Sense and Antisense in Biotech: The First Antisense DNA Company

he could overlook Riordan’s nonmembership in the
guild of molecular biology or among Mass General
alumni. In any case, some preliminary communication
between them went back and forth by facsimile (this
was of course before e-mail), and then, one morning,
Zamecnik walked into my lab (upstairs over his) and
said that Riordan had launched his own antisense DNA
company. I was less surprised than Zamecnik, but
nothing I said could cool him down. I told him that
although we had hoped we were being courted, it was
equally possible that Riordan was checking out the
entire landscape in a mission of self-designed due
diligence. What Riordan had promptly understood was
that although Zamecnik was the undisputed “father of
the concept”, not Mass General, the Worcester Foundation,
or Zamecnik himself was holding enabling
patents (the Worcester Foundation’s granted Allowance
of Claims did not reach into the therapeutic
domain). Also, as I suspect, Riordan’s thoughts were
that even if the Worcester Foundation might hold a
patent soon, it could always be licensed in. From his
perspective, why in the world would he want to fold in
an inventor and his institution at the equity allocation
and start-up phase? And, it is to be noted that Zamecnik
had made it clear in the discussions that he wanted the
Worcester Foundation to have an equity stake. I
warmed to this, of course, but I could see Riordan
integrating this into his calculus. Moreover, I had
sensed—just as a zephyr—that Riordan was not totally
keen about Zamecnik’s choice of HIV as the first target.
If so, there is great irony there, given what Riordan’s
company ultimately went on to do in HIV therapeutics.
In his final decision, Riordan chose to give up the
prestige that Zamecnik’s name would have given to his
company relative to the start-up dilution of equity that
would have meant.
Soon, Zamecnik and I became aware of pending
relationships Riordan was negotiating as he sought to
build his company. For example, there was oligodeoxynucleotide
synthesis technology at Northwestern University
(invented by Robert Letsinger) that Riordan was
seeking to license in. He had also, properly, looked into
work by Michael Gait at the Medical Research Council
Laboratory at the University of Cambridge. Zamecnik
was also pursuing both Letsinger and Gait, but Riordan
had already signed them up. Meanwhile and in the
opposite vector of contact and recruitment, another
antisense start-up planner had tried to engage Zamecnik,
but that is an entirely different story, perhaps for
another time.
HYBRIDON
In 1990, 3 years after Riordan launched his company,
Zamecnik and I cofounded Hybridon. I was a cofounder
only by virtue of being president and scientific
director of the Worcester Foundation, and simply represented
the foundation’s equity stake. (I did not take
founder’s stock and never owned stock after Hybridon
SENSE AND ANTISENSE IN BIOTECH
went public, believing that the company was not based
on work from my lab and that I should therefore not
personally gain just because I happened to be president
of the Worcester Foundation. I did receive an honorarium
of $3000/year as a member of the Hybridon
Scientific Advisory Board from 1990 to 1996 and felt
this was acceptable, as my role there was as a RNA
expert, not as the president of the Worcester Foundation.)
Zamecnik immediately focused the company on HIV.
His reasoning was that his “NIH tennis partner”, as he
always described Robert Gallo after that Fogarty year at
NIH, could help get National Institute of Allergy and
Infectious Disease contract funding for the antisense
idea. Meanwhile, I worried that AIDS might be the
wrong choice for an initial proof of principle and
argued for a Hybridon project using antisense DNA in
the arena of hypertension to knock down the messenger
RNA for the angiotensin-renin-converting enzyme
for treatment of essential hypertension. I had a long
conversation with James Wyngaarden, then chairman
of the Hybridon Scientific Advisory Board. Wyngaarden,
formerly a colleague of Zamecnik at Mass
General and later, director of NIH, was open to my
idea, but after further discussion, we agreed that Hybridon’s
cash position could not support a new project at
the time. One thing I learned (I learned so many things
in this biotech experience) is that it is very difficult—at
least in a cash-strangled start-up (almost always so)—to
change the R&D program.
THE ANTISENSE PATENT LANDSCAPE
The intellectual property landscape was murky in the
early days of the antisense field, as it often is in any new
technology. One of the enabling doctrines in U.S.
patent law—nonobviousness—seemed traversable in
the Worcester Foundation patent according to some
experts, but I worried about this going back to denatured
DNA-RNA reannealing studies in the 1950s. And,
in later years, complementary DNAs with base-pairing
recognition to targeted mRNAs were used to demonstrate
the presence and abundance of these mRNAs in
cellular RNA in solution hybridization experiments and
also, to arrest the translation of a particular mRNA in a
cell-free system. However, these publications (which I
knew well from my own field of RNA science) never
advanced or even hinted at the idea of using a short
DNA (or any other oligo) to interrupt gene expression.
Patent drama soon arose, as we all knew it would. The
aforementioned work at the NCI by Sam Broder and
Jack Cohen had resulted in a patent application on the
use of antisense DNA to inhibit HIV, which was being
pondered by the U.S. Patent and Trademark Office.
Later, when Hybridon was deep into its HIV program,
NIH challenged the Worcester Foundation patent application
relative to its own. Hybridon’s executive team
and an attorney from its outside counsel flew to
Bethesda, MD, on August 14, 1996. They asked me to
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