Ex Parte Carozzi et al

Patent Trial and Appeal Board

Dec 8, 2014

10783417 (P.T.A.B. Dec. 8, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte NADINE CAROZZI, TRACY HARGISS,
MICHAEL G. KOZIEL, NICHOLAS B. DUCK, and BRIAN CARR1
__________

Appeal 2012-005480
Application 10/783,417
Technology Center 1600
__________

Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a nucleic
acid encoding a delta-endotoxin from Bacillus thuringiensis, which have
been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 According to Appellants, the Real Party in Interest is Athenix Corp.
(Appeal Br. 1).
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STATEMENT OF THE CASE
“Crystal (Cry) proteins (delta-endotoxins) from Bacillus thuringiensis
have potent insecticidal activity” (Spec. 1:15–16). The Specification
discloses “nucleic acid molecules encoding sequences for delta-endotoxin
polypeptides. . . . In particular, the present invention provides for isolated
nucleic acid molecules comprising a nucleotide sequence encoding the
amino acid sequence shown in SEQ ID NO:2.” (Id. at 3:3–4, 13–15.)
Claims 1–11, 19, 22, 23, and 30 are on appeal. Claim 1 is illustrative
and reads as follows:
1. An isolated or recombinant nucleic acid molecule selected from
the group consisting of:
a) a nucleic acid molecule comprising the nucleotide sequence
of SEQ ID NO:1;
b) a nucleic acid molecule which encodes a polypeptide
comprising the amino acid sequence of SEQ ID NO:2; and,
c) a nucleic acid molecule comprising a nucleotide sequence
encoding a polypeptide having at least 95% amino acid sequence identity to
the amino acid sequence of SEQ ID NO:2, wherein said polypeptide has
pesticidal activity against lepidopteran or heteropteran pests.

DISCUSSION
Issue
The Examiner has rejected claims 1 and 4–7 under 35 U.S.C. § 103(a)
as obvious based on Ben-Dov,2 Liu,3 Carlton,4 de Maagd,5 and Appellants’

2 Ben-Dov et al., Restriction Map of the 125-Kilobase Plasmid of Bacillus
thuringiensis subsp. israelensis Carrying the Genes That Encode Delta-
Endotoxins Active against Mosquito Larvae, 62 APPL. AND ENVIRON.
MICROBIOL. 3140–3145 (1996).
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response to a Request for Information under 37 C.F.R. § 1.105 (Ans. 5).
The Examiner has rejected claims 2, 3, 8–11, 19, 22, 23, and 30 under
35 U.S.C. § 103(a) as obvious on the same basis, as further combined with
Koziel6 (Ans. 7).
The Examiner finds that Appellants’ response to a Request for
Information under 37 C.F.R. § 1.105 “indicates that the bacterial strain from
which SEQ ID NO: 1-2 were isolated is HD536, and available from the
USDA” (Ans. 5) and that Carlton discloses that “strain HD536 has a 68
MDa plasmid implicated in toxin production” (id. at 6).
The Examiner finds that Ben-Dov discloses “restriction mapping of a
Bacillus thuringiensis plasmid” (id. at 5) and Liu discloses “a method of
isolating B. thuringiensis toxin genes” (id.). The Examiner finds that Liu
also teaches that “it would be advantageous to isolate new B. thuringiensis
toxins to increase the spectrum of biopesticides” (id.). The Examiner finds
that De Maagd discloses “known Cry protein conserved sequence and
structural domains” (id. at 6). The Examiner concludes that it would have
been obvious based on these teachings “to clone delta-endotoxin genes from
strain HD536 described in Carlton et al using the methods described in Ben-
Dov et al and Liu et al” in order to increase the spectrum of toxicity, as
taught by Liu (id.). The Examiner also finds that “[i]n cloning the toxins

3 Liu et al., US 6,156,308, issued Dec. 5, 2000.
4 Bruce C. Carlton and José M. González, Jr., Plasmids and Delta-Endotoxin
Production in Different Subspecies of Bacillus thuringiensis, MOL. BIOL.
MICROB. DIFFER., PROC. INTL. SPORE CONF., 246–252 (1985).
5 de Maagd et al., How Bacillus thuringiensis has evolved specific toxins to
colonize the insect world, 17 TRENDS IN GENETICS 193–199 (2001).
6 Koziel et al., US 5,625,136, issued Apr. 26, 1997.
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from the 68 MDa plasmid from HD536, one of skill in the art would
necessarily isolate a nucleic acid encoding SEQ ID NO:2” (id.).
Appellants contend that the rejections are based on hindsight because
“outside of Applicant’s Specification, one of ordinary skill in the art would
have no reason to select and isolate sequences from HD536 given the
numerous possibilities of well-known strains exhibiting insecticidal activity”
(Appeal Br. 4). Appellants also contend that the references do not provide a
reasonable expectation of success because Ben-Dov is limited to evaluating
a plasmid containing genes encoding endotoxins with activity against
mosquito larvae (id. at 6) and “[w]hile methods for isolating toxin genes
from strains having pesticidal activity were known in the art at the time of
filing of the instant application, . . . there would have been no reasonable
expectation of success in identifying the specific genes claimed in the instant
invention” (id. at 7).
Appellants also contend that “[o]ne of ordinary skill in the art would
fail to recognize any reasonable expectation of success in obtaining any
toxin genes from HD536 since no insecticidal activity was demonstrated for
this strain prior to the Applicant’s disclosure” (id. at 8). Finally, Appellants
contend that the toxin encoded by the claimed nucleic acids unexpectedly
exhibits insecticidal activity against Lygus lineolaris (id. at 9–10).
The issues presented are (1) whether the cited references support the
Examiner’s conclusion that it would have been obvious to isolate a nucleic
acid encoding a delta-endotoxin having the amino acid sequence of SEQ ID
NO:2 from B. thuringiensis strain HD536, and (2) whether Appellants have
provided evidence of unexpected results that, when weighed with the
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evidence of obviousness, shows that the claimed nucleic acids would not
have been obvious.
Findings of Fact
1. The Examiner finds that Appellants’ response to a Request for
Information under 37 C.F.R. § 1.105 “indicates that the bacterial strain from
which SEQ ID NO: 1-2 were isolated is HD536, and available from the
USDA” (Ans. 5). Appellants do not dispute this finding.
2. Carlton discloses that B. thuringiensis strain HD-536 contains a
plasmid with a size of 68 MDa that is implicated in toxin production
(Carlton 249, Table 1).
3. Carlton discloses that the insecticidal activity of B. thuringiensis
“resides in the proteinaceous inclusion . . . known as the parasporal body or
crystal” (id. at 246, left col.).
4. Carlton discloses that “[d]elta-endotoxin genes have been assigned
to specific B. thuringiensis plasmids by studies involving isolation of
acrystalliferous (Cry–) B. thuringiensis variants by plasmid curing” (id.).
5. Carlton discloses that “usually, only a single plasmid was absent or
modified (altered in mobility) in the Cry– variant” (id. at 248, left col.).
6. Ben-Dov discloses that the mosquito larvicidal activity of B.
thuringiensis subsp. israelensis “is included in five polypeptides of a
parasporal crystalline body (delta-endotoxin), CryIVA-D and CytA” (Ben-
Dov 3140, left col.; reference citations omitted).
7. Ben-Dov discloses that “[t]hese, and all the other genetic elements
responsible for toxicity, are located on one of the largest (125-kb) plasmids
of B. thuringiensis subsp. israelensis” (id.).
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8. Ben-Dov discloses that “[g]enes for delta-endotoxin, beta-
exotoxin, and thuricin are clustered on either the same or different replicons,
usually very large plasmids or the chromosome itself, in various B.
thuringiensis subspecies” (id. at 3143, right col.).
9. Ben-Dov discloses that the delta-endotoxin genes of B.
thuringiensis subsp. israelensis were mapped to specific locations on the
plasmid by cutting the plasmid with different restriction enzymes, cloning
the fragments, and screening the cloned fragments to identify which
included delta-endotoxin genes (id. at 3140, abstract).
10. Liu discloses that “[i]t is advantageous to isolate new strains of
Bacillus thuringiensis to produce new toxins so that there exists a wider
spectrum of biopesticides for any given insect pest” (Liu 3:6–8).
11. Liu discloses “Bacillus thuringiensis strain(s) . . . [that] produces
at least two delta-endotoxins” (id. at 3:12–16).
12. Liu discloses “an isolated nucleic acid fragment containing a
nucleic acid sequence encoding each of the delta-endotoxins” (id. at 3:28–
29).
13. Liu discloses that “[i]dentification of the specific DNA fragment
encoding the delta-endotoxin may be accomplished in a number of ways”
(id. at 5:54–55; see also id. at 5:56 to 6:13 (listing some of the ways)).
14. Liu discloses that “[p]roduction of the delta-endotoxin or a
portion thereof at commercially useful levels can be achieved by subcloning
the encoding gene into plasmid vectors that permit stable expression and
maintenance in a suitable host” (id. at 6:26–29).
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15. De Maagd discloses that a given Bacillus thuringiensis strain
“will normally synthesize between one and five [delta-endotoxins] packaged
into a single, or multiple, crystals. . . . The genes encoding the crystal
proteins are found (often clustered) on transmissible plasmids and flanking
transposable elements.” (De Maagd 193, left col.)
16. De Maagd discloses that “[a]lignment of the Cry toxins reveals
the presence of five conserved sequence blocks common to a large majority
of the proteins” (id. at 193, right col.).
Principles of Law
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that it was obvious under § 103.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Analysis
Claim 1 is directed to a nucleic acid encoding a delta-endotoxin from
B. thuringiensis strain HD536 (FF1). Carlton discloses that HD536 contains
a single plasmid that is implicated in toxin production (FF2). Ben-Dov
(FF9) and Liu (FF13, FF14) disclose methods for cloning B. thuringiensis
delta-endotoxin genes. Liu also discloses that isolating new B. thuringiensis
toxins is advantageous because it provides a wider spectrum of biopesticides
(FF10). De Maagd discloses that B. thuringiensis delta-endotoxins share
conserved sequences (FF16). In view of these teachings, we agree with the
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Examiner that it would have been obvious to a person of ordinary skill in the
art to apply the techniques taught by Ben-Dov and Liu to the plasmid from
strain HD536 that Carlton identifies as implicated in toxin production in
order to clone the B. thuringiensis delta-endotoxin gene(s) that are carried on
the plasmid.
Although none of the cited references discloses the actual sequence of
the B. thuringiensis delta-endotoxin gene(s) carried on the plasmid of strain
HD536, the evidence shows that there was a design need or market pressure
to solve a problem—isolation of new B. thuringiensis delta-endotoxin
genes—and a finite number of identified, predictable solutions—strains of
B. thuringiensis known to produce toxin proteins—and known options
within the technical grasp of the ordinary artisan—techniques known in the
art for isolating B. thuringiensis delta-endotoxin genes. Thus, Appellants’
success in isolating a delta-endotoxin gene from B. thuringiensis strain
HD536 was “the product not of innovation but of ordinary skill and common
sense.” KSR, 550 U.S. at 421. See, e.g., Enzo Biochem, Inc. v. Gen-Probe
Inc., 323 F.3d 956, 966 (Fed. Cir. 2002)(“A person of skill in the art . . . can
obtain the claimed sequences from the ATCC depository by following the
appropriate techniques to excise the nucleotide sequences from the deposited
organisms containing those sequences.”). Thus, Enzo exemplifies a situation
where knowledge of the presence of a nucleotide sequence in a specifically
identified microorganism will “describe those sequences sufficiently to the
public for purposes of meeting the written description requirement.” Id.
This supports the conclusion that Carlton’s description of strain HD536
containing a delta-endotoxin gene, combined with the teachings on how to
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obtain that sequence, also describe and render the specific sequences
obvious.Appellants argue that the Examiner’s rejection impermissibly relies
on Appellants’ Specification because “outside of Applicant’s Specification,
one of ordinary skill in the art would have no reason to select and isolate
sequences from HD536 given the numerous possibilities of well-known
strains exhibiting insecticidal activity” (Appeal Br. 4).
This argument is not persuasive. Carlton teaches that B. thuringiensis
strain HD536 produces insecticidal crystal toxin (FF2, FF3) and Liu teaches
that isolating new B. thuringiensis toxins provides a wider spectrum of
biopesticides of insect pests (FF10). These teachings, taken together, provide
ample reason for a skilled artisan to isolate the toxin-encoding gene(s) of B.
thuringiensis strain HD536. The fact that other B. thuringiensis strains were
also known to produce insecticidal toxins, and that it would also have been
obvious to isolate their toxin-encoding genes, does not make the presently
claimed nucleic acids any less obvious. See Merck & Co. v. Biocraft
Laboratories Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (“[D]isclos[ing] a
multitude of effective combinations does not render any particular formulation
less obvious. This is especially true because the claimed composition is used
for the identical purpose taught by the prior art.”).
Appellants argue that the cited references would not have provided a
reasonable expectation of success. Appellants argue that Ben-Dov is limited
to genes encoding delta-endotoxins that are active against mosquito larvae
(Appeal Br. 6) and that Liu’s methods only allow identification of known
endotoxin genes or those that are highly expressed (id. at 7). Appellants also
argue that “[w]hile methods for isolating toxin genes from strains having
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pesticidal activity were known in the art at the time of filing of the instant
application, . . . there would have been no reasonable expectation of success
in identifying the specific genes claimed in the instant invention” (id.).
Finally, Appellants argue:
One of ordinary skill in the art would fail to recognize any
reasonable expectation of success in obtaining any toxin genes
from HD536 since no insecticidal activity was demonstrated for
this strain prior to the Applicant’s disclosure. Outside of
providing a loose correlation between the ~68 MDa plasmid of
HD536 and “toxin production,” Carlton et al. fails to suggest
that genes isolated from HD536 would have any insecticidal
activity.
(Id. at 8.)
These arguments are also unpersuasive. Appellants have pointed to
no evidence showing that the methods taught by Ben-Dov and Liu would not
have been successful in cloning the delta-endotoxin gene(s) taught by
Carlton to reside on the plasmid of B. thuringiensis strain HD536, or that
isolating and sequencing the claimed nucleic acids required anything more
than the routine application of known techniques. Appellants’ argument that
they were the first to demonstrate insecticidal activity for strain HD536 is
contradicted by Carlton, which teaches that this strain produces toxin (FF2)
and that the toxins of B. thuringiensis are insecticidal (FF3). Carlton thus
identifies strain HD536 as having insecticidal activity, and identifies a
specific plasmid as carrying the toxin-producing gene(s).
Appellants argue that “the broad insecticidal activities of the recited
sequences, provide additional support for the nonobviousness of the pending
claims” (Appeal Br. 9–10). Appellants point to the Specification’s Example
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11 as showing that the toxin encoded by the claimed nucleic acids is
unexpectedly effective against Lygus lineolaris (id. at 10).
The cited evidence does not show that the claimed nucleic acids
would not have been obvious. “[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.” In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991). Here, the Specification’s Example 11 does not
show a comparison to any prior art composition, but only to a “control,”
which is not otherwise identified (Spec. 39). The cited evidence therefore
does not show that the protein encoded by the claimed nucleic acids has any
unexpected activity.
For the reasons discussed above, we affirm the rejection of claim 1.
Claims 4–7 have not been argued separately and therefore fall with claim 1.
37 C.F.R. § 41.37(c)(1)(vii).
With respect to the rejection of claims 2, 3, 8–11, 19, 22, 23, and 30,
Appellants’ only additional argument is that
[w]hile Koziel et al. may provide a general concept of
transforming genes into plants, there is no suggestion that any
of the cited references teaches or renders obvious
transformation of plants or plant cells with the specific genes of
the invention, since none of these references render obvious the
genes themselves.
(Appeal Br. 11–12.)
This argument is unpersuasive because, as discussed above, we
conclude that the claimed nucleic acids would have been obvious based on
the cited references.
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Conclusions of Law
The cited references support the Examiner’s conclusion that it would
have been obvious to isolate a nucleic acid encoding a delta-endotoxin
having the amino acid sequence of SEQ ID NO:2 from B. thuringiensis
strain HD536. Appellants have not provided evidence of unexpected results
that, when weighed with the evidence of obviousness, shows that the
claimed nucleic acids would not have been obvious.
SUMMARY
We affirm both of the rejections on appeal.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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