Ex parte Senior

Board of Patent Appeals and Interferences

Jul 31, 2000

08444628 (B.P.A.I. Jul. 31, 2000)

Application for patent filed May 19, 1995. According to appellant, this application1
is a divisional of Application Serial No. 08/357,820, filed December 16, 1994.
1
The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.
Paper No. 12
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte ROBERT M. SENIOR
__________
Appeal No. 1998-0053
Application 08/444,628 1
__________
ON BRIEF
__________
Before WILLIAM F. SMITH, SPIEGEL and SCHEINER, Administrative Patent Judges.
SCHEINER, Administrative Patent Judge.
Appeal No. 1998-0053
Application 08/444,628
As a preliminary matter, we note that this appeal is related to an appeal in2
Application Serial No. 08/357,820 (Appeal No. 1997-2140). We have considered the two
appeals together.
2
DECISION ON APPEAL2
This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 1, 2 and
4, the only claims remaining in the application. The claims are reproduced below:
1. A truncated mutant, SEQ ID NO:1, of the 92 kDa gelatinase having an amino
acid sequence as shown in FIG. 2 consisting of residues 106-216 fused to residues 391-
443 of the parent molecule.
2. The truncated mutant of claim 1 containing an additional Met-Gly dipeptide at the
N-terminus.
4. The method of modifying the 92 kDa gelatinase protein to make it essentially
inactive against insoluble elastin but to remain catalytically active which comprises fusing
amino acid residues 106-216 to residues 391-443 of the parent 92 kDa gelatinase protein
molecule to thereby provide the truncated mutant having an amino acid sequence as
shown in Fig. 2 (SEQ ID NO:1).

The references relied on by the examiner are:
Goldberg et al. (Goldberg) 4,992,537 Feb. 12, 1991
Liotta et al. (Liotta) 5,270,447 Dec. 14, 1993
Hirel et al. (Hirel), “Extent of N-terminal methionine excision from Escherichia coli proteins
is governed by the side-chain length of the penultimate amino acid,” Proc. Natl. Acad. Sci.
USA, Vol. 86, pp. 8247-8251 (November 1989).
Thomas et al. (Thomas), “Expression in Escherichia coli and characterization of the heat-
stable inhibitor of the cAMP-dependent protein kinase,” Journal of Biological Chemistry,
Vol. 266, No. 17, pp. 10906-10911 (June 15, 1991).
Appeal No. 1998-0053
Application 08/444,628
The 92 kDa gelatinase is also known in the art as gelatinase B, and as MMP-9; 3
the 72 kDa gelatinase is also known as gelatinase A, and as MMP-2.
3
Murphy et al. (Murphy), “Assessment of the role of the fibronectin-like domain of gelatinase
A by analysis of a deletion mutant,” Journal of Biological Chemistry, Vol. 269, No. 9, pp.
6632-6636 (March 4, 1994).
O’Connell et al. (O’Connell), “Analysis of the role of the COOH-terminal domain in the
activation, proteolytic activity, and tissue inhibitor of metalloproteinase interactions of
gelatinase B,” Journal of Biological Chemistry, Vol. 269, No. 21, pp. 14967-14973 (May
27, 1994).
Claims 1 and 4 stand rejected under 35 U.S.C. § 103 as unpatentable over
Goldberg, O’Connell, Murphy and Liotta. Claim 2 stands rejected under 35 U.S.C. § 103
as unpatentable over Goldberg, O’Connell, Murphy, Liotta, Hirel and Thomas. We reverse
both rejections.
BACKGROUND
Matrix metalloproteinases comprise a family of enzymes collectively capable of
degrading all components of extracellular matrix. Members of the family include several
collagenases, a 92 kDa gelatinase, a 72 kDa gelatinase, three stromalysins, macrophage
metalloelastase, matrilysin, etc. The 92 kDa gelatinase consists of five structural3
domains: the amino-terminal and zinc-binding catalytic domains shared by all members of
the secreted metalloproteinase gene family, the collagen binding fibronectin-like domain
shared with the 72 kDa gelatinase, a carboxyl-terminal hemopexin-like domain shared by
all matrix metalloproteinases except matrilysin, and a unique 54 amino acid proline-rich
Appeal No. 1998-0053
Application 08/444,628
A zymogen is an inactive enzyme precursor, also known as a proenzyme.4
4
domain homologous to the "-2 chain of type V collagen. The metalloproteinases are
secreted as zymogens, and undergo activation extracellularly through amino-terminal4
proteolytic processing. Once activated, the 92 kDa gelatinase, as its name indicates, has
the ability to degrade gelatin (denatured collagen); it also degrades insoluble elastin.
There are three other metalloproteinases with the ability to degrade insoluble elastin: the
72 kDa gelatinase, matrilysin and macrophage metalloelastase. Specification, pages 2
and 3; Goldberg, columns 1 and 2, and Figure 6.
DISCUSSION
Claim 1 is directed to a truncation mutant representing the zinc-binding catalytic
domain of the 92 kDa gelatinase, but lacking the three fibronectin-like type II repeats
normally present in the catalytic domain of the parent enzyme. Claim 4 is directed to a
method of making the truncation mutant. The truncation mutant consists of amino acid
residues 106-216 fused to residues 391-443 of the parent molecule. In other words, the
truncated protein is distinguished from the parent enzyme by three separate deletions:
amino-terminal residues 1-105, internal residues 217-390, and carboxy-terminal residues
444-707. According to the specification, the truncation mutant is catalytically active
against gelatin, but, unlike the parent enzyme, inactive against insoluble elastin.
Specification, page 3.
Appeal No. 1998-0053
Application 08/444,628
Tissue Inhibitor of Metalloproteinase-1.5
5
Goldberg discloses the full length 92 kDa gelatinase. The 92 kDa gelatinase is
structurally related to the 72 kDa gelatinase, but is unique among matrix
metalloproteinases in having a 54 amino acid proline-rich domain homologous to the "-2
chain of type V collagen. Figure 6 shows the structural domains shared by the 92 kDa and
72 kDa gelatinases in alignment; the two enzymes share some sequence similarity but the
92 kDa gelatinase contains three potential N-glycosylation sites not found in the 72 kDa
gelatinase and is fully glycosylated.
O’Connell assesses the role of the carboxyl-terminal collagen- and hemopexin-like
domains of the 92 kDa gelatinase. Deletion of these domains, which correspond to
carboxy-terminal amino acids 444-707, does not affect the catalytic activity of the enzyme,
but does affect the rate of activation in the presence of the inhibitor TIMP-1. O’Connell5
also discloses activation of the carboxy-terminal truncated protein to delete various
portions of the amino-terminal, including a deletion corresponding to amino acids 1-105.
Murphy assesses the role of the fibronectin-like domain of the 72 kDa gelatinase.
A deletion mutant lacking the fibronectin-like domain was unable to bind collagen or
gelatin; once activated, the deletion mutant exhibited markedly impaired ability to degrade
gelatin. Page 6634, left-hand column, and page 6635, left-hand column.
Liotta teaches that a region of the amino terminus of the 72 kDa gelatinase acts as
an intrinsic enzyme inhibitor when the enzyme is in a latent state.
Appeal No. 1998-0053
Application 08/444,628
6
Claims 1 and 4 stand rejected as unpatentable over the combined disclosures of
Goldberg, O’Connell, Murphy and Liotta. According to the examiner:
It would have been obvious to one of ordinary skill in the art using the 92 kDa
gelatinase of [Goldberg] at the time of the invention, to make truncations in it
to delete the carboxyl terminal collagen-like and hemopexin-like domains, as
taught by [O’Connell] in order to reduce sensitivity to the TIMP-1 inhibitor; to
delete the internal fibronectin domain, as taught by [Murphy] in order to
reduce binding to collagen; and to delete the amino terminal at least up to
Phe as taught by [O’Connell] and [Liotta] in order to reduce intrinsic88
inhibition. Motivation to make a multiply truncated 92 kDa gelatinase is
provided by the teachings of [Goldberg, O’Connell, Murphy and Liotta], who
teach the various improvements in gelatinase activity as described above.
(Examiner’s Answer, page 6, emphasis added).
We disagree. The reason proposed by the examiner for deleting the amino- and
carboxy-terminal regions of the 92 kDa gelatinase is plausible as far as it goes: to
minimize inhibition of enzyme’s ability to degrade gelatin (i.e., denatured collagen).
Indeed, O’Connell discloses a truncated mutant with both of these deletions. The reason
given for the further deletion of the internal fibronectin-like domains, however, is an entirely
different matter. To the extent that manipulation of the 72 kDa gelatinase is relevant to the
92 kDa gelatinase, Murphy shows that deletion of the fibronectin-like domains, by
eliminating the ability of the mutant to bind collagen, markedly impairs the ability of the
truncated mutant to degrade gelatin. Thus, the combination of deletions proposed by the
examiner would seem, based on the references cited, to operate at cross-purposes.
Appeal No. 1998-0053
Application 08/444,628
Having determined that a prima facie case of obviousness has not been6
established, we find it unnecessary to comment on appellants’ arguments regarding the
unexpected properties of the claimed truncation mutants.
7
It is well settled that the initial burden of establishing unpatentability rests on the
examiner, In re Oetiker, 977 F.2d 1443, 1446, 24 USPQ2d 1443, 1445 (Fed. Cir. 1992).
As stated in Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573, 37
USPQ 1626, 1629, (Fed. Cir. 1996) (citation omitted):
[B]efore a conclusion of obviousness may be made based on a combination
of references, there must have been a reason, suggestion, or motivation to
lead an inventor to combine those references.
In our judgment, the only reason or suggestion to modify the references to arrive at the
claimed truncation mutant comes from appellants’ specification. Accordingly, we find that
the examiner’s initial burden of establishing a prima facie case of obviousness has not
been met. The rejection of claims 1 and 4 under 35 U.S.C. § 103 is reversed.6
Claim 2, directed to the truncation mutant of claim 1 containing two additional
amino acids at the amino-terminus, stands rejected as unpatentable over Goldberg,
O’Connell, Murphy, Liotta, Hirel and Thomas. The underlying rationale of the rejection
corresponds to that of claims 1 and 4, and suffers from the same infirmity. Again, we find
that the examiner’s initial burden of establishing a prima facie case of obviousness has not
been met, and the rejection of claim 4 under 35 U.S.C. § 103 is reversed.
REVERSED
Appeal No. 1998-0053
Application 08/444,628
8
)
WILLIAM F. SMITH )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
CAROL A. SPIEGEL )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
TONI R. SCHEINER )
Administrative Patent Judge )
ATTN: Roger A. Williams
G. D. Searle & Company
Corporate Patent Law Department
P. O. Box 5110
Appeal No. 1998-0053
Application 08/444,628
9
Chicago IL 60680-5110