532 patent applications worldwide (in 55 patent families) on such genes, and warns that "[i]n the face of climate chaos and a deepening world food crisis, the Gene Giants are gearing up for a PR offensive to re-brand themselves as climate saviours."  The Group argues, however, that "patented techno-fix seeds will not provide the adaptation strategies that small farmers need to cope with climate change," and that the so-called "Gene Giants" are merely engaging in "climate change profiteering."

To prevent such "profiteering," the ETC Group is pushing for a worldwide suspension of patent grants for climate-related genes and traits.  The Group hopes that such action might be taken at either the U.N. Convention on Biological Diversity on May 19-30 or the United Nations-FAO High-Level Conference on World Food Security and the Challenges of Climate Change and Bioenergy on June 3-5, and that following the implementation of such a suspension, world governments would initiate an investigation into the social and environmental impact of patents directed to climate ready genes and plants.  The ETC Group is also urging "inter-governmental bodies to identify and eliminate policies such as restrictive seed laws, intellectual property regimes, contracts and trade agreements that are barriers to farmer plant breeding, seed-saving and exchange."

Not surprisingly, the companies accused by the ETC Group of engaging in "climate change profiteering" see their role in a much different light.  According to The Washington Post article, the biotech companies seeking gene patents contend that climate ready plants will be critical to solving the problem of world hunger and that absent patent protection, such plants will not be developed.  In addition, a spokesperson for Monsanto noted in the Post report that Monsanto and BASF were participating in a project, funded by the Bill and Melinda Gates Foundation, to develop drought-resistant corn that would be made available to African farmers royalty-free.

One of the ETC Group's criticisms regarding the 532 filed applications is that these applications contain claims that are far too broad, encompassing numerous plants and a litany of environmental stresses.  However, because the vast majority of these applications have yet to issue as patents, the actual claim scope that the applicants will be able to secure remains unclear.  ETC Group executive director Pat Mooney concedes this point in the Nature News article, admitting that "the companies are casting the net as wide as they possibly can, and then they will sort it out afterwards."

Dr. Alan Bennett (at left), a plant geneticist at the University of California, Davis and the head of the the Public Intellectual Property Resource for Agriculture (PIPRA), a non-profit initiative supporting agricultural innovation for both humanitarian and small-scale commercial purposes, put the debate between the ETC Group and the agricultural-biotech industry  into some perspective in the Nature News report.  Calling the introduction of the global warming angle nothing more than a public relations stunt, Dr. Bennett observed that the agricultural-biotech industry was merely engaging in business as usual; namely, focusing on the search for hardy crops that survive in harsher environments (i.e., poor soils, less water, fewer fertilizers), and the genes responsible for conferring such traits.

For additional information regarding other related topics, please see:

• "Playing the Bioterror Card in the Synthetic Biology Debate," December 19, 2007
• "The Synthetic Biology Sky is Not Falling," December 16, 2007
• "Patent Life (Really)," June 11, 2007

Possible Limitations to EGFR-targeted Cancer Therapies

    By Kevin E. Noonan --

An important consequence of the biotechnology revolution has been an increased understanding of the molecular biology of cancer.  Tyrosine kinases, including the eponymous src oncogene, provide important targets, comprising a family of plasma membrane proteins that in certain incarnations act as growth factor receptors.  Until now, therapeutic agents were primarily inhibitors of the tyrosine kinase activity, acting either directly or by preventing dimerization frequently associated with activating the kinase function.  However, a report published in Cancer Cell on May 6th illustrated a heretofore unknown activity of these receptors that calls into question the ultimate efficacy of the known inhibitors (see "Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity").

The study was performed on the epidermal growth factor receptor, one of a family of such receptors that includes the HER2/neu target of Genentech's breast cancer therapeutic Herceptin®.  EGFR (at left) is the target of several anticancer drugs, including several monoclonal antibodies.  These include panitumumab, sold by Amgen as Vectibix® for EGFR-expressing metastatic colorectal cancer, and cetuximab, sold by Bristol-Myers Squibb as Erbitux® for EGFR-expressing metastatic colorectal cancer and head and neck cancers.  Another class of anti-EGFR drugs inhibit the tyrosine kinase activity; these include gefitinib, sold by AstraZeneca as Iressa® for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), and erlotinib, sold by Genentech as Tarceva® for the treatment of NSCLC and pancreatic cancer.  However, the success of these drugs has been more limited than expected, even in light of the otherwise poor prognosis of the typical patients for these therapies.

The authors of the Cancer Cell report propose a reason for the less than expected results:  in addition to the known function of EGFR for promoting cellular proliferation associated with the tyrosine kinase activity, EGFR has the newly-found property of promoting active glucose uptake in cancer cells, preventing cell death.  The experiments were performed on human cancer cells in vitro, showing that treatment with EGFR inhibitors did not kill the cells (although it did prevent receptor autophosphorylation via the tyrosine kinase activity and reduce cell proliferation).  In contrast, transfecting the cells with EGFR-specific siRNA (that reduced EGFR expression) promoted autophagic cell death, i.e. cannibalization of cellular structures and components for energy.  Analysis of the cells for intracellular glucose revealed no change in the presence of EGFR inhibitors, but marked reductions after transfection of EGFR siRNA resulting in lowered or abolished EGFR expression.  Autophagy could be prevented by increasing the extracellular glucose concentration.

The cancer cells assayed in these experiments expressed two cell surface glucose transporters:  GLUT1, which responds to increased extracellular glucose levels and is a passive transporter, and SGLT1, a sodium-dependent ATPase capable of active transport against a glucose concentration gradient.  Reduction of EGFR expression had no effect on GLUT1, but reduced SGLT1 detected by Western blot analysis.  The autophagic effect was mimicked by treating the cells with SGLT1-specific siRNA.  The combination of these results indicated that reduced intracellular glucose concentrations in response to reduced EGFR expression was mediated by SGLT1, and could be compensated by increased GLUT1-mediated glucose transport in response to increased extracellular glucose concentrations.  RT-PCR experiments on SGLT1 mRNA showed that SGLT1 gene expression was unaffected by EGFR downregulation, and treatment of proteosome inhibitors prevented reduction of cellular glucose levels mediated by SGLT1, establishing that SGLT1 degradation was the mechanism responsible for the observed effects.  Physical interaction between EGFR and SGLT1 was shown by co-immunoprecipitation using anti-EGFR antibodies, and this interaction was shown in MCF-7 cells (which express only very low levels of EGFR) transfected with wildtype as well as tyrosine kinase mutant EGFR.  The specificity of these effects was demonstrated by inhibiting endogenous EGFR expression using a 5' untranslated region (UTR)-specific siRNA, and rescuing the phenotype by transfecting the cells with wildtype or tyrosine kinase mutant EGFR species lacking the 5' UTR.  Finally, the specificity of SGLT1 involvement in autophagy caused by reduced intracellular glucose concentrations was established using MCF-7 cells (which do not express SGLT1) showing marked sensitivity to reductions in extracellular glucose in the culture media.

These results provide an explanation for the persistence of cancer cells in the face of EGFR-targeted therapies, but also suggest a molecular explanation for the relative failure of these agents to be more effective as anticancer agents.  Importantly, these results also suggest that combination therapies, perhaps with anti-metabolic or antiglycolytic agents, may provide improvements in treatment for EGFR-expressing tumors.