Appeal No. 2006-0299 Page 8
Application No. 09/964,412
In our view, the evidence of record establishes that a considerable amount
of experimentation and unpredictability was considered to be acceptable in the
field of antisense therapy at the time of the invention. Much of the evidence cited
by the examiner shows that several clinical trials of antisense drugs had been
approved or were ongoing at the time of the invention, despite a widespread
recognition in the art that the effects of administering oligonucleotides in vivo
were highly variable and complex, and the clinical results generally modest. For
example, the examiner cites Jen3 as evidence of “the challenges that remain
before the use of antisense becomes routine in a therapeutic setting” (Answer,
page 9), but it is notable that Jen also provides evidence of the approval of “a
number of phase I/II trials employing oligonucleotides” (Jen, page 315), despite
the fact that “virtually all have been characterized by a lack of toxicity but only
modest clinical effects” (id.). Similarly, Agrawal4 describes several Phase I, II
and III clinical trials involving first-generation antisense oligonucleotides
(Agrawal, Table 1), while at the same time recognizing the need for “the
development of second-generation oligonucleotides, [to] provide improved safety
and efficacy” (id., page 386), i.e., to provide improved biological, pharmacokinetic
and pharmacodynamic properties (id., page 378, Box 1).
In our view, the approval of multiple clinical trials involving antisense
oligonucleotides prior to and at the time of the invention provides evidence that
3 Jen et al., “Suppression of Gene Expression by Targeted Disruption of Messenger RNA:
Available Options and Current Strategy,” Stem Cells, Vol. 18, pp. 307-319 (2000).
4 Agrawal, “Antisense Oligonucleotides: Towards Clinical Trials,” Tibtech, Vol. 14, pp. 376-387
(October 1996).
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