Ex parte RINK et al.

Board of Patent Appeals and Interferences

Jan 20, 1998

07707265 (B.P.A.I. Jan. 20, 1998)

1 Application for Patent filed May 24, 1991. According
to applicants, this application is a continuation of
Application 07/186,828, filed April 27, 1988; which is a
continuation of Application 06/736,601, filed May 21, 1985,
which is a continuation-in-part of Application 06/673,951,
filed November 21, 1984, all abandoned.
THIS OPINION WAS NOT WRITTEN FOR PUBLICATION
The opinion in support of the decision being entered today
(1) was not written for publication in a law journal and
(2) is not binding precedent of the Board.
Paper No. 32
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte HANS RINK, MANFRED LIERSCH,
PETER SIEBER, WERNER RITTEL,
FRANCOIS MEYER, URSULA SEEMULLER,
HANS FRITZ, WALTER MARKI
and SEFIK ALKAN
__________
Appeal No. 94-2592
Application 07/707,2651
__________
ON BRIEF
__________
Before WILLIAM F. SMITH, GRON, and ELLIS, Administrative
Patent Judges.
ELLIS, Administrative Patent Judge.
DECISION ON APPEAL
Appeal No. 94-2592
Application 07/707,265
2
This is an appeal from the final decision of the Primary
Examiner rejecting claims 31 through 33. Claims 20 through 26
and 34 are also pending, but have been withdrawn by the
examiner under 37 CFR § 1.142(b).
Claim 31 is illustrative of the subject matter on appeal
and reads as follows:
31. A process for the preparation of an eglin compound
having the following amino acid sequence:
N-acetyl-Thr-Glu-Phe-Gly-Ser-Glu-Leu-Lys-Ser-Phe-Pro-Glu-Val-
Val-Gly-Lys-Thr-Val-Asp-Gln-Ala-Arg-Glu-Tyr-Phe-Thr-Leu-His-
Tyr
-Pro-Gln-Tyr-Asp-Val-W-Phe-Leu-Pro-Glu-Gly-Ser-Pro-Val-Thr-
Leu-
Asp-Leu-Arg-Tyr-Asn-Arg-Val-Arg-Val-Phe-Tyr-Asn-Pro-Gly-Thr-
Asn
-Val-Val-Asn-His-Val-Pro-His-Val-Gly
(Formula XIV’)
in which W is Tyr or His, said process comprising:
a) transforming host cells of Escherichia coli or
Saccharomyces cerevisiae with an expression vector, said
expression vector comprising a promoter of host cell origin
and
a DNA sequence coding for said eglin compound, wherein said
DNA sequence is directly and operably linked to and in proper
reading frame relative to said promoter, in a liquid medium
containing assimilable sources of carbon and nitrogen,
Appeal No. 94-2592
Application 07/707,265
3
b) culturing the transformed host cells in a liquid
medium containing assimilable sources of carbon and nitrogen
suitable for expression of said expression vector, and
c) isolating said eglin compound.
Appeal No. 94-2592
Application 07/707,265
4
The references relied on by the examiner are:
Riggs 4,431,739 Feb. 14, 1984
(filed Jul. 30, 1982)
DeBoer 4,551,433 Nov. 5, 1985
(filed Jan. 11, 1982)
Seemüller et al. 4,636,489 Jan. 13, 1987
(Seemüller ‘87) (filed Jul. 6, 1984)

Seemüller et al. (Seemüller ‘80), “Structure of the Elastase-
Cathepsin G Inhibitor of the Leech Hirudo medicinalis,”
Z. Physiol. Chem., Vol. 361, pp. 1841-1846 (December, 1980).
Miyanohara et al. (Miyanohara), “Expression of Hepatitis B
Surface Antigen Gene in Yeast,” Proc. Natl. Acad. Sci., USA,
Vol. 80, pp. 1-5 (January, 1983).
Knecht et al. (Knecht), “Sequence Determination of Eglin C
Using Combined Microtechniques of Amino Acid Analysis, Peptide
Isolation, and Automatic Edman Degradation,” Analytical
Biochemistry, Vol. 130, pp. 65-71 (1983).
The references relied on by the appellants are:
Waller et al. (Waller), “Selective Acetylation of the Terminal
Amino Group of Corticotrophin,” Biochem. Journal, Vol. 75, pp.
320-328 (1960).
Brown et al. (Brown), “Evidence that Approximately Eighty per
Cent of the Soluble Proteins from Ehrlich Ascites Cells are
N"-Acetylated,” The Journal of Biological Chemistry, Vol. 251,
No. 4, pp. 1009-1014 (February, 1976).
Roth et al. (Roth), “Acetylation of the NH2-terminal Serine of
Prostaglandin Synthetase by Aspirin,” The Journal of
Biological Chemistry, Vol. 253, No. 11, pp. 3782-3784 (June,
1976).
Smyth et al. (Smyth), “Endorphins are Stored in Biologically
Active and Inactive Forms: Isolation of "-N-acetyl Peptides,”
Appeal No. 94-2592
Application 07/707,265
5
Nature, Vol. 279, pp. 252-254 (May, 1979).
Ross, “Production of Medically Important Polypeptides Using
Recombinant DNA Technology,” in Insulins, Growth Hormone, and
Recombinant DNA Technology, John L. Gueriguian, ed., Raven
Press, pp. 33-48 (May, 1981).
Wetzel et al. (Wetzel), “Synthesis of Polypeptides by
Recombinant DNA Methods,” in The Peptides, Academic Press, NY,
Vol. 5, pp. 1-65 (1983).
Tsunasawa et al. (Tsunasawa), “Amino-Terminal Acetylation of
Proteins: An Overview,” in Methods in Enzymology, Academic
Press, NY, Vol. 106, pp. 165-170 (1984).
Märki et al. (Märki), “Isolation and Characterization of
‘Native’ and Rec. Eglin C From E. coli, Selective Proteinase
Inhibitors for Human Leucocyte Elastase, Cathepsin G and
Chymotrypsin,” in Peptides: Structure and Function,
Proceedings of the Ninth American Peptide Symposium, Deber et
al., eds., pp. 385-388 (1985).
Persson et al. (Persson), “Structures of N-terminally
Acetylated Proteins,” European Journal of Biochemistry, Vol.
152, No. 3,
pp. 523-527 (Nov., 1985).
Tsunasawa et al. (Tsunasawa), “Amino-terminal Processing of
Mutant Forms of Yeast Iso-1-cytochrome c,” The Journal of
Biological Chemistry, Vol. 260, No. 9, pp. 5382-5391 (May,
1985).
Huang et al. (Huang), “Specificity of Cotranslational Amino-
Terminal Processing of Proteins in Yeast,” Biochemistry, Vol.
26,
No. 25, pp. 8242-8246 (Dec., 1987).
Winnacker, From Genes to Clones: Introduction to Gene
Technology, translated by Horst Ibelgaufts, pp. 279-293 (June,
Appeal No. 94-2592
Application 07/707,265
6
1989).
Hallewell et al. (Hallewell), “Amino Terminal Acetylation of
Authentic Human Cu, Zn Superoxide Dismutase Produced in
Yeast,”
Biotechnology, Vol. 5, pp. 363-366 (April, 1987).
Claims 31 through 33 stand rejected under 35 U.S.C. § 103
as being unpatentable over Riggs and either Knecht,
Seemüller(‘87) or Seemüller (‘80), in view of DeBoer or
Miyanohara.
Having considered the entire record which includes, inter
alia, the appellants’ main Brief (Paper No. 25) and Reply
Brief (Paper No. 29), the examiner’s Answer (Paper No. 26) and
Supplemental Answer (Paper No. 30), as well as the declaration
of Dr. Schmitz, we find ourselves in substantial agreement
with the appellants’ position. Accordingly, we reverse the
examiner’s rejection for the reasons set forth in the
appellants’ Brief and Reply Brief. In so doing, we especially
direct the examiner’s attention to the appellants’ statements
with respect to the negative teachings in the prior art as to
the direct expression of proteins less than 100 amino acids in
length. Brief, pp. 5-7; Reply Brief, pp. 3-4. Moreover, in
our view, based on the record before us, one of ordinary skill
Appeal No. 94-2592
Application 07/707,265
7
in the art would have had no expectation that the claimed
eucaryotic protein (eglin) which is not N-acetylated in its
natural state, would be acetylated when expressed in
microorganisms which do not generally acetylate the N-termini
of their own endogenous proteins. Brief, pp. 9-10; Reply
Brief, pp. 7-8. We find statements by the examiner such as
[i]t is considered that such a state of the art does not
clearly teach away from appellants’ invention because the
state of the art was unsettled, there were both successes
and failures at expression of heterologous proteins, and
the successes were sufficient to give those of ordinary
skill in the art a reasonable expectation of successful
expression of any given protein with recombinant methods
[Answer, p. 7];
and
[t]he state of the art of acetylation of proteins was
unsettled at the time the invention was made. It was
known, however, as appellants point out (Brief, page 9,
line 16), that E. coli and S. cerevisiae do acetylate
some proteins. Because the state of the art at the time
the invention was made was not sufficiently predictive,
it would have been expected by one of ordinary skill that
any given protein may or may not be acetylated [Answer,
p. 8];
to show inconsistent reasoning and to be contrary to the
interpretation of obviousness as set forth in the prevailing
case law. If the state of the art with respect to (i) the
direct expression of small proteins in a recombinant host
cell, and (ii) the acetylation of proteins, was unsettled and
Appeal No. 94-2592
Application 07/707,265
8
unpredictable, then it would not have been reasonable for one
of ordinary skill in the art to expect success in producing
either one.
Rejection under 37 CFR § 1.196(b)
Under the provisions of 37 CFR § 1.196(b) we make the
following new ground of rejection.
Claims 31 through 33 are rejected under 35 U.S.C. § 112,
second paragraph, for failing to particularly point out and
distinctly claim the subject matter which the appellants
regard as the invention.
Claims 31 through 33 are confusing and misdescriptive in
the recitation of an eglin compound having the “amino acid
sequence: N-acetyl-Thr. . . .” Since the “N-acetyl” is not an
amino acid, it is not clear whether the appellants intend to
claim just the eglin amino acid sequence or an “N-acetylated
eglin.” An amendment inserting “N-acetylated” between
“following” and “amino” on line 2 of claim 31 would obviate
this rejection.
A similar problem exists in withdrawn claim 34. Since
the DNA sequence in paragraph a) encodes “said eglin
compound,” it is not clear whether the appellants intend to
Appeal No. 94-2592
Application 07/707,265
9
claim the eglin amino acid sequence alone or an “N-acetylated
eglin.” An amendment inserting the phrase “N-acetylated”
between “An” and “eglin” on line 1 of claim 34 would remedy
this defect.
Other Issues
In our review of the application we note that the
examiner’s search of the prior art appears to have been
limited to a word search of the term “eglin.” We find no
indication that the examiner searched (i) the protein data
bases for the amino acid sequence of the claimed protein, or
(ii) the protein by its other name, hirudin. Upon return of
this application to the corps, we suggest the examiner
consider whether all the relevant data bases have been
properly explored.
The decision of the examiner is reversed.
REVERSED
Appeal No. 94-2592
Application 07/707,265
10
WILLIAM F. SMITH )
Administrative Patent Judge )
)
)
)
TEDDY S. GRON ) BOARD OF
PATENT
Administrative Patent Judge ) APPEALS AND
) INTERFERENCES
)
)
JOAN ELLIS )
Administrative Patent Judge )
Appeal No. 94-2592
Application 07/707,265
11
Michael W. Glynn
CIBA-GEIGY Corporation
Patent Department
520 White Plains Road
P. O. Box 2005
Tarrytown, NY 10591-9005
JE/cam