Appeal No. 2006-1036
Application No. 10/191,760
The examiner cites Balagué2 for its teaching that at the lowest dose of
HC-Ad expressing full length human FVIII, serum FVIII levels were below
detection in immunocompetent hemophiliac mice. Id. at 6-7.
VandenDriessche,3 which discusses the results of Balagué, states that the
result suggests a non-linear threshold effect. Id. at 7.
The examiner argues further that the example of treatment of a
hemophiliac dog has been refuted by Brown.4 Id. Brown, according to the
examiner, “reported that a hemophiliac dog treated with HC-Ad encoding
B-domain deleted cFVIII at a dose of 5x1011 viral particles per kg of body
mass did not show any increase in serum FVIII or change in whole blood
clotting times.” Id.
The examiner concludes:
In light of the evidence of record both from the prior art
and the instant application, the claimed invention is inoperative
for at least some immunocompetent mammals, e.g. mouse, that
are treated only with the vector in the dose ranges recited by the
claims. The only guidance on overcoming the apparent
threshold effect is to pretreat the mammal with clodronate
liposomes, ostensibly to deplete the mammal of macrophages.
The specification shows successful treatment of dog without
clodronate, but this contrasts with prior art findings that showed
the low doses required by the claims as being inoperative.
2 Balagué et al. (Balagué), Sustained high-level expression of full-length
factor VIII and restoration of clotting activity in hemophilic mice using a
minimal adenovirus vector, 95 Blood 820 (2000).
3 VandenDriessche et al. (VandenDriessche), Viral Vector-Mediated Gene
Therapy for Hemophilia, 1 Current Gene Therapy 301 (2001).
4 Brown et al. (Brown abstract), Heler-dependent adenovirus delivery of a
canine FVIII B-domain deleted transgene in murine and canine models of
hemophilia A,” 98 Blood 695a, (2001).
4
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