Ex Parte Evans et al

Board of Patent Appeals and Interferences

Dec 10, 2009

10887002 (B.P.A.I. Dec. 10, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte WILLIAM EDWARD EVANS,
MARY RELLING, and QING CHENG
__________

Appeal 2009-007783
Application 10/887,002
Technology Center 1600
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Decided: December 10, 2009
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Before DONALD E. ADAMS, LORA M. GREEN, and
STEPHEN WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for predicting the activity level of the enzyme gamma glutamyl
hydrolase in a human subject. The Patent Examiner rejected the claims for
lack of enablement. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.
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STATEMENT OF THE CASE
According to the Specification, the human enzyme gamma glutamyl
hydrolase (GGH) catalyzes a reaction that reduces the effectiveness of
methotrexate, a drug used in treating childhood acute lymphoblastic
leukemia. (Spec. 1-2.) The gene coding for human GGH was known. (Id.
at 2:2-4.) Appellants disclose that a point mutation in the gene “is directly
correlated with lower levels of GGH activity.” (Id. at 2-3.) The mutation is
said to be a change at position 511 from cytosine to thymine, changing the
codon ACT to ATT, and the encoded amino acid from threonine to
isoleucine. (Id. at 3:3-10.)
Claims 1 and 3-5, which are all the pending claims, are on appeal.
Claim 1 is representative and reads as follows:
1. A method for predicting the level of gamma glutamyl hydrolase
(GGH) activity in a human subject comprising determining the
nucleotide present in each GGH allele of the genomic DNA of said
subject at a position in exon 5 of human GGH corresponding to
position 511 of SEQ ID No. 1, wherein presence of cytosine or
thymine nucleotides in the GGH alleles is indicative of the level of
GGH activity in the subject.

The Examiner rejected all the claims under 35 U.S.C. § 112, first
paragraph, for lack of enablement. The Examiner relied on the following
evidence:
US 2003/0092019 A1 Meyer et al. May 15, 2003

Rong Yao et al., Human γ-glutamyl hydrolase: Cloning and characterization
of the enzyme expressed in vitro, 93 PROC. NATL. ACAD. SCI. USA 10134-
10138 (1996).

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Karen J. Chave et al., Identification of single nucleotide polymorphisms in
the human γ-glutamyl hydrolase gene and characterization of promoter
polymorphisms, 319 GENE 167-175 (2003).

Qing Cheng et al., A substrate specific functional polymorphisms of human
γ-glutamyl hydrolase alters catalytic activity and methotrexate
polyglutamate accumulation in acute lymphoblastic leukaemia cells,
14 PHARMACOGENETICS 557-567 (2004).

Qing Cheng et al., Epigenetic Regulation of Human γ-Glutamyl Hydrolase
Activity in Acute Lymphoblastic Leukemia Cells, 79 AM. J. HUM. GENET.
264-274 (2006).

Joel N. Hirschhorn et al., A comprehensive review of genetic association
studies, 4 GENET. MED. 45-61 (2002).

John P.A. Ioannidis et al., Replication validity of genetic association studies,
29 NATURE GENET. 306-309 (2001).

ENABLEMENT
The Issue
The Examiner contends that the Specification teaches that
polymorphism in the GGH coding region does not play a role in inter-
individual differences in GGH activity. (Fin. Rej. 5, citing Spec. 2:23-35.)
Examiner finds it “unclear” how the determination of a subject’s GGH
alleles can indicate the subject’s level of GGH activity. (Id. at 6.) Based on
a review of references in the field, said to show unpredictability in the art,
the Examiner found that the experimentation required to predict a level of
GGH activity from the alleles present would be undue. (Id. at 6-7.) The
Examiner further found that the Specification “fails to provide any values,
thus, the skilled artisan would be unable to analyze the alleles of a human
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and assess that individual is [sic] high, medium, low activity because there is
no clear guidance what constitutes high, medium, low activity.” (Id. at 8.)
Appellants contend that the Examiner “completely overlooked the
significance of the data provided in the specification,” and cite to multiple
points in the Specification. (App. Br. 9-10.) Appellants also contend that
the references the Examiner relied on “are either not relevant to the claimed
invention or have not been properly applied.” (Id. at 10-11.) Appellants
argue that the claims do not include a step of determining GGH activity but
instead require determining the nucleotide at position 511 in a subject’s
GGH alleles.
The issues with respect to this rejection are:
have Appellants shown that the Examiner gave insufficient weight to
the Specification’s data;
have Appellants shown that the Examiner gave inappropriate weight
to the cited references; and
have Appellants shown that the Examiner misinterpreted the claims
to require an enzyme activity determination?

Findings of Fact
1. The Specification discloses that the Chave paper reported a GGH
coding region polymorphism, +452 C>T, which caused a codon
change. (Spec. 2:16-22.)
2. According to the Specification, the Chave paper “indicates that GGH
promoter polymorphisms may play a role in inter-individual
differences in MTX-PG accumulation, but that the coding region
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polymorphism does not since it did not change the GGH activity.”
(Id. at 2:23-25.)
3. The Specification’s Figure 1 is said to “correlate[] the level of gamma
glutamyl hydrolase (GGH) activity in patients with various subtypes
of acute lymphoblastic leukemia (ALL) with the presence of a
mutated GGH allele (cytosine to thymine) at the position
corresponding to position 511 of SEQ ID No. 1.” (Id. at 4:3-6.)
4. According to the Specification, “[f]or the entire group of ALL patients
studied (n=66), there was a significant difference in frequency of the
mutated GGH allele among patients with low, intermediate and high
GGH activity (p=0.025 by Exact chi square test).” (Id. at 4:3-8.)
5. The Specification states:
Subjects who have a cytosine on each GGH allele at the
position corresponding to position 511 of SED ID No. 1 are
expected to have high levels of GGH activity relative to
subjects who have a thymine on each GGH allele at this
position. Subjects who have a cytosine on one GGH allele at
this position and a thymine on the other GGH allele at this
position are expected to have an intermediate level of GGH
activity lower than subjects who have a cytosine on each GGH
allele at this position and higher than subjects who have a
thymine on each GGH allele at this position. Therefore one can
predict the relative level of GGH activity in a subject by
determining the identity of the nucleotide corresponding to
position 511 of SEQ ID No. 1 in each GGH allele of the
genome of the subject.

(Id. at 8:27 – 9:5.)
6. Enzyme kinetic analysis is said to have shown a significantly higher
Km (2.7 fold) and lower catalytic efficiency (Vmax/Km reduced 67%)
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for the T127I GGH variant compared to wild-type GGH. (Id. at
12:14-17.)
7. The Specification describes dividing patients according to GGH
activity, “i.e. low, intermediate and high GGH activity defined as the
top 25%, intermediate 50%, and bottom 25%.” (Id. at 20:25-28.)
8. Chave reported that when human GGH containing the T127I mutation
was expressed in E. coli, there was no change in enzyme kinetics
compared to wild type. (Chave at 173.)
9. Chave then stated: “[h]owever, no N-linked glycosylation is
performed in E. coli cells. . . . N-linked glycosylation is important .
. . it is possible that hGGH tertiary structure and/or cellular
compartmentalization may be altered . . . [s]tudies are currently in
progress . . . .” (Id.)

Principles of Law
The first paragraph of 35 U.S.C. § 112 requires that the Specification
teach persons skilled in the art to make and use the invention without undue
experimentation. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). A lack
of enablement rejection is appropriate where the written description fails to
teach those in the art to make and use the invention without undue
experimentation. In re Cortright, 165 F.3d 1353, 1356 (Fed. Cir. 1999).
“The PTO cannot make this kind of rejection, however, unless it has reason
to doubt the objective truth of the statements contained in the written
description.” Id., 165 F.3d at 1357. In other words, “the PTO bears an
initial burden of setting forth a reasonable explanation as to why it believes
that the scope of protection provided by [the] claim is not adequately
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enabled by the description of the invention provided in the specification of
the application.” In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).

Analysis
We agree with Appellants that the Examiner gave too much weight to
the cited publications and too little weight to the Specification’s disclosures.
Contrary to the Examiner’s finding, the Specification did not teach that
coding region polymorphisms play no role in GGH activity in human
subjects. See Fin. Rej. 5, citing Spec. 2:23-35. Those lines in the
Specification reported Chave’s results with E. coli expression, which Chave
itself cautioned against taking at face value. (FF9.) The Specification’s
data, collected with cells from human patients, demonstrates that Chave’s
microorganism-based result did not correlate to GGH activity in human
subjects.
After finding that Chave evidenced a problem with Appellants’
disclosure, the Examiner gave weight to post-filing date publications. We
agree with Appellant that the proper conditions for reliance on post-filing
date publications are not present in this case. The Specification’s disclosure
demonstrated that Chave’s E. coli result was an unreliable predictor of
results in human subjects. This is not a situation where prior art established
a problem and the Specification failed to resolve it. Under these
circumstances, reliance on post-filing date publications was inappropriate.
Further, we agree with Appellants that even if considered, the post-filing
date disclosures do not discredit the Specification’s evidence.
Finally, we agree with Appellants that the Specification provided
sufficient guidance to practice the claimed method. There is no dispute that
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determining the nucleotide present at position 511 of each allele in a human
subject could be done without undue experimentation. The claims do not
require a step of determining enzyme activity. Given the Specification’s
detailed disclosure of data and methods, e.g. FF3-7, the Examiner has not
persuaded us that a person of ordinary skill in this art would need undue
experimentation to understand what GGH activity level a subject’s alleles
would indicate.

CONCLUSIONS OF LAW
Appellants showed that the Examiner gave insufficient weight to the
Specification’s data;
Appellants showed that the Examiner gave undue weight to the cited
references; and
Appellants showed that the Examiner misinterpreted the claims as
requiring an enzyme activity determination.

SUMMARY
We reverse the rejection of claims 1 and 3-5 under 35 U.S.C. § 112,
first paragraph.
REVERSED

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