Ex Parte Okuno et al

Patent Trial and Appeal Board

Oct 24, 2016

10573821 (P.T.A.B. Oct. 24, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/573,821 03/28/2006
55694 7590 10/26/2016
DRINKER BIDDLE & REATH (DC)
1500 K STREET, N.W.
SUITE 1100
WASHINGTON, DC 20005-1209
FIRST NAMED INVENTOR
Kazuaki Okuno
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
047259-5001-00-US-223490 9193
EXAMINER
SWOPE, SHERIDAN
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
10/26/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte KAZUAKI OKUNO and MASA YUKI Y ABUT A
Appeal2014-003834
Application 10/573,821
Technology Center 1600
Before DONALD E. ADAMS, TA WEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL 1
This appeal under 35 U.S.C. § 134(a) involves claims 49, 51-56, 59-
61, 67, and 68 (App. Br. 2). Examiner entered rejections under 35 U.S.C.
§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b ).
We REVERSE.
1 Appellants identify "[t]he real party in interest [as] Asubio Pharma Co.,
Ltd." (App. Br. 2.)
Appeal2014-003834
Application 10/573,821
STATEMENT OF THE CASE
Appellants disclose "a method for directly cleaving a physiologically
active peptide, protein or its derivative from a fusion protein utilizing E. coli
OmpT protease or a variant thereof' (Spec. 1 :6-9). Claims 49, 54, 67, and
68 are representative and reproduced below:
49. A process for cleaving a polypeptide comprising cleaving
the polypeptide with an E coli OmpT protease variant
consisting of an amino acid substitution at the 97th position of
the amino acid sequence of SEQ ID NO: 41,
wherein the 97th amino acid from the N-terminus of the E
coli OmpT protease variant is leucine, methionine, or
histidine,
wherein the polypeptide comprises a cleavage site that is a
peptide bond between the Pl position and the Pl' position,
and
wherein the Pl position is arginine or lysine and the Pl'
position is:
(App. Br. 14.)
( 1) serine or alanine when the 97th amino acid from the
N-terminus of the E. coli OmpT protease variant is
leucine;
(2) phenylalanine, alanine, serine, cysteine, or tyrosine
when the 97th amino acid from the N-terminus of
the E. coli OmpT protease variant is methionine; or
(3) alanine, valine, isoleucine, methionine, serine,
threonine, cysteine, or asparagine when the 97th
amino acid from the N-terminus of the E. coli OmpT
protease variant is histidine.
54. The process of claim 49,
wherein the polypeptide is a fusion protein comprising a
protecting peptide and a target peptide,
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Application 10/573,821
wherein the C-tenninus of the protecting peptide is the Pl
position and the N-tenninus of the target peptide is the Pl'
position,
wherein the fusion protein is produced by expressing a
gene encoding the fusion protein in a host cell, and
wherein cleavage of the fusion protein liberates the target
peptide.
(App. Br. 15.)
67. The process of claim 54, wherein the target peptide consists
of between 22 and 45 amino acid residues.
(App. Br. 17.)
68. The process of claim 67, wherein the target peptide is
adrenocorticotropic hormone (1-24 ), motilin, or calcitonin
precursor.
(App. Br. 17.)
The claims stand rejected as follows:
Claims 49 and 51-53 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Kramer, 2 Bott, 3 and Okuno. 4
2 R. Arjen Kramer et al., Identification of essential acidic residues of outer
membrane protease OmpT supports a novel active site, 505 FEBS Letters
426-430 (2001 ).
3 Bott et al., US 5,700,676, issued Dec. 23, 1997.
4 Kazuaki Okuno et al., Substrate Specificity at the P 1 'Site of Escherichia
coli OmpTunder Denaturing Conditions, 66 Biosci. Biotechnol. Biochem.
127-134 (2002).
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Appeal2014-003834
Application 10/573,821
Claims 54--56, 59---61, and 67 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over the combination of Kramer, Bott, Okuno, Stumpe, 5
Suzuki, 6 Dekker, 7 and Darnell. 8
Claim 68 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Yamamoto, 9 Kramer, Bott, Okuno, Stumpe, Suzuki,
Dekker, and Darnell.
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
5 Stefan Stumpe, Identification of OmpT as the Protease That Hydrolyzes the
Antimicrobial Peptide Protamine before It Enters Growing Cells of
Escherichia coli, 180 J. Bacteriol. 4002--4006 (1998).
6 Koichi Suzuki and Toshio Ando, Studies on Protamines XVI. The
Complete Amino Acid Sequence of Clupeine YI!, 72 J. Biochem. 1419-1432
(1972).
7 Niek Dekker et al., Substrate Specificity of the Integral Membrane
Protease OmpT Determined by Spatially Addressed Peptide Libraries, 40
Biochemistry 1694--1701 (2001).
8 James Darnell et al., Molecular Cell Biology 44--45 (2d ed. 1990).
9 Yamamoto et al., US 5,506, 120, issued Apr. 9, 1996.
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Application 10/573,821
FACTUAL FINDINGS (FF)
FF 1. Kramer's Figure 4 is reproduced below:
Asp85 Asp83
8 c:~!
•' ~
, ..
"' ' f\sp21 o~:~··· ......... ,, ~~1~s2i 2
Kramer's Figure 4 represents a "[s]chematic two-dimensional model of a
peptide in the active site of OmpT. Hydrogen bonds and ionic interactions
are indicated by dashed lines. The curved arrow represents the nucleophilic
attack on the carbonyl carbon of the scissile peptide bond" (Kramer 428:
Fig. 4, Legend). The arginine (Arg) residue to the left of the scissile peptide
bond represents the Pl position of the OmpT polypeptide substrate. The Arg
residue to the right of the scissile peptide bond represents the P 1' position of
the OmpT polypeptide substrate. The Asp97 residue represents the amino
acid at the 97th position of the OmpT protease. See Ans. 2-3.
FF 2. Kramer discloses OmpT protease variants, wherein the "six
aspartates (at positions 43, 83, 85, 97, 208 and 210) and five glutamates (at
positions 27, 111, 136, 193 and 250) ... were replaced by alanines and the
residual activities of the resulting variants were measured" (Kramer 426; see
generally Ans. 2-3).
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Application 10/573,821
FF 3. Kramer reports that the activity of the OmpT protease variants is "in
good agreement with" Kramer's earlier proposal, which was "based on the
crystal structure of OmpT [],that Glu27 and Asp208 may define the high
specificity of OmpT for Arg or Lys at position Pl in the substrate" and
"[ fJor the Pl' position, the specificity was less exclusive, but a positively
charged amino acid was preferred there as well [], likely due to interaction
with an anionic residue of OmpT." Thus, Kramer reasons that "[a]ssuming
[] the substrate has an extended conformation and that the P 1 side chain
points towards Glu27 and Asp208 , the Pl' chain would be located close to
Asp97" (Kramer 428--429 (endnotes omitted); see generally Ans. 2-3).
FF 4. Kramer reports that by replacing Arg97 residue with an alanine, "only
6% residual activity" was observed; therefore, Kramer "propose[ s] that
Asp97 is responsible for the observed Pl' specificity" (Kramer 429; see Ans.
2).
FF 5. Examiner finds that Kramer fails to disclose "variants of Omp T
protease having the single Asp97 substituted with any amino acids other than
Ala" (Ans. 3).
FF 6. Bott "relates to novel carbonyl hydrolase mutants derived from the
amino acid sequence of naturally-occurring or recombinant non-human
carbonyl hydro lases and to DNA sequences encoding the same" (Bott 1 :22-
25; Ans. 3--4).
FF 7. Bott discloses subtilisin mutants, wherein amino acids Gly 166 and
Gly 169 were substituted with all 19 naturally occurring amino acids and
finds that "the preferred replacement amino acids for Gly 166 and/or Gly 169
will depend on the specific amino acid occupying the P-1 position of a given
substrate" (Bott 40:37-51).
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Application 10/573,821
FF 8. Okuno discloses modified OmpT substrates, wherein the "cleavage
site of the substrate PRR was Arg140-Arg141 and the modified substrates PRX
substituted all 19 natural amino acids at the Pl' site instead of Arg 141 "
(Okuno, Abstract; see Ans. 3--4).
FF 9. Examiner relies on Stumpe to suggest that "OmpT protease cleaves
protamines" (Ans. 4).
FF 10. Examiner relies on Suzuki to disclose "the sequence of the protamine
component Clupein YII" (Ans. 4).
FF 11. Examiner relies on Dekker to "rank[] the P2-P 1' positions for
cleavage by OmpT" (Ans. 4).
FF 12. Examiner relies on Darnell to "provide[] guidance as to the
molecular basis for non-covalent bonding between amino acids" (Ans. 5).
FF 13. Examiner relies on Yamamoto to disclose "fusion proteins
comprising a target peptide, including motilin or calcitonin, and cleaving
such fusion protein using OmpT protease" (Ans. 6).
FF 14. Examiner finds that Yamamoto fails to suggest "cleaving a motilin-
or calcitonin-comprising fusion protein using an OmpT variant having a
single Asp97Xaa substitution, wherein the target protein is released without
any additional N-terminal amino acids" and relies on the combination of
Kramer, Bott, Okuno, Stumpe, Suzuki, Dekker, and Darnell to make up for
this deficiency in Yamamoto (Ans. 6).
ANALYSIS
The combination of Kramer, Bott, and Okuno:
Based on the combination of Kramer, Bott, and Okuno, Examiner
concludes that, at the time Appellants' invention was made, it would have
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Application 10/573,821
been prima facie obvious "to use the strategy of Bott [] to make all 19
Asp97Xaa variants of OmpT protease, including [those required by
Appellants' claimed invention] and test said variants for substrate specificity
at the P 1' position" using Okuno' s fusion protein substrate library in order to
arrive at Appellants' claimed invention (Ans. 3--4). We are not persuaded.
Initially, we note Examiner's concession that Kramer fails to disclose
"variants of OmpT protease having the single Asp97 substituted with any
amino acids other than Ala" (FF 5). To make up for this deficiency in
Kramer, Examiner directs attention to Bott's work with a protease, which is
not OmpT, wherein glycine, not arginine, residues are substituted with
various amino acids (FF 7). At best, Bott provides general guidance on the
modification of a non-OmpT protease, that one may consider applying to
Kramer to make additional OmpT protease variants. Nevertheless, even if a
person of ordinary skill in this art would have combined Kramer with Bott's
general guidance on the modification of a non-OmpT protease, a person of
ordinary skill would have, at best, a collection of OmpT protease variants,
with no knowledge of the variant's biological activity, or, if biologically
active, what substrate cleavage motif any particular OmpT protease variant
would recognize. To make up for the foregoing deficiency in the
combination of Kramer and Bott, Examiner relies on Okuno to suggest that a
collection of OmpT protease variant substrates was known in the art at the
time of Appellants' claimed invention (FF 8).
In sum, Examiner concludes that a person of ordinary skill in this art
could follow the general guidance set forth in the combination of Kramer,
Bott, and Okuno and thereby arrive at Appellants claimed invention, which
requires specific amino acids to be present in the P 1 and P 1 ' position of the
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Appeal2014-003834
Application 10/573,821
OmpT substrate when the 97th amino acid from the N-terminus of the OmpT
protease contains a specifically defined amino acid (see, e.g., App. Br. 14).
We conclude the Examiner's reasoning is precisely what the
0 'Farrell court articulated as an improper application of an "obvious to try"
standard in an obviousness analysis In re 0 'Farrell, 853 F.2d 894, 903 (Fed.
Cir. 1988). That is, Examiner reasons that a person of ordinary skill in this
art would have "var[ied] all [the prior art] parameters or tr[ied] each of
numerous possible choices until one possibly arrived at a successful result,
where the prior art gave either no indication of which parameters were
critical or no direction as to which of many possible choices is likely to be
successful" and/or "explore[d] a ... general approach that seemed to be a
promising field of experimentation, where the prior art gave only general
guidance as to the particular form of [Appellants'] claimed invention or how
to achieve it." Id.; see also Appeal Br. 6-7. On this record, we find no
evidence or reasoning from Examiner to support a conclusion that there were
a finite number of identified and/or predictable solutions as to which specific
modification(s) to the OmpT protease were necessary in order to define a
specific OmpT substrate cleavage motif. Cf KSR Int 'l Co. v. Teleflex Inc.,
550 U.S. 398, 421 (2007).
The combination of Kramer, Bott, Okuno, Stumpe, Suzuki, Dekker, and
Darnell, with or without Yamamoto:
Examiner failed to establish that any of Stumpe, Suzuki, Dekker,
Darnell or Yamamoto make up for the foregoing deficiency in the
combination of Kramer, Bott, and Okuno (see App. Br. 12 and 13; cf FF 9--
14).
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Application 10/573,821
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness.
The rejection of claims 49 and 51-53 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Kramer, Bott, and Okuno is reversed.
The rejection of claims 54--56, 59---61, and 67 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Kramer, Bott, Okuno,
Stumpe, Suzuki, Dekker, and Darnell is reversed.
The rejection of claim 68 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Yamamoto, Kramer, Bott, Okuno, Stumpe, Suzuki,
Dekker, and Darnell is reversed.
REVERSED
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