By Donald Zuhn —

On Thursday, the California Healthcare Institute (CHI), an independent organization comprising more than 250 biomedical companies, academic and research institutions, and companies involved in supporting the biomedical community, released a white paper entitled "Impact of Patent Law Changes on Biomedical Investment and Innovation."  The CHI white paper analyzes the implications of recent patent law developments on the biomedical industry, and concludes that a handful of Supreme Court decisions, Congress’ attempt to enact patent reform legislation, and the Patent Office’s push for new patent rules have combined to reduce the value of life sciences patents will have a "chilling effect on biomedical investment and innovation."

According to the white paper, the first challenge to the patenting of life sciences inventions comes from the Supreme Court’s "apparent growing anti-patent stance," which is reflected in a number of Supreme Court decisions, including: Merck KgaA v. Integra Lifesciences I, Ltd. (2005), eBay Inc. v. MercExchange, L.L.C. (2006), MedImmune, Inc. v. Genentech, Inc. (2007), and KSR Int’l Co. v. Teleflex Inc. (2007).  In particular, the report contends that the Court, in Merck, "weakened the ability of patent holders to enforce their rights against companies performing drug research."  The report also concludes that the Court’s decision in eBay, which reduces the availability of permanent injunctions to patentees, "weakens the value of patent rights for patent owners who are not commercializing their inventions by making it more difficult for those parties to enjoin an infringer."  With respect to the MedImmune decision, the report observes that the Court has made it easier for a patent licensee to challenge the validity of a licensed patent.  Finally, the report concludes that the Court’s decision in KSR lowers the standards used to evaluate obviousness, thus making it harder for applicants to obtain patents and easier for defendants to invalidate them.

The second challenge to the patenting of life sciences inventions comes from Congress’ attempt to enact patent reform legislation.  The report contends that the most recent round of proposed patent reforms reflects fundamental differences in business models of two distinct high-tech industries:  life sciences on one side and software/IT on the other.  The report notes that because life sciences products are long-lived and less susceptible to incremental improvement, and further because investors must be able to rely on patent protection to justify the costs of bringing life science products to market, the relative value of life sciences patents is much higher than the relative value of software/IT patents.

According to the CHI report, the final challenge to the patenting of life sciences inventions comes from the "heavy handed approach taken by the U.S. Patent and Trademark Office (USPTO) towards making and promulgating new patent rules."  The report takes the Patent Office to task for its proposed limitations on the permissible number of claims and continuation applications, contending that such modifications will "significantly change the way applicants file their applications and would decrease an applicant’s ability to obtain full patent coverage for its inventions," and predicting that the proposed changes to the rules will "have a devastating effect on mid-sized and start-up life science companies."  The report believes that if the proposed rules changes are implemented, life sciences companies will motivated to accept narrower claims in order to obtain the allowances needed to secure investment funding, or even worse, will be forced into a lengthy appeal process that could preclude investment altogether.

The CHI white paper ultimately concludes that these three areas of change "represent an extensive and dramatic shift that will make patents harder to obtain, easier to invalidate, and cheaper to infringe, thus creating incalculable problems for the life sciences community in procuring and maintaining the essential patent protections for their inventions."

For additional information regarding the recent patent law developments discussed in the CHI white paper, please see:

• "Merck v. Integra: The Supreme Court Misses a Golden Opportunity"
• "MedImmune, Inc. v. Genentech, Inc. (2007)"
• "KSR Int’l Co. v. Teleflex Inc. (2007)"
• "They Just Don’t Get It – "Patent Reform" at the USPTO"

    By Kevin E. Noonan —

One of the many benefits touted by proponents of the Human Genome Project has been the prospect of personalized medicine, based on a determination of an individual’s entire genomic DNA sequence.  The advantages of this information are expected to include an understanding about the status of disease propensity-associated genes, as well as the existence of isoforms of enzymes, such as the P450 system in liver, that can affect how efficacious a particular drug may be in the individual, or alternatively, how ineffective or even toxic the individual’s reaction to the drug may be.  Since both types of information represent a huge increase in specific knowledge about an individual (as opposed to the statistical data that underlie such determinations at present), the prospect of being able to ascertain this sequence information is widely considered to be the harbinger of a brave new world of 21st century medicine.

Two more steps towards this brighter tomorrow were taken today.  First, and entirely fittingly, Dr. James Watson (at left) was presented with a pair of CD-ROMs containing approximately 3 billion basepairs encoding his genomic DNA.  The presentation was made by Dr. Richard Gibbs, director of Baylor College of Medicine’s Human Genome Sequencing Center, and Dr. Jonathan Rothberg, founder of the company 454 Life Sciences.  Dr. Rothberg’s company makes the automated DNA sequencing machines that enabled Dr. Gibbs’ team to determine Dr. Watson’s genomic DNA sequence in months rather than years, and at a cost of less than one million dollars.  It is thought that expected advances in the technology will reduce the cost even further, to perhaps as little as ten thousand dollars; at that point widespread genomic DNA sequencing may become economically feasible.

The Watson DNA sequence will be made publicly available, with one exception:  Dr. Watson will not disclose the sequence of the gene that encodes apolipoprotein E in his genome, since certain alleles of this gene are associated with the development of Alzheimer’s disease.

Ironically, another total genomic DNA sequence will also soon become available, that of Dr. J. Craig Venter (at right), the man whose for-profit company, Celera Corporation, is credited with motivating completion of the human genomic DNA sequence (obtained from a mixture of different individual’s DNA) by the Human Genome Project, headed by Dr. Watson.

The other announcement came from the National Human Genome Research Institute (NHGRI), involving a study of 1,000 individuals with symptoms of coronary artery disease.  This study is limited to determining the genomic sequence of between 200 and 400 genes known to be associated with this disease, although there will also be an analysis of other genetic variations.  These genomic determinations will take about two years, and will be correlated with changes in disease states of the participants.  The goal is better understanding of the association between disease and genetic variability.

As promising as these efforts may be, there are reasons to be skeptical about them, at least in the short term.  The determination of individual genomes, while informative for the individuals, may not provide any broader information about the "canonical" human sequence, because there is good evidence from classical population genetics that such a sequence does not exist.  In studies done 40 years ago, Richard Lewontin (at right) and others showed that natural populations contain a great deal of genetic variation in the amino acid sequence of common cellular enzymes.  This variation did not appear to confer any evolutionary advantage on the organisms expressing them (typically, Drosophila), leading to what has been called the "neutralist" school of population biologists.  The explanation is that organisms have this vast genetic variability that is neutral under normal circumstances, but provides a reservoir of adaptability during times associated with speciation – natural disasters, isolated sub-populations, and geographic allopatry.  Thus, a determination of any individual’s genomic DNA can be expected to say little about "the" sequence for any particular gene; "the" sequence will, at best, be the most common sequence in a population, requiring information from thousands or perhaps millions of individuals to be accurately portrayed.

Another reason for skepticism about projects like the NHGRI’s is that it will be limited to the 200-400 genes now known to be associated with coronary artery disease.  By limiting the scope of the study to these genes, the data produced will increase our understanding of the genes, but not perhaps the underlying disease, for example, if there are genes not yet identified that play an unappreciated (and perhaps important) role in the disease etiology.

Finally, the problem with applying genomics in this way is reminiscent of Abraham Maslow’s aphorism, that "if you only have a hammer, you tend to see every problem as a nail."  The determination of the human genomic sequence has been a landmark achievement, but caution suggests that the problems of biology are unlikely to be solved in any meaningful way merely by detecting variabilities in DNA sequence.  Certainly these do exist – sickle cell anemia is the result of a transversion (A to T) mutation that changes a valine residue to a glutamic acid residue.  However, clinicians know that there is variability in how different sickle cell anemia patients react to environmental stimuli, reflecting the interactions of the millions of other genes they express.  Systems biologists are just now beginning to explore the relationships between the biological products of genes, proteins and the cellular structures they create.  It is well to be reminded that we are merely at the beginning of this journey, and that the projects announced today are only the smallest of steps to unraveling (to the extent we are able) the fascinating riddle of life.

    By Christopher P. Singer —

In a May 29, 2007 press release, sanofi-aventis and UCB announced that the FDA approved Xyzal® (active ingredient: levocetirizine dihydrochloride) a once-daily prescription antihistamine for the relief of seasonal and perennial allergic rhinitis, as well as for the treatment of chronic idiopathic urticaria (hives) in adults and in children age six and older.  UCB filed the new drug application (NDA) in July 2006 and researched the drug in a number of clinical trials.  Xyzal® was shown to reduce the severity of common symptoms associated with allergies, such as runny nose, itchy eyes, and sneezing.  In patients with hives, the drug was able to reduce the number, size, and itch associated with the hives.

In the fall of 2006, sanofi-aventis signed an agreement with UCB in which it agreed to launch and co-market and Xyzal®, which is expected to be ready for launch for the upcoming fall allergy season.

    By Kevin E. Noonan —

There are new developments in global drug pricing policy today, but while they are good news for sub-Saharan Africa they fall far short of addressing the overarching disaster facing Western drug companies in these disputes (see "Worldwide Drug Pricing Regime in Chaos").

In a move kindly described as charity, The Wall Street Journal reports that Roche Holdings AG announced that it had agreed with two African generic drug companies to transfer technology related to production of the anti-AIDS drug saquinavir "free of charge."  The deal also includes the right for these companies, located in Ethiopia and Zimbabwe, to distribute the drug to any country in sub-Saharan Africa characterized by the United Nations as a "least developed" nation.  Roche also expressed a willingness to enter similar technology transfer agreements under the same terms with other generic drug companies in such countries.

This agreement is one avenue for addressing the economic and political effects of the developing world efforts to reap the benefits of World Trade Organization membership while being able to provide needed drugs for their citizens.  The crisis is particularly acute with regard to anti-AIDS drugs, and in this regard Roche has astutely chosen the countries most affected by the pandemic, and least capable of affording the drugs, to garner the benefits of its charitable largess.  Its actions are also likely to blunt the effectiveness of "more" developed countries, such as Brasil, from establishing markets in such countries for their own generic drug industries.  And by supporting local drug production in Africa, Roche has also began a process for building the types of development relationships that may render these countries’ governments less intractable in respecting Roche’s patent rights for other, less critically-needed drugs.

The downside of Roche’s actions, however, is that they perpetuate the model of Western drug companies treating intellectual property rights as bargaining chips.  They do not address the larger question of resolving the tensions between the once-hoped-for international IP protection regime and resistance to respecting Western drug companies’ IP rights when it comes to anti-AIDS and other drugs.  It is possible that deals like the ones Roche has struck with these local drug companies are the best now possible, and insofar as they lessen the pressure of rhetoric (from governments, non-governmental organizations, and even individuals like former President Clinton) to eliminate such IP rights entirely (and have the other benefits mentioned above), they are clearly a coup for Roche.  But they also represent a throwback to the more paternalistic posture of the past, where less developed countries are dependent not on a regulated international system of rights and privileges but on the West’s inclinations to act humanely in the face of a crisis (something whose effects can be variable, as seen most recently in Darfur).  They also raise the question of whether Western drug companies, and their governments, have the political will to address the challenges raised by specific actions (like the Doha Declaration and actions taken pursuant thereto by Brasil and others) that most seriously, and systemically, challenge the reigning drug development paradigm.

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

• "U.S. Trade Policy Becoming Less Pharma-Friendly," May 18, 2007
• "The "Unfairness" of World Intellectual Property Protection According to The New Yorker," May 17, 2007
• "Worldwide Drug Pricing Regime in Chaos," May 9, 2007
• "Not Getting It about Patented Drug Prices at The Wall Street Journal," May 6, 2007
• "A Modest Proposal Regarding Drug Pricing in Developing Countries," May 2, 2007
• "The Law of Unintended Consequences Arises in Applying TRIPS to Patented Drug Protection in Developing Countries," May 1, 2007
• "Abbott Agrees to Offer AIDS Drug at Reduced Price," April 12, 2007
• "No New Abbott Medicines for Thailand," March 14, 2007
• "More Compulsory Licensing in Thailand," February 1, 2007
• "Thailand Compulsory License Still in the News," December 18, 2006
• "Thailand Issues Compulsory License for AIDS Drug," December 6, 2006