Last Tuesday the U.S. Patent and Trademark Office (PTO) droppedPEC's other shoe.

PEC stands for Protein Engineering Corp., of Cambridge, Mass. Thecompany had filed a patent application in the fall of 1988, seeking toprotect its invention of phage-display technology. The PTO cleavedthis submission in two _ process and composition-of-matter _ andon June 29, 1993, issued U.S. Patent No. 5,223,409, "Directedevolution of binding proteins." (See BioWorld Today, June 30, 1993,p. 1.)

Now, part two, No. 5,403,484, "Viruses expressing chimeric bindingproteins," has been issued (but is not yet printed).

During those seven lean years, PEC generated an array of high-affinity, high-specificity protease inhibitors, antibody surrogates andother useful proteins and peptides, the firm's CEO, L. EdwardCannon, told BioWorld Today. That interval also saw the technologytaken up by numerous other biotechnology firms.

"To companies known to be practicing our invention," Cannon said,"we are sending out letters this week letting them know the patent hasissued, and asking them to contact us."

Putative infringers "have published widely in the literature andpresented at meetings," he added. BioWorld has identified amongthese phage-display users: Affymax NV, of Amsterdam, theNetherlands, ARRIS Pharmaceutical Corp., of South San Francisco,Chiron Corp., of Emeryville, Calif., Chugai Pharmaceutical Co. Ltd.,of Tokyo, Genentech Inc., of South San Francisco and GenzymeCorp., of Cambridge, Mass.

PEC's Policy: License, Not Litigate

In June 1993, Cannon's predecessor as CEO, John Freeman, toldBioWorld anent possible freeloaders on his firm's discovery: "PEC'spurpose is not to sue, but to make products and create values."Cannon endorsed this policy, but said, "PEC is also prepared toenforce its rights under its phage display patents, if necessary. Weintend to make licenses available under these patents, and inviteinquiries from interested parties."

The patents' lead inventor, molecular biologist Robert Ladner, issenior vice president and scientific director of PEC. He toldBioWorld Today, "If you are using, or have, that composition ofmatter, then this second patent applies. It represents, I'd say, at least99 percent of the work on phage display that has been published."

Cannon recalled that the situation "is not dissimilar" to what arose in1981, when the Universities of California and Stanford jointlylicensed to industry the Cohen-Boyer patents, which covered the coretechnologies of genetic engineering. He observed that PEC still paysits annual dues to license the Cohen-Boyer know-how, andanticipates that "our licensing arrangements would be similar."

He is not aware that any other phage-display patents have issued, atleast in the U.S.

PEC's initial patent, covering process, Cannon explained, "claims themethods of doing phage display. In a process claim, you will forexample claim a method of diversifying DNA, incorporating thatDNA into a bacteriophage genome, so its product protein or peptideis expressed on the phage's surface, then bringing that into contactwith a target molecule."

The composition-of-matter claim, he continued, goes from theory topractice: "It will claim a fusion protein, consisting of a foreignprotein fused to the amino terminus of a gene-3 protein on the coat ofa filamentous phage _ an actual physical entity."

High-Affinity/Specificity Peptides Ready To Go

Ladner further explained: "By thus expressing a peptide on theoutside of that replicable genetic package _ the phage _ then usingrecombinant-DNA technology to vary the thing displayed, you end upwith a vast number of different binding entities. And by recovering asfew as a single one of those, you would discover the sequence of avery high-affinity binder."

PEC's first phage-display product was a high-affinity, high-specificity inhibitor of a particularly villainous enzyme, neutrophilelastase. "It's a protease," Cannon elucidated, "that degrades tissuesand tissue structures, especially in disorders such as emphysema,cystic fibrosis, bronchitis, adult respiratory distress syndrome,arthritis _ any place where you have an inflammatory condition outof control."

Two other protease inhibitors now ready for licensing are kallikrein,which is involved in shock, hypotension, edema of trauma orinfection, and plasmin, which perpetrates tumorigenesis andmetastasis.

"So there's a variety of therapeutic indications," Cannon added,"where inhibitors of these enzymes potentially could be used. And byoutlicensing them, or attracting sufficient financing, we hope toundertake preclinical and clinical studies ourselves."

PEC "is in discussion with several foreign pharmaceuticalcompanies," Cannon allowed, and has signed up a corporate partner"in the bio-separations area, using the same technology."

Besides protease inhibition, PEC also has a different finger in thehuman immunodeficiency virus pie. "We have built phage librariesthat contain variants of the first extracellular domain of CD4,"Cannon said. "From those libraries we've obtained molecules thatbind gp120, with substantially greater affinity than does the nativeCD4 molecule. So these would be useful in competing with cell-surface CD4 for binding HIV, and therefore block AIDS infections."n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.