Ex Parte Scott

Board of Patent Appeals and Interferences

Jun 2, 2009

10058825 (B.P.A.I. Jun. 2, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RODERICK JOHN SCOTT
__________

Appeal 2008-004077
Application 10/058,825
Technology Center 1600
__________

Decided:1 June 2, 2009
__________

Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

Appeal 2008-004077
Application 10/058,825

STATEMENT OF CASE
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for indefiniteness, lack of written description and lack of
enablement. We have jurisdiction under 35 U.S.C. § 6(b).
The following claims are representative.
20. A method for the production of modified endosperm, which comprises
the step of introducing a nucleic acid molecule into a plant, the nucleic acid
molecule comprising a promoter that targets expression to female germ line
cells and a sequence whose transcription product comprises a partial or full-
length Arabidopsis DNA methyltransferase 1 (Metl) sequence, wherein the
introduced nucleic acid is effective for down-regulating one or more DNA
methylating enzymes present in the plant, whereby the degree of DNA
methylation of nucleic acid in the plant is reduced as compared to a control
plant.

21. A method as claimed in claim 20 wherein the transcription product
comprises an antisense nucleic acid.

62. A method for the production of modified endosperm, which comprises
the step of introducing a nucleic acid molecule into a plant, the nucleic acid
molecule comprising a promoter that targets expression to female germ line
cells and a sequence whose transcription product comprises a partial or full-
length Z. mays DNA sequence orthologous to the Arabidopsis DNA
methyltransferase 1 (Metl) sequence, wherein the introduced nucleic acid is
effective for down-regulating one or more DNA methylating enzymes
present in the plant, whereby the degree of DNA methylation of nucleic acid
in the plant is reduced as compared to a control plant.

63. A method as claimed in claim 62, wherein the transcription product
comprises an antisense nucleic acid.

64. A method as claimed in claim 20, wherein the plant is a dicotyledonous
plant.

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65. A method as claimed in claim 20, wherein the transcription product
down-regulates one DNA methylating enzyme.

66. A method as claimed in claim 20, wherein the transcription product
comprises a full or partial sense copy of the Arabidopsis DNA
methyltransferase 1 (Metl) sequence.

67. A method as claimed in claim 66, wherein the sense copy is a partial
sense copy.

69. A method as claimed in claim 62, wherein the transcription product
comprises a full or partial sense copy of the Z. mays sequence.

71. A method as claimed in claim 66, wherein the plant is a dicotyledonous
plant.

76. A method as claimed in claim 62, wherein the plant is a dicotyledonous
plant.

77. A method as claimed in claim 20, wherein the promoter targets
expression in female gametic cells.

78. A method as claimed in claim 77, wherein the transcription product
comprises an antisense nucleic acid.

80. A method as claimed in claim 77, wherein the transcription product
comprises a partial sense copy of the Arabidopsis DNA methyltransferase 1
(Metl) sequence.

81. A method as claimed in claim 77, wherein the plant is a dicotyledonous
plant.

82. A method as claimed in claim 77, wherein the plant is a
monocotyledonous plant.

83. A method as claimed in claim 81, wherein the plant is a Brassica plant.

84. A method as claimed in claim 81, wherein the plant is a B. napus plant.

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85. A method as claimed in claim 82, wherein the plant is a Zea mays plant.

86. A method as claimed in claim 62, wherein the promoter targets
expression to female gametic cells.

87. A method as claimed in claim 86, wherein the transcription product
comprises an antisense nucleic acid.

88. A method as claimed in claim 86, wherein the transcription product
comprises a partial sense copy of the Z. mays sequence orthologous to
Arabidopsis DNA methyltransferase 1 (Metl) sequence.

89. A method as claimed in claim 86, wherein the plant is a dicotyledonous
plant.

90. A method as claimed in claim 86, wherein the plant is a
monocotyledonous plant.

91. A method as claimed in claim 89, wherein the plant is a Brassica plant.

92. A method as claimed in claim 89, wherein the plant is a B. napus plant.

93. A method as claimed in claim 90, wherein the plant is a Zea mays plant.

Cited References
E. Jean Finnegan and Elizabeth S. Dennis, Isolation and identification by
sequence homology of a putative cytosine methyltransferase from
Arabidopsis thaliana, 21 NUCLEIC ACIDS RESEARCH 2383-2388 (1993).

Jacobsen et al., Ectopic hypermethylation of flower-specific genes in
Arabidopsis, 10 CURRENT BIOLOGY 179-186 (2000).

Neal Gutterson, Anthocyanin Biosynthetic Genes and Their Application to
Flower Color Modification through Sense Suppression, 30 HORTSCIENCE
964-966 (1995).

Emery et al, Radial Patterning of Arabidopsis Shoots by Class III HD-ZIP
and KANADI Genes, 13 CURRENT BIOLOGY 1768-1774 (2003).

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Fourgoux-Nicol et al., Isolation of rapeseed genes expressed early and
specifically during development of the male gametophyte, 40 PLANT
MOLECULAR BIOLOGY 857-872 (1999).

Temple et al., Modulation of glutamine synthetase gene expression in
tobacco by the introduction of an alfalfa glutamine synthetase gene in sense
and antisense orientation: molecular and biochemical analysis, 236 MOL.
GEN GENERT 315-325 (1993).

Oliver et al., Inhibition of tobacco NADH-hydroxypyruvate reductase by
expression of a heterologous antisense RNA derived from a cucumber
cDNA: Implications for the mechanism of action of antisense RNAs, 239
MOL. GEN GENET 425-434 (1993).

van der Krol et al., An anti-sense chalcone synthase gene in transgenic
plants inhibits flower pigmentation, 333 NATURE 866-869 (1988).

Carron et al., Genetic modification of condense tannin biosynthesis in Lotus
corniculatus. 1. Heterologous antisense dihydroflavonol reductase down-
regulates tannin accumulation in “hairy root” cultures, 87 THEORETICAL
AND APPLIED GENETICS 1006-1015 (1994).

John W. Einset, Differential expression of antisense in regenerated tobacco
plants transformed with an antisense version of a tomato ACC oxidase gene,
46 PLANT CELL TISSUE AND ORGAN CULTURE 137-141 (1996).

Trevanion et al., NADP-Malate Dehydrogenase in the C4 Plant Flaveria
bidentis. 113 PLANT PHYSIOL. 1153-1165 (1997).

Faske et al., Transgenic Tobacco Plants Expressing Pea Chloroplast Nmdh
cDNA in Sense and Antisense Orientation, 115 PLANT PHYSIOL 705-715
(1997).

Herbik et al, Isolation, characterization and cDNA cloning of nicotianamine
synthase from barley, 265 EUR. J. BIOCHEM 231-239 (1999).

Veena et al., Glyoxalase I from Brassica juncea: molecular cloning
regulation and its over-expression confer tolerance in transgenic tobacco
under stress, 17 THE PLANT JOURNAL 385-395 (1999).

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Genbank Accession No AF063403 (1998).

Genbank Accession No AF007807 (1998).

Genbank Accession No AF034419 (1998).

Genbank Accession No AJ002140 (1998).

Cannon et al., Organ-specific modulation of gene expression in transgenic
plants using antisense RNA, 15 PLANT MOLECULAR BIOLOGY 39-47 (1990).

Hibino et al., Increase of Cinnamaldehyde Groups in Lignin of Transgenic
Tobacco Plants Carrying an Antisense Gene for Cinnamyl Alcohol
Dehydrogenase, 59 BIOSEI. BIOTECH BIOCHEM 929-931 (1995).

Bolitho et al., Antisense apple ACC-oxidase RNA reduces ethylene
production in transgenic tomato fruit, 122 PLANT SCIENCE 91-99 (1997).

Elkind et al., Abnormal plant development and down-regulation of
phenylpropanoid biosynthesis in transgenic tobacco containing a
heterologous phenylalanine ammonia-lyase gene, 87 PROC. NATL. ACAD.
SCI. USA 9057-9061 (1990).

Salehuzzeman et al., Isolation and characterization of a cDNA encoding
granule-bound start synthase in cassava (manihot eculenta Crantz) and its
antisense expression in potato, 23 (5) PLANT MOL. BIOL. 947-962
(1993).

Grounds of Rejection
1. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. § 112, second paragraph.
2. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. § 112, first paragraph, for lack of enablement throughout the claim
scope.

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3. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. § 112, first paragraph, as containing subject matter which was not
described in the specification in such away as to reasonably convey to one
skilled in the relevant art that the inventor(s), at the time the application was
filed, had possession of the claimed invention.

Discussion
1. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. § 112, second paragraph.

ISSUE
The Examiner argues that Appellant has disclosed that "the
designation Arabidopsis Metl sequence will always refer to the sequence of
Accession No. L 10692... (page 13 of Remarks filed 11/7/2005, 1st full
paragraph).” (Ans. 3.) The Examiner finds that this sequence is a DNA
sequence, therefore, it is unclear how a transcription product can be a
DNA sequence and not a mRNA sequence. One skilled in the
art knows transcription products are RNA molecules that may
comprise non-translated regions, i.e., introns and 5' and 3' non-
translated regions. In addition, the transcription product would
be a mRNA molecule that is in reverse orientation from the
strand from which it was transcribed. Therefore, the
transcription product would not have the same sequence as the
DNA sequence disclosed in Accession No. L10692.

(Ans. 3-4.)
Appellant contends that one of ordinary skill would understand what
is claimed based on basic tenets of molecular biology, i.e., that the
transcription product of an Arabidopsis Met1 sequence (or the Z. mays

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ortholog) is an RNA sequence that is a faithful copy of the DNA template
from which the transcription product was transcribed.
The issue is: Is the designation Arabidopsis Metl sequence of
Accession No. L 10692 indefinite.

FINDINGS OF FACT
1. The Examiner finds that “Claim 20 is indefinite in the recitation ‘a
sequence whose transcription product comprises a partial or full length
Arabidopsis DNA methyltransferase 1 (Metl) sequence.’” (Ans. 3.)
2. Appellant has disclosed that “the designation Arabidopsis Metl sequence
will always refer to the sequence of Accession No. L 10692… (page 13 of
Remarks filed 11/7/2005, 1st full paragraph).” Id.
3. The Examiner finds that the
sequence is a DNA sequence, therefore, it is unclear how a
transcription product can be a DNA sequence and not a mRNA
sequence. One skilled in the art knows transcription products
are RNA molecules that may comprise non-translated regions,
i.e., introns and 5' and 3' non-translated regions. In addition, the
transcription product would be a mRNA molecule that is in
reverse orientation from the strand from which it was
transcribed. Therefore, the transcription product would not have
the same sequence as the DNA sequence disclosed in Accession
No. L10692.

Id. at 3-4.

4. The Appellants argue that “one of ordinary skill would immediately
understand that the DNA and RNA sequences of Accession No. L10692 are
the same, with U (uracil) substituted for T (thymine).” (App. Br. 10.)

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5. The Appellants argue that the “[r]eferences previously cited during
prosecution to show that the designation Arabidopsis Met1 sequence refers
to the sequence of Accession No. L10692 indicate that the DNA sequence of
L10692 was itself derived from an RNA sequence.” (App. Br. 10.)
6. A copy of Genbank Accession No. L10692 is of record, Evidence
Appendix A. Id.
7. The Appellants argue that Finnegan states at page 2385, right-hand
column that:
“The length of the methyltransferase cDNA assembled from the overlapping
cDNA clones Yc8 and Yc2 is 4720bp not including a poly A tail (Accession
No. L10692), which agrees with the estimate based on Northern analysis of
4.7kb (data not shown).” Id.
8. The Appellants argue that Finnegan
[C]reated cDNAs from an Arabidopsis RNA, sequenced the
cDNAs and deposited the resulting nucleotide sequence as
Accession No. L10692. The results presented in the Finnegan
et al article show that the sequence presented in Accession No.
L10692 was derived from an RNA sequence and that the DNA
and RNA sequences are the same, with U substituted for T. One
of ordinary skill would immediately understand that the
transcription product of Accession No. L10692 is an RNA that
has the same sequence as L10692, with U substituted for T.
Id.
9. One of ordinary skill in the art at the time of filing of the present
application would have been aware of the orthologous sequence of Zea
Mays Met 1. (Genbank Accession No. AF063403 of record.)
10. Partial is defined as “incomplete” or “relating to only part” of
something. Webster’s II New Riverside Dictionary, Boston, Ma., p. 856
(1994).

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PRINCIPLES OF LAW
With respect to the “indefiniteness” requirement 35 U.S.C. § 112,
second paragraph, Datamize LLC v. Plumtree Software Inc., 417 F.3d 1342,
1347-1348 (Fed. Cir. 2005) stated that
According to the Supreme Court, “[t]he statutory
requirement of particularity and distinctness in claims is met
only when [the claims] clearly distinguish what is claimed from
what went before in the art and clearly circumscribe what is
foreclosed from future enterprise.” United Carbon Co. v.
Binney & Smith Co., 317 U.S. 228 . . . (1942). The definiteness
requirement, however, does not compel absolute clarity. Only
claims “not amenable to construction” or “insolubly
ambiguous” are indefinite. See Novo Indus., L.P. v. Micro
Molds Corp., 350 F.3d 1348, 1353 (Fed.Cir.2003); Honeywell
Int’l, 341 F.3d at 1338; Exxon Research & Eng’g Co. v. United
States, 265 F.3d 1371, 1375 (Fed.Cir.2001). Thus, the
definiteness of claim terms depends on whether those terms can
be given any reasonable meaning. Furthermore, a difficult issue
of claim construction does not ipso facto result in a holding of
indefiniteness. Exxon Research & Eng’g, 265 F.3d at 1375. “If
the meaning of the claim is discernible, even though the task
may be formidable and the conclusion may be one over which
reasonable persons will disagree, we have held the claim
sufficiently clear to avoid invalidity on indefiniteness grounds.”
Id.

ANALYSIS
The Examiner finds that the Arabidopsis Metl Genbank Accession
No. L 10692 sequence is a DNA sequence, and that it is unclear how a
transcription product can be a DNA sequence and not a mRNA sequence.
(Ans. 4.) The Examiner argues that
One skilled in the art knows transcription products are RNA
molecules that may comprise non-translated regions, i.e.,
introns and 5' and 3' non-translated regions. In addition, the

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transcription product would be a mRNA molecule that is in
reverse orientation from the strand from which it was
transcribed. Therefore, the transcription product would not
have the same sequence as the DNA sequence disclosed in
Accession No. L10692.

(Ans. 4.)
Appellant contends that “one of ordinary skill would understand what
is claimed based on basic tenets of molecular biology, i.e., that the
transcription product of an Arabidopsis Met1 sequence (or the Z. mays
ortholog) is an RNA sequence that is a faithful copy of the DNA template
from which the transcription product was transcribed.” (App. Br. 10.)
We find that the Examiner has not established a prima facie case of
indefiniteness or shown that reasonable efforts at claim construction of
Arabidopsis Met1 prove futile. The Examiner has not shown that one of
ordinary skill in the art, upon reading the present Specification would not
have understood that the phrase “Arabidopsis Metl sequence” refers to the
sequence of Genbank Accession No. L10692 described in the Specification
and of record. Reasonable efforts to review references cited during
prosecution show that the designation Arabidopsis Met1 sequence refers to
the sequence of Genbank Accession No. L10692 and the Genbank
Accession No. L10692 deposit information sheet indicates that the DNA
sequence of L10692 was itself derived from a mRNA sequence. (FF 6-8.)
In view of the above, the indefiniteness rejection is reversed.

Claim 62
The Examiner finds that claim 62 is indefinite in the recitation "‘a
sequence whose transcription product comprises a partial or full length Zea

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mays sequence orthologous to the Arabidopsis methyltransferase 1 (Metl)
sequence.’" (Ans. 4.)
The Examiner argues that
One skilled in the art knows transcription products are RNA
molecules that may comprise nontranslated regions, i.e., introns
and 5' and 3' non-translated regions. In addition, the
transcription product would be a mRNA molecule that is in
reverse orientation from the strand from which it was
transcribed. Therefore, the transcription product would not
have the same sequence as the DNA sequence disclosed in
Accession No. L10692 . . . and because Accession No. L10692
is the Arabidopsis sequence and not the Zea mays sequence.

(Ans. 4.)
Appellant acknowledges that claim 62 is rejected for indefiniteness
for essentially the same reasons that claim 20 was rejected. (App. Br. 9.)
Therefore, we reverse the rejection of claim 62 for the same reasons
indicated herein for the reversal of the indefiniteness rejection of claim 20.
With respect to the Zea mays Met1 sequence, we find that one of ordinary
skill in the art at the time of filing of the present application would have
been aware of the Zea mays Met 1 orthologous to Arabidopsis Met1.
(Genbank Accession No. AF063403 of record.) We further find that one of
ordinary skill in the art would have understood that “partial sequences” of
Met 1 refers to incomplete sequences of Met1, i.e., less than the full length
sequence of Met1. In view of the above, we reverse the indefiniteness
rejection of claim 62.

2. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. 112, first paragraph, for lack of enablement.

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ISSUE
The Examiner finds that the Specification is
[E]nabling for a method for increasing the amount of
endosperm in an Arabidopsis or Brassica seed or increasing the
weight of an Arabidopsis or Brassica seed comprising a
construct comprising a full length METl DNA sequence
operably linked to the AGLS promoter, wherein the sequence is
in antisense orientation, or wherein the METl DNA sequence is
isolated by RT-PCR from Arabidopsis using the primers
MET1F of SEQ ID NO: 5 and MET1R of SEQ ID NO: 6 and
Arabidopsis and Brassica plant transformation therewith.

(Ans. 7.)

However, the Examiner finds that the Specification
[D]oes not reasonably provide enablement for claims broadly
drawn to a method of modifying the endosperm from any plant
comprising downregulating any DNA methylating enzyme
using a sequence whose transcription product comprises a
partial or full length Arabidopsis Metl sequence or which
comprises a partial or full-length Zea mays sequence
orthologous to the Arabidopsis Metl sequence, or wherein the
nucleic acid is a partial or full length sequence in sense or
antisense orientation.

Id. [Emphasis added.]

Appellant contends that the Jacobsen Declaration of record points out
that the data in the Fourgoux-Nicol article indicate the Arabidopsis Met1
sequence would hybridize to and therefore down regulate a heterologous
sequence in any plant. (App. Br. 25.)
The issue is: Does the Specification enable a method of modifying
the endosperm from any plant comprising downregulating any DNA

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methylating enzyme using a sequence whose transcription product
comprises a partial or full length Arabidopsis Metl sequence.

FINDINGS OF FACT
11. The Examiner finds that the Specification
[D]oes not reasonably provide enablement for claims broadly
drawn to a method of modifying the endosperm from any plant
comprising downregulating any DNA methylating enzyme
using a sequence whose transcription product comprises a
partial or full length Arabidopsis Metl sequence or which
comprises a partial or full-length Zea mays sequence
orthologous to the Arabidopsis Metl sequence, or wherein the
nucleic acid is a partial or full length sequence in sense or
antisense orientation.

(Ans. 7.)
12. The Examiner finds that the claims are not only drawn to decreasing
overall methylation in a plant, but are drawn to decreasing methylation
which results in production of a modified or altered endosperm development
(Final Rej. 8). According to the Specification, pages 1 and 16, one example
of a modified endosperm is a larger, heavier endosperm.
13. The Examiner finds that a method of modifying the endosperm from
any plant is not supported by an enabling disclosure taking into account the
Wands factors.
14. With respect to the Wands factors, the Examiner finds that Appellant
“discloses cloning a sequence that encodes the Arabidopsis MET1 protein,
wherein the nucleic acid sequence is 4.7kb long, in which the sequence was
isolated by RT-PCR from an Arabidopsis cDNA library using the METlF
primer of SEQ ID NO: 5 and METl R primer of SEQ ID NO:6.” (Ans. 8.)

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15. The Examiner agrees that Appellant “discloses subcloning the nucleic
acid sequence into a vector comprising the AGL5 or AP3 promoter in
antisense orientation (page 30, Example 3; and Figures 6 and 7) and
Arabidopsis, Brassica campestris and Brassica oleraceae transformation
therewith (page 31, Example 4, page 33, Example 5). Plants expressing the
pAGL5Met1 as construct produced seed with increased weight (page 31,
lines 26-28).” (Ans. 8.)
16. The Examiner finds that the state-of-the-art teaches down-regulating
methylating genes produces unpredictable results. (Ans. 9.) To support this
position, the Examiner relies on Jacobsen (2000) which teaches
“transforming Arabidopsis with a nucleic acid encoding the MET1 protein
operably linked to a promoter in antisense orientation caused a decrease in
methylation by 80%-90%.” (Ans. 9) (emphasis added.) Jacobsen also
discloses that "‘[s]urprisingly,… the floral development gene SUPERMAN,
was ectopically hypermethylated [emphasis added] and silenced’ (page
180, left column, 1st full paragraph)” (Ans. 9).
17. The Examiner finds that “Appellant has only disclosed primer
sequences to be used for isolating the full length Arabidopsis MET1
sequence from an Arabidopsis cDNA library (See pages 30-31, Example
3a).” (Ans. 10.)
18. The Examiner further finds that “Appellant has not disclosed how one
makes or isolates any of the other sequences that are encompassed by
Appellant's broad claims.” (Ans. 10.)
19. The Examiner finds that Appellant has not
[T]aught which regions of the respective polynucleotides can be
used to amplify, for example, the Zea Mays orthologous
sequence, or which regions can be used as a probe to isolate any

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of said polynucleotide sequences whose transcription product
comprises a partial Arabidopsis or Zea mays Met1 sequence
that is effective for downregulating one or more DNA
methylating enzymes present in the plant and produce a plant
whose seeds produce modified endosperm.
Id.
20. The Examiner also finds that “[u]sing DNA sequences to reduce
expression of the endogenous corresponding gene through the mechanism of
sense suppression produces unpredictable results.” (Ans. 10.) For example,
Gutterson “teaches that the chrysanthemum and petunia chalcone synthase
(CHS) genes are 70% identical to each other, and that transforming petunia
plants with the chrysanthemum CHS gene did not co-suppress the
endogenous petunia CHS gene (page 965, left column, second paragraph).
Gutterson reports similar data using another petunia gene in the anthocyanin
pathway.” (Ans. 10.)
21. Regarding the state-of-the-art, the Examiner finds that the art teaches
that “antisense molecules that exhibit less than 100% sequence identity to
the target sequence produce unexpected results.” (Ans. 10.) To support this
position, the Examiner relies on Emery which “discloses experiments in
which a target sequence of a micro-RNA was changed by two base-pairs.
The altered base-pairs caused the complementary micro-RNA not to bind to
the target sequence, which subsequently led to an increased expression of
the target sequence's encoded protein (page 1769, right column, 2nd full
paragraph).” (Ans. 10-11.)
22. “Finnegan … discloses that there are three classes of methyltransferases
in Arabidopsis, METI, METII and METIII (page 228, top paragraph) and
homology between METI and METII is higher in the methyltransferase
domain than in the amino-terminal domain (sentence bridging pages 227-

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228).” (Ans. 18-19.) Finnegan (1998) states "There is evidence supporting
the notion that plant methyltransferases may differ in target specificity”
(page 229, bottom paragraph).
23. The Examiner finds Appellant has not described essential regions of the
MET1 sequence that can be used to down regulate a methyltransferase in a
plant so that the plant produces seeds with the expected phenotype.” (Ans.
19) (Emphasis added.)
24. The Examiner concludes that the
[A]bsence of guidance, undue trial and error experimentation
would be required for one of ordinary skill in the art to screen
through the multitude of non-exemplified sequences, either by
using non-disclosed fragments of a nucleic acid encoding the
Arabidopsis Metl protein as probes or by designing primers to
undisclosed regions of a nucleic acid encoding the Arabidopsis
Met1 protein and isolating or amplifying fragments, subcloning
the fragments, producing expression vectors and transforming
plants therewith, in order to identify those, if any, that when
over-expressed in female germ line cells down-regulate one or
more DNA methylating enzymes present in a plant and produce
a plant whose seeds produce a modified endosperm.

(Ans. 11.)
25. Jacobsen Declaration
Appellant puts forth the Declaration of Dr. Jacobsen as evidence of
predictability and lack of undue experimentation in the relevant art.
26. Cannon
Dr. Jacobsen concludes that one of ordinary skill would have
understood from Cannon that “a 41-base pairing homology was sufficient to
give up to a 100% inhibition of GUS [gene] expression." Cannon 46.
Jacobsen Declaration at ¶ 11.

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The Cannon reference also states at page 39 that "antisense RNA has
a complementary sequence to mRNA and inhibits gene translation by a
mechanism as yet unknown but presumed to involve duplex formation."
27. Jacobsen and Finnegan
According to Dr. Jacobsen, the Jacobsen 2000 reference concerned
[T]he observation that the AGAMOUS gene was
hypermethylated in an Arabidopsis line expressing a Metl
antisense construct. These lines were previously described as
having up to a 90% decrease in overall DNA methylation.
Finnegan et al., (1996) Proc. Natl. Acad. Sci. U.S.A. 93:8449.
An earlier publication, the Jacobsen 1997 reference, showed
that the SUPERMAN gene was hypermethylated in the same
Arabidopsis line expressing a Metl antisense construct, and
these experiments also confirmed the simultaneous overall
hypomethylation in this line. (Jacobsen et al., Science 1997
277: 1100- 1103).

Jacobsen Declaration at ¶12.

28. The Jacobsen Declaration indicates that the “observation of
hypermethylation of the SUPERMAN gene or the AGAMOUS gene in
Arabidopsis Metl antisense construct-containing lines does not change the
fact that these lines had a significant reduction in the degree of overall DNA
methylation.” Jacobsen Declaration at ¶ 14.
29. Dr. Jacobsen further concluded that the
[T]echniques required to screen and identify Metl
downregulation construct-containing plants that have a decrease
in DNA methylation would have been routine for one of
ordinary skill, because the techniques involved would have
been typical of those carried out by one of ordinary skill. Such
techniques include constructing DNA clones containing partial
and full-length Arabidopsis or Zea mays DNA
methyltransferase 1 Metl sequences, constructing plant

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transformation vectors, transforming plants, and screening for
overall DNA methylation status.

Jacobsen Declaration at ¶ 16.
30. Dr. Jacobsen does not address how to predictably alter the
phenotype of the endosperm or seed in any plant or evidence that
methyltransferase is present in the endosperm of any plant.
31. Fourgoux-Nicol
According to Dr. Jacobsen, Fourgoux-Nicol shows that
hybridization techniques were used successfully to isolate desired
clones. Jacobsen Declaration at ¶ 18. Dr. Jacobsen finds that
The authors of the Fourgoux-Nicol reference focused
their analysis on one of the thirteen cDNA clones whose
expression was strictly confined to the male gametophyte and
was high in the microspore. The selected clone was designated
M3 and had a length of 497 bp. Fourgoux- Nicol at page 863,
left-hand column. M3 was used in a second round of screening
by stringent hybridization to isolate a second cDNA clone,
designated M3.21. M3.21 has a length of 674 bp. Fourgoux-
Nicol at page 863, left-hand column. M3 and M3.21 were
sequenced and found to have non-identical sequences, including
a 99 base pair insertion in M3 that was not present in M3.21,
and several single nucleotide polymorphisms between the two.
Fourgoux-Nicol at page 863, right-hand column, and page 862
Figure 2. Further analysis, including Southern hybridization,
indicated that the M3 and M3.21 cDNAs were derived from
two homologous genes. Fourgoux-Nicol at page 864, left-hand
column. Thus, the reference shows that 100% sequence identity
is not required in order to successfully isolate related sequences
by nucleic acid hybridization.

Jacobsen Declaration at ¶ 19.

32. Dr. Jacobsen concludes that

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The fact that nucleic acids that do not have 100% DNA
sequence identity, such as M3 and M3.21, can hybridize to each
other would indicate to one of ordinary skill that hybridization
would likely occur between a partial or full length Arabidopsis
or Zea mays DNA methyltransferase 1 Metl sequence and an
endogenous DNA methyltransferase 1 Metl target even when
there is less than 100% sequence identity.

Jacobsen Declaration at ¶ 20.

33. Hibino
Dr. Jacobsen finds that Hibino report that “introduction of an Aralia
cordala cinnamyl alcohol dehydrogenase (CAD) antisense construct into
tobacco resulted in an approximately 20-55% reduction in CAD activity.
See page 929 and Figure 1 of Hibino.” Jacobsen Declaration at ¶ 22.
Two plants showed a reduction in CAD whereas others showed no
significant change, evidencing unpredictability in the art. (Hibino, page 929,
col.2.)
34. Bolitho
Bolitho report that introduction of an apple antisense ACC-oxidase
reduced the level of RNA and the activity of the corresponding gene for
ethylene production in tomato. See Figures 3 and 4 of Bolitho. Jacobsen
Declaration at ¶ 22.
35. Bolitho states that high levels of antisense sequence were not always
associated with reduction in ethylene levels evidencing unpredictability in
the art. (Abstract.)
36. Salehuzzaman
Salehuzzaman report that introduction of a cassava granule bound
starch synthase antisense gene suppressed levels of the corresponding

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protein in potato. See Figure 10 in Salehuzzaman. Jacobsen Declaration at
¶ 22.
In Salehuzzaman the gene in question was abundantly expressed in
tubers (not endosperm), minimally expressed in petioles and stems and not
expressed in roots. (Salehuzzaman, page 955.) Levels of antisense
inhibition varied from complete inhibition to no visible effect, evidencing
unpredictability in the art. (Salehuzzaman, page 960, col. 2.)
37. Elkind
Elkind report that introduction of a bean phenylalanine ammonia-
lyase (PAL) sense sequence into tobacco resulted in reduced levels of PAL
activity and reduced accummulation of endogenous PAL transcripts. See
Elkind at page 9059-9060. Jacobsen Declaration at ¶ 22.
Dr. Jacobsen concluded that one of ordinary skill would have
expected that, in general, heterologous partial or full length sequences can be
used to downregulate endogenous genes based on, inter alia, the successful
results reported in the references of paragraph 22, including Elkind.
38. Elkind concludes that transgenic plants can evidence a series of unusual,
i.e., unexpected phenotypes, evidencing unpredictability in the art.
(Abstract.) Expression of phenotype is also affected by the environment.
(Elkind, page 9059.)
39. Emery
Emery looked at the function of HD-ZIP and KANADI genes in the
meristem of plants with respect to adaxial and abaxial leaf production. The
authors found five class III HDZIP genes in Arabidopsis and that they have
diversified common and unique functions. (Emery 1771, col. 2.) Jacobsen
Declaration at ¶ 25. Dr. Jacobsen concluded that one of ordinary skill, after

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reviewing the Emery reference, would not conclude that use of antisense
techniques in plant molecular biology requires a 100% sequence match
between an introduced sequence and its target.
While the Emery reference reports that mismatches introduced within
microRNA target sites can abolish mRNA function, such a result does not
mean that sequences with imperfect homology would necessarily be
ineffective for downregulation. Jacobsen Declaration at ¶ 25.
40. Gutterson
Dr. Jacobsen found after reviewing the Gutterson reference, that one
of ordinary skill
would not conclude that use of sense suppression techniques in
plant molecular biology requires a 100% sequence match
between an introduced sequence and its target. While the
Gutterson reference reports that a chrysanthemum chalcone
synthase sense sequence did not suppress a petunia chalcone
synthase, such a result does not mean that sequences with
imperfect homology would necessarily be ineffective for
downregulation.

Jacobsen Declaration at ¶ 27.

41. Gutterson discloses that the proportion of plants with high levels
of suppression decreased with decreasing fragment length. (Gutterson
965, col. 2.)
42. The complete carrot, corn, pea and tomato Metl sequences were known
from the earliest priority date from Genbank Accession Numbers AF007807,
AF063403, AF034419 and AJ002140. Evidence Appendices G, F, H, and I.
43. Appellant argues that there are numerous regions in carrot, corn, pea
and tomato Metl sequences that are highly conserved even though Zea mays
is a monocot and the remainder are dicots, directing one of ordinary skill to

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partial Arabidopsis Metl sequences that would have been effective for
downregulation in heterologous species. (App. Br. 19-20.)
44. “Applicant submitted eight additional references that report
downregulation using heterologous sequences, including sequences having
less than 100% sequence identity to an endogenous gene. Evidence
Appendix N.”2
45. According to Appellants, “[t]hese other prior art references show one of
ordinary skill would have concluded that antisense sequences with less than
100% sequence identity can be used to downregulate a heterologous
endogenous gene.” (App. Br. 34.)
46. Oliver discloses that the production of heterologous hydroxypyruvate
reductase (HPR) RNA did not systematically reduce levels of tobacco HPR.
(Oliver, Abstract.)
47. VanderKrol discloses that the pattern of plant pigmentation derived
from the flavonoid biosysnthesis pathway varies among flowers of different
transgenic plants indicating that the antisense gene is influenced by DNA
sequences that border the site of insertion in both a quantitative and
qualitative way. (VanderKrol, Abstract.)

2 Temple, et al. Mol. Gen. Genet Vol. 236(3): pp. 3 15-325(1993); Oliver,
M.J., et al. Mol. Gen Genet, Vol. 239(2): pp. 425-434 (1993); Van der Krol,
A.R., et al., Nature Vol. 333: pp. 866-869 (1988); Canon, et al. Theoretical
and Applied Genetics Vol. 87(8): pp. 1006- 10 15 (1994); Einset, J.W., Plant
Cell Tissue and Organ Culture Vol. 46(2): pp. 137- 14 1 (1 996); Trevanion,
et al. Plant Phvsiol. Vol. 1 13(4): pp. 1 153-1 165 (1997); Faske, et al. Plant
Physiol. Vol. 1 15(2): pp. 705-7 15 (1 997); Herbik, et al. Eur. J. Biochem.
265(1): pp. 23 1-239 (1999); Veena, et al. Plant Journal 17(4): pp. 385-395
(1999).

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48. Carron indicates that downregulation of tannin biosynthesis is
dependent upon Lotus genotype. (Carron, Abstract.)
49. Einset discloses that there is differential expression of antisense genes
involving ethylene production. Ethylene production in flowers was not
effected but ethylene production in fruits was inhibited. (Einset, Abstract.)

PRINCIPLES OF LAW
“[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed
invention without ‘undue experimentation.’” Genentech, Inc. v. Novo
Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright,
999 F.2d 1557, 1561 (Fed. Cir. 1993) (emphasis added). In order to make a
rejection, the examiner has the initial burden to establish a reasonable basis
to question the enablement provided for the claimed invention. Wright, 999
F.2d at 1561-1562.
Enablement is a question of law, based on underlying findings of fact.
See, e.g., In re Wands, 858 F.2d 731, 735 (Fed. Cir. 1988). Thus, “there
must be sufficient disclosure, either through illustrative examples or
terminology, to teach those of ordinary skill how to make and use the
invention as broadly as it is claimed.” In re Vaeck, 947 F.2d 488, 496 & n.
23 (Fed. Cir. 1991), quoted in Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d
1362, 1372.
Factors to be considered in determining whether a
disclosure would require undue experimentation . . . the
quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the

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predictability or unpredictability of the art, and (8) the breadth
of the claims.

Wands. 858 F.2d at 737.
“Patent protection is granted in return for an enabling disclosure . . . ,
not for vague intimations of general ideas that may or may not be workable.”
Genentech, 108 F.3d at 1366. “Tossing out the mere germ of an idea does
not constitute enabling disclosure. While every aspect of a generic claim
certainly need not have been carried out by an inventor, or exemplified in
the specification, reasonable detail must be provided in order to enable
members of the public [skilled in the art] to understand and carry out the
invention.” Id. (emphasis added).
“[S]ufficient disclosure . . . to teach those of ordinary skill in the art
how to make and how to use the invention . . . . means that the disclosure
must adequately guide the art worker to determine, without undue
experimentation, which species among all those encompassed by the
claimed genus possess the disclosed utility.” In re Vaeck, 947 F.2d 488, 496,
(Fed Cir 1991). A claim that covers many inoperative embodiments may be
non-enabled. Genentech Inc. v. The Wellcome Foundation Ltd., 29 F.3d
1555, 1560 (Fed. Cir. 1994).
The evidentiary standard to be used throughout ex parte examination
in setting forth a rejection is a preponderance of the totality of the evidence
under consideration. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992)
(“After evidence or argument is submitted by the applicant in response,
patentability is determined on the totality of the record, by a preponderance
of evidence with due consideration to persuasiveness of argument.”). A
preponderance of the evidence exists when it suggests that it is more likely

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than not that the assertion in question is true. Herman v. Huddleston, 459
U.S. 375, 390 (1983).

ANALYSIS
The Examiner argues that the claims are not enabled for at least two
reasons. The first reason is that the Appellant’s Specification does not
enable the use of the claimed method in any plant. (Ans. 7.) The second
reason is that the Appellant’s Specification does not enable partial sequences
of Arabidopsis Met1. (Ans. 7.) We will focus primarily on the first reason.
The Examiner contends that the Specification
[D]oes not reasonably provide enablement for claims broadly
drawn to a method of modifying the endosperm from any plant
comprising downregulating any DNA methylating enzyme
using a sequence whose transcription product comprises a
partial or full length Arabidopsis Metl sequence or which
comprises a partial or full-length Zea mays sequence
orthologous to the Arabidopsis Metl sequence, or wherein the
nucleic acid is a partial or full length sequence in sense or
antisense orientation.

(Ans. 7.) In particular, the Examiner finds that the claims are not only
drawn to decreasing overall methylation in a plant, but are drawn to
decreasing methylation which results in production of a modified or altered
endosperm development (Final Rej. 8). Thus, the Examiner argues that a
method of modifying the endosperm from any plant is not supported by an
enabling disclosure taking into account the Wands factors.
With respect to the Wands factors, the Examiner finds that Appellant
“discloses cloning a sequence that encodes the Arabidopsis MET1 protein,
wherein the nucleic acid sequence is 4.7kb long, in which the sequence was

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isolated by RT-PCR from an Arabidopsis cDNA library using the METlF
primer of SEQ ID NO: 5 and METl R primer of SEQ ID NO:6.” (Ans. 8.)
The Examiner agrees that Appellant “discloses subcloning the nucleic
acid sequence into a vector comprising the AGL5 or AP3 promoter in
antisense orientation (page 30, Example 3; and Figures 6 and 7) and
Arabidopsis, Brassica campestris and Brassica oleraceae transformation
therewith (page 31, Example 4, page 33, Example 5). Plants expressing the
pAGL5Met1 as construct produced seed with increased weight (page 31,
lines 26-28).” (Ans. 8.)
However, the Examiner finds that the state-of-the-art teaches down-
regulating methylating genes produces unpredictable results. (Ans. 9.) To
support this position, the Examiner relies on Jacobsen (2000) which teaches
“transforming Arabidopsis with a nucleic acid encoding the MET1 protein
operably linked to a promoter in antisense orientation caused a decrease in
methylation by 80%-90%.” (Ans. 9) (emphasis added.) Jacobsen also
discloses that "‘[s]urprisingly,… the floral development gene SUPERMAN,
was ectopically hypermethylated [emphasis added] and silenced’ (page
180, left column, 1st full paragraph)” (Ans. 9).
The Examiner finds that “Appellant has only disclosed primer
sequences to be used for isolating the full length Arabidopsis MET1
sequence from an Arabidopsis cDNA library (See pages 30-31, Example
3a).” The Examiner further finds that “Appellant has not disclosed how one
makes or isolates any of the other sequences that are encompassed by
Appellant's broad claims.” (Ans. 10.) Nor has Appellant
[T]aught which regions of the respective polynucleotides can be
used to amplify, for example, the Zea Mays orthologous
sequence, or which regions can be used as a probe to isolate any

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of said polynucleotide sequences whose transcription product
comprises a partial Arabidopsis or Zea mays Met1 sequence
that is effective for downregulating one or more DNA
methylating enzymes present in the plant and produce a plant
whose seeds produce modified endosperm.
Id.
The Examiner also finds that “[u]sing DNA sequences to reduce
expression of the endogenous corresponding gene through the mechanism of
sense suppression produces unpredictable results.” (Ans. 10.) For example,
Gutterson “teaches that the chrysanthemum and petunia chalcone synthase
(CHS) genes are 70% identical to each other, and that transforming petunia
plants with the chrysanthemum CHS gene did not co-suppress the
endogenous petunia CHS gene (page 965, left column, second paragraph).
Gutterson reports similar data using another petunia gene in the anthocyanin
pathway.” (Ans. 10.)
Regarding the state-of-the-art, the Examiner finds that the art teaches
that “antisense molecules that exhibit less than 100% sequence identity to
the target sequence produce unexpected results.” (Ans. 10.) To support this
position, the Examiner relies on Emery which “discloses experiments in
which a target sequence of a micro-RNA was changed by two base-pairs.
The altered base-pairs caused the complementary micro-RNA not to bind to
the target sequence, which subsequently led to an increased expression of
the target sequence's encoded protein (page 1769, right column, 2nd full
paragraph).” (Ans. 10-11.)
The Examiner asserts that Appellant has not indicated which regions
of MET1 are specific to the methyltransferases of the instant invention.
(Ans. 18-19.) The Examiner argues that “Finnegan … discloses that there
are three classes of methyltransferases in Arabidopsis, METI, METII and

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METIII (page 228, top paragraph) and homology between METI and METII
is higher in the methyltransferase domain than in the amino-terminal domain
(sentence bridging pages 227-228).” (Ans. 18-19.) Finnegan (1998) states
"There is evidence supporting the notion that plant methyltransferases may
differ in target specificity” (page 229, bottom paragraph). Therefore, the
Examiner asserts, Appellant has not described essential regions of the MET1
sequence that can be used to down regulate a methyltransferase in a plant so
that the plant produces seeds with the expected phenotype.” (Ans. 19)
(Emphasis added.)
In sum, the Examiner concludes that the
[A]bsence of guidance, undue trial and error experimentation
would be required for one of ordinary skill in the art to screen
through the multitude of non-exemplified sequences, either by
using non-disclosed fragments of a nucleic acid encoding the
Arabidopsis Metl protein as probes or by designing primers to
undisclosed regions of a nucleic acid encoding the Arabidopsis
Met1 protein and isolating or amplifying fragments, subcloning
the fragments, producing expression vectors and transforming
plants therewith, in order to identify those, if any, that when
over-expressed in female germ line cells down-regulate one or
more DNA methylating enzymes present in a plant and produce
a plant whose seeds produce a modified endosperm.

(Ans. 11.) Therefore, given the breadth of the claims; the lack of guidance
and examples; the level of unpredictability in the art; and the state-of-the-art
as discussed above, the Examiner concludes that undue experimentation
would be required to practice the claimed invention, and therefore the
invention is not enabled. Id.

Appellant’s Position

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Appellant takes issue with the references cited by the Examiner to
support unpredictability in the art and lack of enablement. Appellant argues
that the general principles of gene downregulation technologies were known.
(App. Br. 31.) Appellant argues that
[T]he specification at page 16, lines 8-28, page 18, lines 26-28
and pages 30-32, for example, disclose the construction of
partial Arabidopsis Metl sequences linked to a female germ line
promoter, discloses their usefulness for downregulation and
discloses the use of a construct to produce seeds with modified
endosperm.

(App. Br. 34-35.) Appellant argues that the Examiner has failed to identify a
single reported instance where downregulation of a Metl gene failed to
reduce the degree of methylation.
Appellant puts forth the Declaration of Dr. Jacobsen in support of the
predictability of the art. (App. Br. 34.)

Jacobsen Declaration
To summarize, the Declarant concludes that the evidence of record
supports that one of ordinary skill in the art would have expected
hypomethylation in various plants and supports that sequences of less than
100% identity hybridize to methyltransferases.

Cannon
Dr. Jacobsen concludes that one of ordinary skill would have
understood from Cannon that “a 41-base pairing homology was sufficient to
give up to a 100% inhibition of GUS [gene] expression." Cannon 46.
Jacobsen Declaration at ¶ 11.

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The Cannon reference also states at page 39 that "antisense RNA has
a complementary sequence to mRNA and inhibits gene translation by a
mechanism as yet unknown but presumed to involve duplex formation."
Thus, Cannon dealt with inhibition of the GUS gene in plant leaves
and roots (Cannon 46) and does not support that the resulting decrease in
overall methylation in any plant would predictably result in production of a
modified (heavier) endosperm.

Jacobsen and Finnegan
According to Dr. Jacobsen, the Jacobsen 2000 reference concerned
[T]he observation that the AGAMOUS gene was
hypermethylated in an Arabidopsis line expressing a Metl
antisense construct. These lines were previously described as
having up to a 90% decrease in overall DNA methylation.
Finnegan et al., (1996) Proc. Natl. Acad. Sci. U.S.A. 93:8449.
An earlier publication, the Jacobsen 1997 reference, showed
that the SUPERMAN gene was hypermethylated in the same
Arabidopsis line expressing a Metl antisense construct, and
these experiments also confirmed the simultaneous overall
hypomethylation in this line. (Jacobsen et al., Science 1997
277: 1100- 1103).

Jacobsen Declaration at ¶12.

The Jacobsen Declaration indicates that the “observation of
hypermethylation of the SUPERMAN gene or the AGAMOUS gene in
Arabidopsis Metl antisense construct-containing lines does not change the
fact that these lines had a significant reduction in the degree of overall DNA
methylation.” Appellant argues that “the data about the SUPERMAN and
AGAMOUS genes in the Jacobsen 1997 and 2000 references have no bearing
on whether one of ordinary skill would have expected a decrease in the

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degree of overall DNA methylation upon downregulation of Metl
expression.” Jacobsen Declaration at ¶ 14.
We agree with the Examiner and Appellant that Jacobsen 2000
discloses a reduction in the DNA methylation in Arabidopsis (not any plant),
but only shows that this decreased methylation results in a changed floral
phenotype (Jacobsen 2000 abstract) and does not disclose a change in
phenotype in the endosperm or seed, as claimed.
Dr. Jacobsen further concluded that the
[T]echniques required to screen and identify Metl
downregulation construct-containing plants that have a decrease
in DNA methylation would have been routine for one of
ordinary skill, because the techniques involved would have
been typical of those carried out by one of ordinary skill. Such
techniques include constructing DNA clones containing partial
and full-length Arabidopsis or Zea mays DNA
methyltransferase 1 Metl sequences, constructing plant
transformation vectors, transforming plants, and screening for
overall DNA methylation status.

Jacobsen Declaration at ¶ 16. Dr. Jacobsen does not address how to
predictably alter the phenotype of the endosperm or seed in any plant
or evidence that methyltransferase is present in the endosperm of any
plant.

Fourgoux-Nicol
According to Dr. Jacobsen, Fourgoux-Nicol shows that
hybridization techniques were used successfully to isolate desired
clones. Jacobsen Declaration at ¶ 18. Dr. Jacobsen finds that
The authors of the Fourgoux-Nicol reference focused
their analysis on one of the thirteen cDNA clones whose

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expression was strictly confined to the male gametophyte and
was high in the microspore. The selected clone was designated
M3 and had a length of 497 bp. Fourgoux- Nicol at page 863,
left-hand column. M3 was used in a second round of screening
by stringent hybridization to isolate a second cDNA clone,
designated M3.21. M3.21 has a length of 674 bp. Fourgoux-
Nicol at page 863, left-hand column. M3 and M3.21 were
sequenced and found to have non-identical sequences, including
a 99 base pair insertion in M3 that was not present in M3.21,
and several single nucleotide polymorphisms between the two.
Fourgoux-Nicol at page 863, right-hand column, and page 862
Figure 2. Further analysis, including Southern hybridization,
indicated that the M3 and M3.21 cDNAs were derived from
two homologous genes. Fourgoux-Nicol at page 864, left-hand
column. Thus, the reference shows that 100% sequence identity
is not required in order to successfully isolate related sequences
by nucleic acid hybridization.

Jacobsen Declaration at ¶ 19.

Dr. Jacobsen concludes that
The fact that nucleic acids that do not have 100% DNA
sequence identity, such as M3 and M3.21, can hybridize to each
other would indicate to one of ordinary skill that hybridization
would likely occur between a partial or full length Arabidopsis
or Zea mays DNA methyltransferase 1 Metl sequence and an
endogenous DNA methyltransferase 1 Metl target even when
there is less than 100% sequence identity.

Jacobsen Declaration at ¶ 20.

While Fourgoux-Nicol supports the position that, in a particular
instance with a gene involving male gametophyte development, that nucleic
acids that do not have 100% DNA sequence identity can hybridize to each
other, it does not provide evidence to address the Examiner’s concern that

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the hybridization to Met1 in any plant would necessarily result in the desired
endosperm, modified phenotype.

Hibino
Dr. Jacobsen finds that Hibino reports that “introduction of an Aralia
cordala cinnamyl alcohol dehydrogenase (CAD) antisense construct into
tobacco resulted in an approximately 20-55% reduction in CAD activity.
See page 929 and Figure 1 of Hibino.” Jacobsen Declaration at ¶ 22.
Two plants showed a reduction in CAD whereas others showed no
significant change, evidencing unpredictability in the art. (Hibino, page 929,
col.2.) Thus Hibino dealt with inhibition of the CAD gene and does not
support that the resulting decrease in overall methylation in any plant would
predictably result in production of a modified endosperm.

Bolitho
Bolitho report that introduction of an apple antisense ACC-oxidase
reduced the level of RNA and the activity of the corresponding gene for
ethylene production in tomato. See Figures 3 and 4 of Bolitho. Jacobsen
Declaration at ¶ 22.
Bolitho, however also states that high levels of antisense sequence
were not always associated with reduction in ethylene levels evidencing
unpredictability in the art. (Abstract.) Thus, Bolitho does not support that a
resulting decrease in overall methylation in any plant would predictably
result in production of a modified endosperm.

Salehuzzaman

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Salehuzzaman report that introduction of a cassava granule bound
starch synthase antisense gene suppressed levels of the corresponding
protein in potato. See Figure 10 in Salehuzzaman. Jacobsen Declaration at
¶ 22.
In Salehuzzaman the gene in question was abundantly expressed in
tubers (not endosperm), minimally expressed in petioles and stems and not
expressed in roots. (Salehuzzaman, page 955.) Levels of antisense
inhibition varied from complete inhibition to no visible effect, evidencing
unpredictability in the art. (Salehuzzaman, page 960, col. 2.) Thus,
Salehuzzaman does not support that a resulting decrease in overall
methylation in any plant would predictably result in production of a
modified endosperm.

Elkind
Elkind report that introduction of a bean phenylalanine ammonia-
lyase (PAL) sense sequence into tobacco resulted in reduced levels of PAL
activity and reduced accumulation of endogenous PAL transcripts. See
Elkind at page 9059-9060. Jacobsen Declaration at ¶ 22.
Dr. Jacobsen concluded that one of ordinary skill would have
expected that, in general, heterologous partial or full length sequences can be
used to downregulate endogenous genes based on, inter alia, the successful
results reported in the references of paragraph 22, including Elkind.
However, Elkind concludes that transgenic plants can evidence a
series of unusual, i.e., unexpected phenotypes, evidencing unpredictability in
the art. (Abstract.) Expression of phenotype is also affected by the
environment. (Elkind, page 9059.) Thus, Elkind does not support that a

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resulting decrease in overall methylation in any plant would predictably
result in production of a modified endosperm.

Emery3
Emery looked at the function of HD-ZIP and KANADI genes in the
meristem of plants with respect to adaxial and abaxial leaf production. The
authors found five class III HDZIP genes in Arabidopsis and that they have
diversified common and unique functions. (Emery 1771, col. 2.) Jacobsen
Declaration at ¶ 25. Dr. Jacobsen concluded that one of ordinary skill, after
reviewing the Emery reference, would not conclude that use of antisense
techniques in plant molecular biology requires a 100% sequence match
between an introduced sequence and its target.
While the Emery reference reports that mismatches introduced within
microRNA target sites can abolish mRNA function, such a result does not
mean that sequences with imperfect homology would necessarily be
ineffective for downregulation. Jacobsen Declaration at ¶ 25.
Thus, Emery does not support that the resulting decrease in overall
methylation in any plant would predictably result in production of a
modified endosperm.

3 Appellant argues that Emery is a post filing date reference that has
no evidence of what one skilled in the art would have known on or before
the effective filing date. Therefore, the Emery reference is not relevant to
whether the claimed invention would have been enabled as of the effective
filing date. Appellant argues that Emery actually demonstrates the
precision with which one of ordinary skill can upregulate or downregulate a
particular gene. (App. Br. 33-34.)

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Gutterson
Dr. Jacobsen found after reviewing the Gutterson reference, that one
of ordinary skill in the
would not conclude that use of sense suppression techniques in
plant molecular biology requires a 100% sequence match
between an introduced sequence and its target. While the
Gutterson reference reports that a chrysanthemum chalcone
synthase sense sequence did not suppress a petunia chalcone
synthase, such a result does not mean that sequences with
imperfect homology would necessarily be ineffective for
downregulation.

Jacobsen Declaration at ¶ 27.

Gutterson also discloses that the proportion of plants with high levels
of suppression decreased with decreasing fragment length. (Gutterson 965,
col. 2.) Thus, Gutterson does not support that a resulting decrease in overall
methylation in any plant would predictably result in production of a
modified endosperm.

Other evidence
Appellant further argues that the complete carrot, corn, pea and
tomato Metl sequences were known from the earliest priority date from
Genbank Accession Numbers AF007807, AF063403, AF034419 and
AJ002140. Evidence Appendices G, F, H, and I. Appellant argues that
there are numerous regions in these sequences that are highly conserved
even though Zea mays is a monocot and the remainder are dicots, directing
one of ordinary skill to partial Arabidopsis Metl sequences that would have
been effective for downregulation in heterologous species. (App. Br. 19-20.)

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While these references support that the Met1 sequences of other plants
were known, they do not evidence that a resulting decrease in overall
methylation in any plant would predictably result in production of a
modified endosperm.
“Applicant submitted eight additional references that report
downregulation using heterologous sequences, including sequences having
less than 100% sequence identity to an endogenous gene. Evidence
Appendix N.”4 According to Appellants, “[t]hese other prior art references
show one of ordinary skill would have concluded that antisense sequences
with less than 100% sequence identity can be used to downregulate a
heterologous endogenous gene.” (App. Br. 34.)
These references are purported to evidence downregulation using
heterologous sequences, including sequences having less than 100%
sequence identity to an endogenous gene. However, Oliver discloses that
the production of heterologous hydroxypyruvate reductase (HPR) RNA did
not systematically reduce levels of tobacco HPR. (Oliver, Abstract.)
VanderKrol discloses that the pattern of plant pigmentation derived from the
flavonoid biosysnthesis pathway varies among flowers of different

4 Temple, et al. Mol. Gen. Genet Vol. 236(3): pp. 3 15-325(1993); Oliver,
M.J., et al. Mol. Gen Genet, Vol. 239(2): pp. 425-434 (1993); Van der Krol,
A.R., et al., Nature Vol. 333: pp. 866-869 (1988); Canon, et al. Theoretical
and Applied Genetics Vol. 87(8): pp. 1006- 10 15 (1994); Einset, J.W., Plant
Cell Tissue and Organ Culture Vol. 46(2): pp. 137- 14 1 (1 996); Trevanion,
et al. Plant Phvsiol. Vol. 1 13(4): pp. 1 153-1 165 (1997); Faske, et al. Plant
Physiol. Vol. 1 15(2): pp. 705-7 15 (1 997); Herbik, et al. Eur. J. Biochem.
265(1): pp. 23 1-239 (1999); Veena, et al. Plant Journal 17(4): pp. 385-395
(1999).

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transgenic plants indicating that the antisense gene is influenced by DNA
sequences that border the site of insertion in both a quantitative and
qualitative way. (VanderKrol, Abstract.) Carron indicates that
downregulation of tannin biosynthesis is dependent upon Lotus genotype.
(Carron, Abstract.) Einset discloses that there is differential expression of
antisense genes involving ethylene production. Ethylene production in
flowers was not effected but ethylene production in fruits was inhibited.
(Einset, Abstract.) Thus, the cited references do not evidence that a resulting
decrease in overall methylation in any plant would predictably result in
production of a modified endosperm, and support a level of unpredictability
in the art.

Wands Factors
With respect to the Wands factors, Appellant argues that the
Specification states in the context of decreasing the degree of methylation
that "the transgene can incorporate sequences which cause down regulation
of methylating enzymes already present in the plant, and states that ‘[for
example, one can use antisense sequences, e.g., the Metlas 'gene'."
Specification at page 18, lines 26-28. (App. Br. 13.)
Second, Appellant argues that the present specification indicates the
inventor considered part of the invention to be the use of a female germ line
promoter to downregulate DNA methyltransferases.
For example, the Specification indicates that
[e]xpression of the METl gene can be reduced in the female or
male germ lines by employing techniques known in the art. For
example METl down-regulation can be achieved by expressing
antisense MET1 or antisense MET 1 fragments or sense MET1

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or partial sense METl or ribozymes directed against MET1 or
combinations of the preceding, from promoters expressed in
the required germ-line. Specification at page 30, lines 15-19.
Id.
Third, Appellant argues that the Specification “discloses a working
example using a partial Metl sequence. Example 3 describes the preparation
of a construct having a partial Arabidopsis Metl antisense sequence targeted
to the female germ line. Example 4 describes its use to produce modified
endosperm. Examples 3-4, pages 30-32.” (App. Br. 13.)
Fourth, the Arabidopsis Metl sequence was known in the
art. See, e.g., Finnegan et al., Nucleic Acids Res. 23:2383-2388
(1993). Evidence Appendix B. The specification indicates that
the Arabidopsis Met1 sequence is published as Accession No.
L10692. The specification indicates that "down-regulation can
be achieved by expressing antisense MET1 or antisense MET1
fragments or sense MET1 or partial sense METl or ribozymes
directed against MET1 or combinations of the preceding, from
promoters expressed in the required germ-line." Specification at
page 30, lines 16-19. Rather than mechanically reciting partial
Arabidopsis Met1 sequences in the specification, Applicant
referred to partials of the known sequence because one of
ordinary skill would have easily visualized the identity of
partial Arabidopsis Metl sequences based on the full-length
sequence. That is, a partial or full-length Arabidopsis Metl
sequence is not a new or unknown biological material that one
of ordinary skill would easily miscomprehend. Amgen Inc. v.
Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1332 (Fed. Cir.
2003).

(App. Br. 13-14.)
Appellant concludes that, in view of the specific recitation of the
Arabidopsis Metl sequence in the claim, the guidance provided in the
Specification, and the evidence presented in the Jacobsen Declaration, no

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more than routine experimentation would have been required to practice the
full scope of the claim. (App. Br. 33.)
The Examiner does not find the evidence of record convincing of
enablement or lack of undue experimentation because the evidence does not
support that the resulting decrease in overall methylation in a plant would
predictably result in production of a modified endosperm. (Final Rej. 8.)
Reviewing the evidence anew, we find that a preponderance of the
evidence before us supports the finding that the state of the art is
unpredictable and that more disclosure is required to enable and support the
down regulation of Met1 in any plant to produce a modified endosperm.
(FF 21, 22, 35, 36, 38, 41, 46, 47, 48, and 49.) In particular, we find that the
evidence before us shows that down regulation of plant genes often has an
effect on one portion of a plant and not other portions of a plant. Down
regulation of a plant gene may affect a tuber, root, flower, or endosperm in
an unpredictable manner.

Separately argued claims5
On pages 35 to 37 of the Brief, Appellant separately argues claims 21,
64, 65, 66, 67, 71, 77, 78, 80, 81, and 82. These claims also broadly cover
downregulation of Met1 in any plant and therefore fall for the same reasons
indicated herein.

5 Appellant attempts to argue claims 63, 69, 76, and 86-93 separately by
simply listing their limitations (App. Br. 45-47). Technically, this does not
constitute a separate argument under 37 C.F.R. 41.37(c)(1)(vii) (“A
statement which merely points out what a claim recites will not be
considered an argument for separate patentability of the claim.”).

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Claims 83, 84, 91 and 92
Appellant contends that Examples 3 and 4 of the Specification
describe transformation of Arabidopsis thaliana, a member of the
Brassicaceae family. (App. Br. 38.) The Examiner admits on page 7 of the
Answer that the Specification is enabling for increasing the amount of
endosperm in an Arabidopsis or Brassica seed. Therefore, the enablement
rejection of claims 83, 84, 91 and 92 are reversed.

Claim 85
Appellant traverses this rejection for the same reasons given for
claims 77 and 82. (App. Br. 39.) The Specification does not exemplify
transformation of a plant of the Zea mays species. For the reasons given
herein for claims 20, 77 and 82, we affirm the rejection of claim 85.
In view of the weight of the evidence, the lack of enablement rejection
for all claims (except claims 83, 84, 91 and 92) is affirmed.

3. Claims 20-21, 62-67, 69, 71, 76-78, 80-93 stand rejected under 35
U.S.C. 112, first paragraph, as containing subject matter which was not
described in the specification in such away as to reasonably convey to one
skilled in the relevant art that the inventor(s), at the time the application was
filed, had possession of the claimed invention.

ISSUE
The Examiner argues that “[a]ppellant does not identify essential
regions of the Arabidopsis Metl sequence, nor any partial sequences thereof,
nor any partial sequence of the Zea mays orthologue of the Arabidopsis Metl

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sequence, that can be used to down-regulate one or more methylating
enzymes present in any plant.” (Ans. 5.) The Examiner further argues that
Appellant does not disclose any sequence whose transcription product is a
partial Arabidopsis Met 1 or Zea mays orthologous sequence to the
Arabidopsis Met1 sequence. (Ans. 5.)
Appellant contends that
[T]he evidence above and the record as a whole strongly
support a conclusion that the present specification provide more
than adequate written description for the pending claims to one
of ordinary skill in the art.

(App. Br. 27.)

The issue is: Does the evidence above and the record as a whole
demonstrate that one of ordinary skill would understand that Appellant has
describe the invention in the full scope claimed, that is production of a
modified endosperm in any plant.

PRINCIPLES OF LAW
The ‘written description’ requirement . . . serves both to
satisfy the inventor’s obligation to disclose the technologic
knowledge upon which the patent is based, and to demonstrate
that the patentee was in possession of the invention that is
claimed. . . .
The descriptive text needed to meet these requirements
varies with the nature and scope of the invention at issue, and
with the scientific and technologic knowledge already in
existence.

Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). The law must be
applied to each invention that enters the patent process, for each patented

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advance is novel in relation to the state of the science. Since the law is
applied to each invention in view of the state of relevant knowledge, its
application will vary with differences in the state of knowledge in the field
and differences in the predictability of the science. It is well recognized that
in the “unpredictable” fields of science, it is appropriate to recognize the
variability in the science in determining the scope of the coverage to which
the inventor is entitled. Such a decision usually focuses on the
exemplification in the specification. See, e.g., Enzo Biochem, Inc. v. Gen-
Probe Inc., 323 F.3d 956 (Fed. Cir. 2002).
With respect to the written description requirement, while "examples
explicitly covering the full scope of the claim language" typically will not be
required, a sufficient number of representative species must be included "to
demonstrate that the patentee possessed the full scope of the [claimed]
invention." LizardTech, Inc. v. Earth Resource Mapping, Inc., 424 F.3d
1336, 1345 (Fed. Cir. 2005).
The court has since clarified that the complete structure of the
representative species does not necessarily have to be described. See Enzo,
323 F.3d at 964-65. However, a correlation between the claimed function
and structure must be “known or disclosed.” Id. at 964 (citing with approval
PTO’s Guidelines, 66 Fed. Reg. at 1106).

ANALYSIS
The Examiner finds that
Appellant fails to describe a representative number of
sequences whose transcription product is a partial sequence of
the Arabidopsis Metl sequence, or partial sequences of the Zea
mays homologue of the Arabidopsis Metl sequence, that can be

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used to down-regulate one or more methylating enzymes in any
plant. Furthermore, Appellant fails to describe structural
features common to members of the claimed genus of
polynucleotides. Hence, Appellant fails to meet either prong of
the two-prong test set forth by Eli Lilly. Furthermore, given the
lack of description of the necessary elements of said sequences
that can be used to down-regulate any methylating enzyme in
any plant, it remains unclear what features identify an
Arabidopsis Metl sequence or identify the Zea mays homologue
of the Arabidopsis Metl sequence, or what sequences can be
used to identify partial sequences of the Arabidopsis Metl or
partial sequences of the Zea mays homologue of the
Arabidopsis Metl sequence. Since the genus of said sequences
has not been described by specific structural features, the
specification fails to provide an adequate written description to
support the breath of the claims.

(App. Br. 6.)

Appellant’s arguments do not persuade us that the Examiner erred in
finding that the claims lack descriptive support.
“The descriptive text needed to meet the written description varies
with the nature and scope of the invention at issue, and with the scientific
and technologic knowledge already in existence.” Capon, 418 F.3d at 1357.
The application of the written description requirement varies with
differences in the state of knowledge in the field and differences in the
predictability of the science. It is well recognized that in the “unpredictable”
fields of science, it is appropriate to recognize the variability in the science
in determining the scope of the coverage to which the inventor is entitled.
Such a decision usually focuses on the exemplification in the specification.
We found with respect to the enablement rejection that the state of the
art is unpredictable regarding the ability to down regulate MET1 in any

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plant. Appellant has failed to provide evidence that one of ordinary skill in
the art was aware that Met1 is present in the endosperm of any plant type or
that a full or partial antisense sequence to Met1 would result in a modified
endosperm.
Similarly, we find with respect to the written description rejection that
in this unpredictable field of science that additional exemplification in the
Specification is required to describe modification of endosperm in any plant
as claimed. Thus, given the disclosure of a single species of Arabidopsis
Met1 sequence, shown only to be capable of modifying endosperm
production in one plant species, we agree with the Examiner that the
disclosure as filed does not adequately demonstrate possession of the
claimed genus encompassing all partial sequences that act to modify the
endosperm of any plant.

Separately argued claims6
On pages 17 to 20 of the Brief, Appellant separately argues claims 21,
64, 65, 66, 67, 71, 77, 78 80, 81, and 82. These claims also broadly cover
downregulation of Met1 in any plant, which has not been exemplified or
described in the Specification, and therefore fall for the same reasons
indicated herein.

6 Appellant attempts to argue claims 63, 69, 76, and 86-93 separately by
simply listing their limitations (App. Br. 25-27). Technically, this does not
constitute a separate argument under 37 C.F.R. 41.37(c)(1)(vii) (“A
statement which merely points out what a claim recites will not be
considered an argument for separate patentability of the claim.”).

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Claims 83, 84, 91 and 92
Appellant contends that Examples 3 and 4 of the Specification
describe transformation of Arabidopsis thaliana, a member of the
Brassicaceae family. (App. Br. 20.) While this may be true, the
Specification does not describe the structures of those members of the genus
of partial sequences that act to modify the endosperm of the claimed plants.
We therefore agree with the Examiner that the single species of Met1
sequence is insufficient to show possession of the entire genus, even with
respect to these claims. Thus, the written description rejection of claims 83,
84, 91 and 92 is affirmed.

Claim 85
Appellant traverses this rejection for the same reasons given for
claims 77 and 82. (App. Br. 39.) The Specification does not exemplify
transformation of a plant of the Zea mays species. For the reasons given
herein for claims 20, 77 and 82, we affirm the written description rejection
of claim 85.
In view of the weight of the evidence, the lack of written description
rejection for all claims (except claims 83, 84, 91 and 92) is affirmed.
SUMMARY
The indefiniteness rejections are reversed. The enablement and lack
of written description rejections are affirmed except, that the enablement
rejections of claims 83, 84, 91, and 92 are reversed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

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AFFIRMED

cdc
FISH & RICHARDSON P.C.
PO BOX 1022
MINNEAPOLIS MN 55440-1022

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