Appeal No. 1997-2751
Application No. 08/159,096
essential part of the fracture repair process. Kanis, for example,
teaches in Lancet 1984, 27-33 that bisphosphonates, as inhibitors
of bone resorption, may indeed halt skeletal losses but on the other
hand delay the repair of microfractures by reducing the rate of
remodelling of damaged bone and inhibiting callus formation. As
another example, Reid et al. in Lancet 1988, 143-146 found that
bisphosphonate treatment, in this particular case done with
disodium pamidronate (= APD), caused a reduction in bone
formation and a very low rate of bone turnover which raised the
possibility of impaired microfracture repair. Furthermore, Alpar, in
J. Clin. Hosp. Pharmacy 9 (1984) 341-344, expressed the view that
the natural process of bone healing cannot be influenced by any
drug.
Furthermore, one commercially available bisphosphonate, disodium
etidronate, is even known to inhibit bone mineralization and to delay
callus formation and fracture healing in man and animals at doses
within the therapeutic range [see G.A.M. Finerman et al., Clin.
Orthopaed. Rel. Res. 120 (1976) 115-124; L. Flora et al., Metabol.
Bone Dis. Rel. Res. 4/5 (1981) 289-300].
The specification accurately summarizes the prior art. Alpar reviews the
bone healing process and concludes that “[i]t appears that this natural process
cannot be influenced by drugs.” Page 343. Kanis states that inhibitors of bone
resorption such as bisphosphonates may “increase the risk of microfracture or
delay their repair and lead to skeletal failure . . ., by reducing the rate of
remodeling of damaged bone, inhibiting callus formation, or both.” Page 27. In
addition, Reid states that administration of (3-amino-1-hydroxypropylidene)-1,1-
bisphosphonate causes a “very low rate of bone turnover,” and “raises the
possibility of impaired micro[]-fracture repair.” Page 145.
Experimental evidence generated by Finerman, Henricson, and Lenehan
confirmed these expectations. Finerman reported that withholding
diphosphonate treatment in two patients allowed fracture healing to proceed.
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