Pullan Consulting

Biotech Business Development Consulting

www.pullanconsulting.com and www.lindapullan.com

email:  lpullan@msn.com  805-558-0361

Issue #23

Pullan's Pieces

Commentary on Science & Business of Drug Development

For Business Development & Others

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Flaw in appointing process for patent judges may jeopardize MANY patent decisions

The U.S. Patent and Trademark Office may have a major problem -- the possibly unconstitutional appointment of nearly two-thirds of its patent appeals judges, a problem that could call into question hundreds of decisions on patents in the past eight years. 

Translogic Technology has filed a petition in the U.S. Supreme Court.  Its patent was rejected by a three-judge Board of Patent Appeals and Interferences panel. That panel decision was subsequently affirmed by the U.S. Court of Appeals for the Federal Circuit, which set aside an $86.5 million infringement verdict won by the company.

Translogics's petition contends that one of the three panel judges in its case was named to the board in violation of the Constitution's appointments clause, citing the published analysis of John Duffy of George Washington University Law School.  The Board of Patent Appeals and Interferences has 61 judges, nearly 40 appointed, as a 1999 law required, by the director of the Patent and Trademarks Office (PTO).  Professor Duffy found that the Board of Patent Appeals and Interferences judges qualify as "inferior officers" under the appointments clause of the US Constitution. The clause requires that inferior officers be appointed either by the president, the courts of law or heads of departments. The PTO director is not a head of a department.

In the high court, Translogic's lawyer argues that the remedy for the constitutional violation is to throw out the Board of Patent Appeals and Interferences decision

Given the large number of judges appointed after March 2000, Duffy said, the odds are that the vast bulk of appeals since then had at least one invalidly appointed judge sitting on the panel.  If the Supreme Court finds that the appointment clause has been violated, many more patent cases will be challenged. 

http://www.law.com/jsp/article.jsp?id=1209114346908 

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GPCRs as drug targets

The G-protein coupled receptors (GPCRs), with their 7 transmembrane spans, are the largest family of membrane bound receptors (with at least 799 full-length human GPCRS), and are the targets of many drugs.  A recent review by Lagerstrom and Schioth (Nature Reviews: Drug Discovery 7; 339-357, 2008) noted that GPCR ligands include small organic compounds, eicosanoids, peptides and proteins.  In addition to ligand specificity, specificity can arise from receptor dimerization, and from interactions with diverse intracellular signaling components including RAMPS, arrestins, G-proteins and rho-GTPases.  Presumably because of the specificity conferred by such diversity in ligands, dimerization and downstream interactions, the GPCRs play a key role in neural, endocrine, and paracrine signaling.  Senses such as vision, taste and smell also depend on GPCRs. 

Only a small fraction of the human GPCRs have been targeted successfully for drugs so far.  39 of the 672 members of the Rhodopsin family of GPCRs have been major drug targets (for antihistamines, antacids, cardiovascular amine drugs, antipsychotics, endothelin, gonadotrophin releasing hormone and oxytocin receptor ligands, opioids, somatostatins, angiotensins, and the HIV entry blocker antagonizing CCR5).  The Rhodopsin phylogenetic family of GPCRs uses a combined ligand binding pocket and signaling region built from the transmembrane regions and extracellular loops.  The transmembrane domains provide most of the diversity of the Rhodopsins.  There are now two crystal structures in the Rhodopsin family, which will encourage homology models for drug designs for other members of the family.   

The authors argue that the receptors that bind peptides are desirable drug targets as only 17% of the 133 have been targeted successfully.  The receptors that bind peptides (unlike the receptors that bind amines) generally bind a limited number of ligands, and are involved in important functions such as regulation of body weight, pain sensation and the immune system. 

The 35 lipid binding receptors are being increasingly targeted as the biology of lipids as regulatory factors is becoming apparent. 

The 33 member Adhesion family may be challenging for small molecules drug targeting, because of conserved domains shared with other proteins, but may be attractive for monoclonal antibody targeting as the high domain diversity within their N terminals could be the basis of selectivity.  30 of the 33 members of the Adhesion family are orphans, with no identified ligand. 

Despite the complexity of the biology, I expect to read about drugs targeting additional GPCRs soon. 

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The impact of the credit crunch on biotech?

Loans are scarce.  A Wall Street Journal article (May 13, 2008, p C5) highlights that small business loans are now facing tightening credit standards.  But venture firms have money to spend, having raised $34.7 billion last year, the most since 2001.  IPOs seem unlikely to return soon as the exit of choice.  Only 5 companies backed by VCs staged IPOs in the first quarter of the year, the lowest number since Q3 of 2003.  Mergers and acquisitions of venture backed companies are down.  Only 56 companies backed by VCs merged with other companies or were acquired for the period ended March 31.  (Rebecca Buckman, WSJ.com April 2, 2008).  Pharmaceutical companies still have cash and still need pipeline.  Last year the dollar volume of partnering deals was up 30% from 2006 (Biopharm International, March 2008).  Many of my clients have term sheets right now.  Let’s hope deal making continues!

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Genes of the Platypus are a fascinating mix of mammal, birds, and reptiles. 

In the Abecedarian books, from A for Aardvark to Z for Zebra, there is often P is for Platypus, that strange Australian furry egg-laying animal with a duck bill and webbed feet.  The platypus has been classified as a mammal because it is warm-blooded, has fur, and feeds its young milk (but it does so through the skin of the abdomen as it has no nipples).   Now this strange mammal has had its genome analyzed.  

The platypus genome has 18,500 genes (about 2/3rds the size of the human genome).  It is divided up into large and small chromosomes reminiscent of the macro- and microchromosomes of reptiles and birds. Among the genes in common with other mammals, the platypus has genes for the family of milk proteins called caseins, which map together in a cluster that matches that of humans. This is a sign that one of the genetic innovations that led to the development of milk occurred more than 166 million years ago.  

Gene families were identified that link the platypus to reptiles (like those for egg-laying, vision and venom production). 

Other characteristics that seem purely reptilian turn out to have evolved independently, the analysis suggests. Male platypuses have spurs on their hind legs that are loaded with venom so potent it can kill a dog. Like the venom of reptiles, the poison is a cocktail of at least three kinds of peptides.  But the variations arose from duplications of different genes in platypuses than in modern reptiles. This is an example of convergent evolution, arising at a similar point through distinct genetic mechanisms.  

The sex chromosomes are also completely different from other mammals, with 10 chromosomes that link during meiosis to form a chain that ensures every sperm gets a set of all Xs or all Ys.  Despite the similar designations, none of the platypus X chromosomes resembles the human, dog or mouse X.    Instead, the platypus Xs better match the avian Z sex chromosome.   

The microRNAs, which regulate gene expression, were found to be diverse, some shared with chickens and mammals as well as ones shared with mammals but not chicken. 

Another surprise was finding genes responsible for sensitive odor receptors.  As a primarily aquatic animal, the platypus was already known to rely on electrosensory receptors in its bill, detecting faint electric fields of underwater prey.  Now it may be that the platypus also uses water-soluble odorants to navigate and hunt underwater. 

The genome studies provide a fascinating glimpse into the evolutionary tree of early mammals. 

(NY Times, May 8, 2008, p.A23, http://www.nature.com/news/2008/080507/full/453138a.html, http://genome.wustl.edu/genome.cgi?GENOME=Ornithorhynchus%20anatinus ).

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Pullan Consulting

Linda M. Pullan, Ph.D.

Biotech Business Development

www.pullanconsulting.com and www.lindapullan.com

e-mail: lpullan@msn.com

805-558-0361

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