Appeal No. 2001-0733 Page 4
Application No. 09/095,429
The rejection concludes:
Rybak [ ] disclose[s] that onconase is in clinical trial for the
treatment of cancer, see page 4, first paragraph, which is
motivation to one of ordinary skill in the art to make large quantities
of onconase. Since the proteolytic processing of the methionine
residue at the N-terminus of eukaryotic protein expressed in E. Coli
is a known problem in the art, the amino acid sequence of SEQ ID
NO: 1 has only one methionine residue at position 23 which is
cleavable by cyanogens bromide as taught by Ardelt [ ] and the N-
terminus amino acid methionine is cleavable with cyanogens
bromide, it would have been obvious to one of ordinary skill in the
art at the time of the invention to mutate Met-23 to another residue
with comparable size such as Leu to cleave the N-terminus Met
with cyanogen bromide. The person of ordinary skill in the art
would have been guided by the high resolution three dimensional
structure of the enzyme taught by Mosimann [ ] to select the most
appropriate amino acid that replaces Met-23 without perturbing the
structure of onconase. There are many commercially available
computer software packages such as QUANTA that utilizes the
three dimensional structure of an enzyme/protein to analyze the
effects of specific mutation on the structure. Thus, it would have
been obvious at the time of invention to one of ordinary skill in the
art to chemically synthesize a gene encoding the 104 amino acid
sequence of SEQ ID NO: 1 taught by Ardelt [ ] or Mosimann [ ] with
the appropriate mutation at position 23 and include the ATG
initiation codon (coding for methionine residue in the -1 position)
which is required for the expression of almost all proteins in any cell
including E. coli (claims 15 and 16). It should be noted that one of
ordinary skill in the art would expect that the natural gene coding
for the onconase from Rana pipiens oocytes (eukaryotic organism)
must contain the ATG codon followed by a codon for glutamine
residue as the genetic code does not have a codon for
pyroglutamic acid. ATG is the most common initiation codon for
protein transcription in both prokaryotic and eukaryotic cells. . . .
Once the N-terminus Met is cleaved, the new N-terminus glutamine
autocyclizes to form the pyroglutamic acid residue in position 1 as
taught by Creighton. The ordinary skill in the art would have had
the motivation, skills, knowledge and expectation of success.
Thus, the claimed invention was within the ordinary skill in the art to
make and use at the time the invention was made and was as a
whole, clearly prima facie obvious.
Id. at 10-12.
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