Ex Parte Gossele et al

Patent Trial and Appeal Board

Nov 29, 2017

12602327 (P.T.A.B. Nov. 29, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/602,327 11/30/2009 Veronique Gossele 037212.00042 4133
4372 7590 12/01.
ARENT FOX LLP
1717 K Street, NW
WASHINGTON, DC 20006-5344
EXAMINER
VISONE, LEE A
ART UNIT PAPER NUMBER
1663
NOTIFICATION DATE DELIVERY MODE
12/01/2017 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
following e-mail address(es):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte VERONIQUE GOSSELE, FRANK MEULEWAETER,
BERNADETTE SAEY, and STEFAN JANSENS1
Appeal 2016-002512
Application 12/602,327
Technology Center 1600
Before JOHN G. NEW, TIMOTHY G. MAJORS, and DAVID COTTA,
Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
chimeric gene with certain operably-linked sequences. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
Appellants’ “invention relates to new DNA sequences encoding
insecticidal proteins produced by Bacillus thuringiensis strains.” (Spec. 1.)
1 Appellants identify the Real Party in Interest as Bayer CropScience NV.
(App. Br. 1.)
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Application 12/602,327
More specifically, the Specification explains, “new chimeric genes encoding
a Cry 1C protein are provided which are useful to protect plants from insect
damage.” {Id.) Further, the Specification discloses, “the current invention
provides novel Cry 1C genes encoding an insecticidal protein comprising a
functional plant intron in their coding sequence,” which is said to “allow[]
for high expression in plant cells” while “secur[ing] that the gene does not
express the insecticidal protein when . . . contained in a prokaryotic
(micro)organism, such as during cloning steps.” {Id. at 3.)
As background, the Specification discloses that “proteins derived
from Bacillus thuringiensis (abbreviated herein as ‘Bf) are well known . . .
and have been used since almost a century to control insect pests.” {Id. at 1.)
Numerous classes of Bt proteins (e.g., CrylAa, Cry IB, Cry 1C, etc.) are
known and “several different forms of these protein classes exist” (e.g.,
about 14 different Cry 1C and about 20 different CrylAb forms have been
reported). {Id. at 1-2.) According to the Specification, however, “no
scientific publication describes the activity of the CrylCa4 protein to
specific rice insect pests” and “[n]o rice plants containing a cry 1C gene are
commercially available.” {Id. at 2.)
Claims 1-30, 34, and 36^19 are on appeal. Claim 1 is illustrative:
1. A chimeric gene, comprising the following operably-
linked sequences:
(a) a promoter region capable of directing expression in
plant cells;
(b) a DNA encoding an insecticidal Cryl C protein,
comprising a DNA sequence with at least 99% sequence identity
to the DNA sequence of SEQ ID No. 1 from nucleotide position
82 to nucleotide position 2415, or to the DNA sequence of SEQ
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Application 12/602,327
ID No. 5 from nucleotide position 7 to nucleotide position 2784;
and
(c) a 3' polyadenylation and transcript termination region,
wherein said Cry 1C protein comprises a sequence with at least
99 % sequence identity to the amino acid sequence from the
amino acid at position 28 to the amino acid at position 627 in
SEQ ID No. 2, and wherein said Cry 1C protein contains a Glu
amino acid at position 124 in SEQ ID No. 2.
(App. Br. 17 (Claims App.).)
The claims stand rejected as follows:
I. Claims 1-6, 11, 16-30, 43, 48, and 49 under 35 U.S.C. § 103(a)
as obvious over Van Mellaert,2 Nakamura,3 McElroy,4 Diehn,5
Goff,6 and Tang7 (“Rejection I”).
II. Claims 7-10, 12-15, 34, 36^12, and 44^17 under 35 U.S.C.
§ 103(a) over the combination of art in Rejection I, in further
2 Van Mellaert et al., US 7,501,559 B2, issued Mar. 10, 2009.
3 Nakamura et al., Codon usage tabulated from international DNA sequence
databases: status for the year 2000, 28:1 Nucleic Acid Research 292
(2000).
4 McElroy et al., Isolation of an Efficient Actin Promoter for Use in Rice
Transformation, 2 The Plant Cell 163-71 (1990).
5 Diehn et al., US 2005/0097633 Al, published May 5, 2005.
6 Goff et al., A Draft Sequence of the Rice Genome (Oryza sativa L. ssp.
Japonica), 296 Science 92-100 (2002) (inch erratum dated Aug. 5, 2005).
7 Tang et al., Development of insect-resistant transgenic indica rice with a
synthetic cry 1C* gene, Mol. Breeding (2006). Tang does not include page
numbers; we treat Tang herein as including pages 1-10.
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Application 12/602,327
view of Jansens,8 Van den Broeck,9 Kota,10 Castle,* 11 and Zhao12
(“Rejection II”).
DISCUSSION
Because the same issues are dispositive for Rejections I and II, we
address the rejections together.
Claim 1 is the only independent claim. It is drawn to a chimeric gene
including promoter and termination regions, as well as a DNA sequence for
a Cry 1C protein having 99% sequence identity to SEQ ID No. 1 from
nucleotide position 82 to 2415. While not expressly apparent in the claim,
an Adhl monocot intron is inserted into this coding sequence from
nucleotide 591 to 1124. (Spec. 26.)
Claim 1 further includes two wherein clauses. The first specifies that
the Cry 1C protein (encoded by SEQ ID No. 1) comprises an amino acid
sequence from position 28 to 627 with at least 99% sequence identity to
SEQ ID No. 2. And the second specifies that the amino acid at position 124
is Glu (glutamate).
8 Jansens et al., US 7,049,491 B2, issued May 23, 2006.
9 Van den Broeck et al., Targeting of a foreign protein to chloroplasts by
fusion to the transit peptide from the small subunit of ribulose 1,5-
bisphospate carboxylase, 313 Nature 358-63 (1985).
10 Kota et al., Overexpression of the Bacillus thuringiensis (Bt) Cry2Aa2
protein in chloroplasts confers resistance to plants against susceptible and
Bt-resistant insects, 96 Proc. Natl. Acad. Sci. USA 1480^15 (1999).
11 Castle et al., Agricultural input traits: past, present and future, 17
Current Opinion in Biotechnology 105-12 (2006).
12 Zhao et al., Different Cross-Resistance Patterns in the DiamondbackMoth
(Lepidoptera: Plutellidae) Resistant to Bacillus thuringiensis Toxin Cry 1C,
94:6 J. of Economic Entomology 1547-52 (2001).
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To address the limitations of claim 1, the Examiner relies principally
on the teachings of Van Mellaert, Nakamura, Diehn, and McElroy. (Ans. 2-
4.) According to the Examiner, Van Mellaert “teach[es] a Cry 1C protein
that shares 100% identity with the protein of SEQ ID NO:2,” transgenic
plants comprising a nucleic acid encoding this protein, and “promoter and []
3’octopine synthase terminator” regions. (Id. at 3.) The Examiner finds that
Van Mellaert does not “teach the DNA sequence of SEQ ID NO: 1, the Adh
intron sequence . . . nested within SEQ ID NO:l,” or the use of a particular
promoter from rice plants. (Id.) The Examiner thus turns to Diehn and
McElroy, and finds that Diehn “teach[es] that the Adhl intron has been
shown to enhance the expression of foreign genes in cereal crops” and that
McElroy “teaches the actin 2 promoter from rice.” (Id.)
The Examiner concludes that “given that the prior art teaches the
exact amino acid sequence required by the instant claims, any of the nucleic
acids encoding this protein are obvious.” (Id. at 4.) In support, the
Examiner asserts that “cloning and sequencing techniques to produce nucleic
acids were well-known, routine, and reliable at the time of filing.” (Id.
(citing In reKubin, 561 F.3d 1351 (Fed. Cir. 2009).) According to the
Examiner, “[alternatively,” to the extent differences exist between known
coding sequences for the Cry 1C protein and the DNA sequence in claim 1,
those differences can be “attributed to codon optimization” as evidenced by
Nakamura. (Id. at 5-7 (see “Codon Optimization Table for Oryza saliva”).)
As for the intron of Diehn and the promoter of McElroy, the Examiner
reasons it would have been obvious to modify Van Mellaert’s teachings to
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include these sequences “because such elements were well known in the art
to be efficient for plant transformation.” (Id. at 8.)
For the reasons explained below, we are unpersuaded that the
preponderance of the evidence supports the Examiner’s conclusion that
claim 1 would have been obvious.
The Examiner finds, and Appellants do not dispute, that the amino
acid sequence disclosed in Van Mellaert and the amino acid sequence in
claim l’s wherein clauses are identical. This includes, among other things,
the glutamate residue at position 124. (Ans. 7.) Using routine techniques, it
is true that a skilled person could sequence a polynucleotide encoding for the
amino acid sequence disclosed in Van Mellaert. But this does not resolve
the issue. Instead, the question is whether the ordinarily skilled person
predictably would have designed a chimeric/synthetic DNA of SEQ ID No.
1. Claim 1 does not recite a broad genus of DNA encoding a protein with
the roughly 600 amino acid sequence of SEQ ID No. 2. To the contrary,
claim 1 is far narrower — it recites a specific sequence that is at least 99%
identical to SEQ ID No. I.13 And therein lies a material difference from the
13 The genetic code is degenerate with several different codons specifying
the same amino acid. (See, e.g., Ans. 5-7 (Codon Table).) Because of this
degeneracy and the fact that most amino acids are encoded by at least two
(and sometimes more) distinct codons, an extraordinarily large number of
nucleotide sequences may encode a protein having roughly 600 amino acids.
Even putting aside the intron inserted into SEQ ID No. 1, the claimed
sequence represents a small fraction of the vast number of potential
sequences. On the record here, the notion that an ordinarily skilled person
would have designed a DNA of SEQ ID No. 1 is closer to the prohibited
throwing of “metaphorical darts at a board” than the permitted trying of a
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facts of Kubin. In Kubin, the claims, which were held to be obvious, were
drawn to a genus of polynucleotides encoding a known amino acid sequence
— essentially any nucleic acid molecule encoding the protein would satisfy
the claim. In re Kubin, 561 F.3d at 1353.14
The Examiner’s invocation of “codon optimization” as making
obvious the differences between the known and the claimed DNA sequences
is also unpersuasive. As Appellants point out, if codon optimization
explained these differences, one would not expect to see significant
differences between the claimed sequence and the codon-optimized
sequences in the prior art. (App. Br. 11-12; Reply Br. 8-9.) In fact, the
claimed sequence differs significantly from codon optimized prior art
sequences. For example, Tang’s prior art codon-optimized gene encoding
CrylCa5 — a protein differing from the claimed protein by only one amino
acid — was 84% identical to native CrylCa5 DNA. (Tang 3 (left col.);
Spec. 2.)15 Strizhov16 similarly discloses roughly 84.9% homology between
its prior art codon-optimized sequence and the native CrylCa5. (Strizhov
11:40-60.) In contrast, the claimed sequence “is 69.7% identical to the
“finite number of identified, predictable solutions.” In re Kubin, 561 F.3d at
1359 (citations and internal quotation marks omitted).
14 In Kubin the claims also stood rejected for inadequate written description
because the specification disclosed only two sequences falling within the
scope of the genus. In re Kubin, 561 F.3d at 1353. The Federal Circuit,
upon affirming the rejection for obviousness, declined to reach the written
description rejection. Mat 1361.
15 In Tang, the gene was codon-optimized for indica rice plants (Oryza
sativa). (Tang 3.)
16 Strizhov et al., US 6,043,415, issued Mar. 28, 2000.
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native crylCa5 DNA,” and only 55% identical when accounting for the
intron sequence. (Spec. 2; see also id. at 3 (“the DNA of SEQ ID No. 1 only
has 61.1 % sequence identity to the synthetic crylCa5 gene of Strizhov.”).)
The Examiner’s response, stating that the “rejection does not make any
assertion that Tang or Strizhov teach the polypeptide corresponding to the
DNA of SEQ ID NO: 1” elides Appellants’ arguments on these points.
(Ans. 25.) Although codon optimization for a particular organism (e.g., rice
plants) might bring one closer to the claimed DNA sequence (something the
Examiner has not clearly shown), we do not agree on this record that codon
optimization would predictably produce a sequence encompassed by claim
1.
Turning to the nested intron in SEQ ID No. 1, Appellants argue Diehn
“does not suggest insertion of an intron into a coding sequence.” (App. Br.
7.) Rather, Appellants contend, “Diehn adds an intron in the non-coding
leader sequence” and, when considered with the teachings of Callis,17 the
skilled artisan would not insert an intron into the coding sequence of a
synthetic gene like claimed. {Id.) As Appellants point out, Callis teaches
that “the Adhl intron efficiently stimulated CAT expression only when
located between the promoter and the CAT coding region.” (Callis Abstract;
see also App. Br. 7.)
The Examiner provides no persuasive rebuttal to Appellants’
arguments about placement of the intron in the coding sequence as claimed.
The Examiner points out that the intron is ultimately spliced out incident to
17 Callis et al., Introns increase gene expression in cultured maize cells, 1
Genes & Development 1183-1200 (1987).
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production of the protein, and asserts that “Appellant has not described any
unexpected result stemming from the insertion of the intron in the coding
sequence.” (Ans. 20.) The Examiner, however, has it backwards. It is the
Patent Office’s burden to first provide findings and/or explanation sufficient
to support a prima facie showing of obviousness before demanding evidence
of unexpected results from the patent applicant. (Reply Br. 2-3.) Here, the
Examiner has simply not identified any disclosure in the art of placing an
Adhl intron into the coding sequence of a chimeric gene, or provided any
persuasive reason why the skilled person would have done so, especially
considering Diehn’s and Callis’s teachings.
With respect to the encoded protein including a glutamate residue at
position 124, Appellants argue the prior art teaches away from designing a
chimeric gene that encodes a Cry 1C protein with that structure. (App. Br.
8-10.) Appellants identify Strizhov’s discussion related to the CrylCa4
protein and amino acid sequence disclosed in Van Mellaert. (Id. at 8-9.)
According to Appellants, “Strizhov teaches that the occurrence of glutamate
at position 124 in prior art Cry 1C protein sequences was a ‘critical error,’
and that this error results in ‘negative consequences either for function or
stability of the Cry 1C protein,’ if a synthetic DNA would be made encoding
such a protein.” (Id. at 8.)
Appellants’ argument is persuasive. Strizhov teaches the sequencing
of three independent Cry 1C genes isolated from different B. thuringiensis
strains, each of which showed discrepancies from known sequences
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including the CrylCa4 sequence described in Van Mellaert.18 (Strizhov
10:7-22.) Strizhov thus designed a “CrylCa5 protein [that] differs by amino
acid replacements ... by the A124E from the CryICa4.” {Id. at 10:23-26.)
In other words, Strizhov’s protein includes alanine (A), not a glutamate (E)
residue at position 124. The reason, Strizhov explains, is “[t]he occurrence
of glutamate in position 124 .. . [was] clearly due to previous errors, since
A124 . . . [was] found to be conserved in all CrylC proteins.” {Id. at 10:31—
34.) Strizhov’s explanation continues: “we believe that the CrylC
sequences, known in the prior art, contain critical errors with negative
consequences either for function or stability of CrylC protein, had the
protein a corresponding synthetic gene designed on the basis of the wild-
type DNA sequences known in the art.” {Id. at 10:42^16.) This is a
quintessential teaching away, which likely would have discouraged the
ordinarily skilled person from designing a chimeric gene encoding a CrylC
protein with a glutamate residue at position 124 as in claim 1. In re Gurley,
27 F.3d 551, 553 (Fed. Cir. 1994) (“A reference may be said to teach away
when a person of ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant.”).
The Examiner responds that Strizhov is “more of an opinion” and, the
Examiner asserts, “Strizhov [] is not supported by empirical evidence . . .
[and] does not actually demonstrate that any purported consequence will
18 Strizhov specifically references this protein and sequence as disclosed in
Van Mellaert, EP 0400246 Al, published Dec. 5, 1990, which is the
European counterpart of Van Mellaert. (Reply Br. 4 n. 4.)
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occur if a Glu is present at position 124.” (Ans. 21-22.) The Examiner’s
finding is unpersuasive. Strizhov is objective evidence that, even if partly
opinion-based, reflects knowledge and a belief of skilled persons in this field
prior to the invention. Moreover, in identifying errors in known sequences,
Strizhov is hardly equivocal. Indeed, Strizhov describes the occurrence of
glutamate in position 124, as disclosed in Van Mellaerf s sequence, as
arising “clearly due to previous errors.” (Strizhov 10:31-33.) Strizhov also
calls into doubt whether the encoded toxins tested in Van Mellaert had a
glutamate at position 124 given Strizhov’s finding that A124 was conserved
in all Cry 1C proteins. Accordingly, the Examiner’s emphasis on stability
and activity of the Cry 1C proteins in Van Mellaert is not persuasive. (Ans.
8, 22.) Finally, we agree with Appellants that a teaching away may arise
even if the teaching is not backed by “empirical evidence.” (Reply Br. 4.)
Were it otherwise, and a teaching away required scientific proof, one could
only prevail in advancing the argument by citing evidence that the path
taken by the inventors does not, in fact, work.
The Examiner has not shown that any of the other references cited in
Rejections I or II (Goff, Tang, Jansens, Van den Broeck, Kota, Castle, or
Zhao) make up for the deficiencies in the prima facie case explained above.
We decline to reach Appellants’ argument and evidence related to alleged
unexpected results, which is unnecessary on this record. (App. Br. 13-14.)
For all the above reasons, we conclude the preponderance of the
evidence does not support the Examiner’s conclusion that claim 1 would
have been obvious. The remaining claims, which depend from claim 1,
similarly have not been shown to be obvious.
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SUMMARY
We reverse the rejection of claims 1-30, 34, and 36^49 as obvious.
REVERSED
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