In contrast to so many current political debates–climate change, abortion, health care–intellectual property law often appears to occupy a rarefied perch accessible only to patent experts, clerks and judges.  Patent policy is unnervingly complicated, with deceptively simple patent laws that are burdened with complicated webs of judicial interpretations.  It is little wonder, then, that most of us take for granted our government’s policy of granting and enforcing patents–if only as a cognitive coping strategy.  This complexity-induced apathy, by the way, suits patent lawyers just fine, and might be acceptable most of the time because, as in the case of an undersea oil-well blowout-preventer, patents may work pretty well, except when they don’t.

Patents on human DNA sequences (at least 20% of our genes are locked up) are increasingly viewed as deterrents to a new generation of genetic-diagnostic technologies, as well as to basic biomedical research itself.  That is the belief held growing number of physicians, researchers and legal experts, as well as this author.

Why do I use the word, “belief”?  Simply put, though the specifics of patent law are largely excluded from raucous public debate, the costs and benefits of patent reform are nevertheless as hypothetical, and worthy of argument, as in the cases of health-care reform, climate-change strategy or nuclear disarmament.  Proponents of the current system claim that the current patent regime is nothing less than vital to innovation.  As in any debate, those in favor of the status quo can point to experience, arguing that current technology would not have arisen without patent protection.  The apparent conservatism of this position belies the fact that our current patent regime–and any patent regime–is an artificial, legislated concept.  Defending it from alteration by claiming that it is an optimal policy is, thus, rationally unfeasible.

Some of the current momentum behind the reform of gene patent policy results from evidence that future genetic tests will be hamstrung by patents held by universities and companies–patents that give these organizations control over virtually any use of the human genes they claim.  That is the conclusion shared by a recent report from the HHS Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS).  The prediction that patents will impede progress may not, in itself, be sufficient reason to make changes to the policy.  However, the Committee points out the exceptionalism of patient care:

Indeed, in the realm of commodities or consumer electronics it may well be that dramatic harms and a profound lack of benefit should be required to compel any recommendation for change. But genetic tests affect patients’ lives and health.  Thus, the current system’s net negative effects on test development and patient access to these tests argue strongly for the narrowly tailored changes that are proposed.

These proposed changes are two-fold: (1) a diagnostic test exemption, allowing human genes to be analyzed even if they are protected from other uses (i.e. as therapeutics) by patents; and (2) a research exemption, allowing any use of patented genes in the pursuit of biomedical research.  This second exemption may come as a surprise to many, even to scientific researchers themselves.  Many scientists I’ve talked to either assume that common law (or common sense) already exempts their work from violating patents (mostly because it is unbelievable to many genetic researchers that DNA sequences could be patented in this way).  However, court decisions have decreased the research exemption to nil.  The SACGHS report argues for the clear enunciation of the legality of research on patented genes, if only to promote the rule of law.

Agree or disagree with these proposals–that is their major benefit!  They give something concrete to agree or disagree with to those citizens (especially relatively apolitical research scientists) who may have felt sidelined by the complexities of patent law debates.  Furthermore, gene patents are a natural starting point for a more general debate over patent policy because they affect anyone who intends to ever get medical care.

Patent 7,553,674 : Methods of identifying compounds useful for modulating intraflagellar transport . Granted June 30, 2009. full text from USPTO.

Inventors:  George B. Witman, Gregory J. Pazour, Joel L. Rosenbaum (Yale faculty), Douglas G.Cole.

Background

It’s the goal of any cell biologist to discover and describe a totally new molecular mechanism or cellular process.  Just such a discovery was made during the mid-90s, in the laboratory of Joel Rosenbaum at Yale.

Cross-section of two Chlamydamonas cilia. Click for Wikipedia entry.

Rosenbaum and colleagues were looking at the green algae Chlamydamonas–specifically at the long, slender cilia that project outward from its cell body.  Cilia, called flagella in cells that have only one of these structures, are present in many eukaryotic cells and can function both as a type of cellular paddle (as in the case of a swimming sperm cell) or as an antenna, positioned to sense the surrounding environment.

What the Yale researchers saw when they looked carefully inside the cilia, at high magnifications, were tiny granules that were moving along the cilia.  What became clear in subsequent experiments is that these particles move back and forth along the cilium, like miniature cargo elevators, to transport proteins and lipids.  These cargo include sensory molecules, as well as the building blocks needed to extend the growing structure.

Rosenbaum and colleagues termed this mechanism intraflagellar transport (IFT). Most importantly, though it was discovered in the model green algae cells, IFT is a mechanism that has been exquisitely conserved during evolution.  Microscopic parasites and human beings, confronted alike with the necessity of building and maintaining cilia and flagella in many different types of cells, all use the same basic transport molecules, with only minor variations.

As with any molecules so central to diverse cellular functions, when something goes wrong, like an inherited mutation in the gene coding for an IFT protein, severe diseases can develop.  In humans, difficulty building and maintaining cilia and flagella contribute to diseases of organs that depend on these structures, like the kidneys, the eyes and the heart during early development

Patent implications

The new patent claims the use, for “diagnostic, screening, and therapeutic” purposes, of 14 key proteins that are present in humans and other organisms with flagella.  These proteins are assembled together within the cell to make a multi-molecular machine for transporting cargo in the flagellum.  The exact workings of these protein complexes are still poorly understood.

The patent claims any pharmaceutical agent to diagnose or treat a problem with these complexes, or at least those drugs designed to interact with the 14 patented proteins, for uses including to “modulate flagellar function”.  Although much of the biomedical research into IFT has been directed at curing human genetic disorders, this patent would also appear to cover the design of any antibiotics targeting the IFT proteins in human parasites, such as Leishmania or Trypanosoma brucei,  which rely on their flagella for survival.

The diagnostic claim appears to broaden the scope of the patent in a significant way.  Severe diseases resulting from cilia defects, such as Bardet-Biedl syndrome, may not be cured by drugs that target IFT proteins, because there are many other molecules involved.  However, a diagnostic test, using IFT proteins to evaluate the “size”, “beating” or “cell motility” of a sample, as is imagined by the authors of the patent, may not be as far-fetched.

——–

Read this recent New York Times article on ciliary diseases, flagellum research and IFT.

US Patent Application 20080260706 : Transient Transfection with RNA. Received October 23, 2008. Full text from Patent Office

Inventors: Peter M. Rabinovich, Sherman M. Weissman, Marina E. Komarovskaya, Erkut Bahceci

Background

Biologists frequently transfect foreign DNA into cells; if the DNA encodes a functional gene, the normal machinery within the cell will transcribe the DNA into RNA, which will be translated to protein.  Expressing either foreign proteins or altered versions of native proteins within cells is extremely useful for determining protein function, or for altering cell behavior.  “Gene therapy” involves introducing foreign genes within cells in the human body to ameliorate disease.

Though it is possible to introduce the proteins themselves into a cell, the techniques for doing so are very cumbersome relative to nucleic acid introduction.  Additionally, the location of expression is very important–different cells may introduce modifications into proteins as they are expressed, so the same protein may have different properties depending on the cell that produces it.  A foreign protein may not have the same properties as one that is produced locally.

The patent

The patent application prepared by Rabinovich, et al., aims to protect an improvement on the expression of foreign proteins: the transfection of the gene-coding RNA itself.  The authors claim that transfecting RNA is more efficient than transfecting DNA and also has a number of other advantages, including allowing more precise regulation of the quantities of protein produced, something that would be particularly important in a gene-therapy context.  The introduction of RNA is also inherently transient, avoiding the long-term exposure to exogenous genes that results from other forms of gene therapy, such as those employing viral vectors.  Short-term gene therapy would be particularly useful for a protein-based treatment regimen, rather than the permanent genetic change intended by viral gene-therapy.

Specifically, the patent application specifies the transfection of RNA “that encodes a therapeutic, prophylactic or diagnostic polypeptide or nucleic acid molecule”.    This process includes the in vitro transcription into RNA of DNA including a gene and other sequence elements necessary for efficient transcription and translation.

Implications

If granted, the patent would appear to protect the use of one of the two information-containing biological polymers, RNA, for medical puposes involving transient transfection.  Moreover, it claims invention of the process for production of RNA molecules for those medical purposes.

Viral gene therapy systems have been patented, including this patent held by Mount Sinai School of Medicine.

Update 2/10: There has been much more commentary as the Myriad case has progressed.  For starters, a Bob Carlson wrote this news piece, summarizing the court case and discussing the implications.  A case study from 2008 chronicles the longer-term legal and business context.  For one critique of the patents, based on their fundamental biological nature, see David Koepsell’s post on the subject.

A recent controversy involving a biomedical patent has gotten extensive coverage in the media.  The New York Times reported that a cancer patient in Austin, Texas, assisted by the ACLU, is suing Myriad Genetics and the US Patent and Trademark Office for granting a monopoly on testing for an allele of BRCA-2, highly correlated with some types of cancers.

The patent on genotyping BRCA-2 is a classic intellectual property case because the discovery of the BRCA-2-cancer correlation was a biomedical breakthrough, but the diagnostic technology Myriad markets for genotyping BRCA-2 is cheap, even mundane.   Myriad agrues it needs the patent to protect itself from free-riding companies who wish to offer the diagnostic technology, but didn’t have to pay for its development.

• ACLU page on the case.
• Myriad BRACAnalysis.