Ex Parte Kluxen et al

Patent Trial and Appeal Board

Dec 17, 2012

10498238 (P.T.A.B. Dec. 17, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte FRANZ-WERNER KLUXEN, BERND HENTSCH, THOMAS
EHRING, MARIAN BRANDLE, JORG DIETRICH HOHEISEL,
MARCUS FROHME, and DIMITRI ZUBAKOV
__________

Appeal 2011-001269
Application 10/498,238
Technology Center 1600
__________

Before LORA M. GREEN, ERICA A. FRANKLIN, and
RAMA G. ELLURU, Administrative Patent Judges.

FRANKLIN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to
methods for screening a compound for its ability to enhance tumor necrosis
factor-α (TNFα) production. The Patent Examiner rejected the claims as
anticipated and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.

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STATEMENT OF THE CASE
Claims 1-3 and 22-37 are on appeal. Claims 1, 2, 3, 22, and 23 are
representative and read as follows:
1. A method for screening a compound for its ability to enhance tumor
necrosis factor-α (TNFα ) production by inhibiting and/or reversing the
binding of tristetraprolin (TTP) to TNFα mRNA comprising:
a) contacting a test compound with a cell-free sample comprising TTP
protein and an expression construct comprising a reporter gene which
is fused to a part of a 3' untranslated region of the TNF- α mRNA
which contains an AU-rich element (ARE) fragment known to
destabilize the TNF- α mRNA under conditions sufficient for the
expression of a reporter protein,
b) determining the level of expression of the reporter protein in the
presence and absence of the compound, and
c) selecting a compound which enhances tumor necrosis factor- α
(TNFα) production based on the elevated expression of the reporter
protein in presence of the compound in comparison to the expression
thereof in the absence of the compound.

2. A method for screening a compound for its ability to enhance tumor
necrosis factor-α (TNFα) production by inhibiting and/or reversing the
binding of tristetraprolin (TTP) to TNFα mRNA comprising:
a) contacting a test compound with a cell-free sample comprising TNF-α
mRNA, in the presence of TTP and under conditions sufficient for the
expression of TNFα,
b) determining the level of expression of TNFα in the presence and
absence of said compound, and
c) selecting a compound which enhances tumor necrosis factor-a (TNFα)
production based on the elevated expression of TNF-a protein in
presence of the compound in comparison to the expression thereof in
the absence of the compound.

3. A method for screening a compound for its ability to enhance tumor
necrosis factor-α (TNFα) production by inhibiting and/or reversing the
binding of tristetraprolin (TTP) to TNFα mRNA comprising:
a) contacting a test compound with a cell line which expresses TTP and
TNFα or a reporter protein that is expressible in said cell line using a
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construct comprising a reporter gene fused to a part of a 3'
untranslated region of the TNFα mRNA which contains an AU-rich
element (ARE) fragment known to destabilize the TNF-α mRNA,
b) determining the level of expression of TNF-α or of the reporter
protein in the presence or absence of the compound, and
c) selecting a compound which enhances tumor necrosis factor-α (TNFα)
production based on the elevated expression of TNFα or the
expression of the reporter protein in presence of the compound in
comparison to the expression thereof in the absence of the compound.

22. A method for screening a compound for its ability to enhance tumor
necrosis factor-α (TNFα) production by inhibiting and/or reversing the
binding of tristetraprolin (TTP) to TNFα mRNA comprising:
a) contacting a test compound with a cell-free sample comprising TTP
protein and an expression construct comprising a reporter gene which
is fused to a part of a 3' untranslated region of the TNF-α mRNA
which contains an AU-rich element (ARE) fragment known to
destabilize the TNF- α mRNA under conditions sufficient for the
expression of a reporter protein,
b) determining the level of expression of the reporter protein in the
presence and absence of the compound, and
c) selecting a compound which enhances tumor necrosis factor- α
(TNFα) production based on the elevated expression of the reporter
protein in presence of the compound in comparison to the expression
thereof in the absence of the compound,
wherein the ARE comprises bases 1197 to 1350 of the
polynucleotide with GenBank accession number X02611
(SEQ ID NO: 2).

23. A method for screening a compound for its ability to enhance tumor
necrosis factor- α (TNFα) production by inhibiting and/or reversing the
binding of tristetraprolin (TTP) to TNFα mRNA comprising:
a) contacting a test compound with a cell line which expresses TTP and
TNFα or a reporter protein that is expressible in said cell line using a
construct comprising a reporter gene fused to a part of a 3'
untranslated region of the TNFα mRNA which contains an AU-rich
element (ARE) fragment known to destabilize the TNF- α mRNA,
b) determining the level of expression of TNF-α or of the reporter
protein in the presence or absence of the compound, and
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c) selecting a compound which enhances tumor necrosis factor- α
(TNFα) production based on the elevated expression of TNFα or the
expression of the reporter protein in presence of the compound in
comparison to the expression thereof in the absence of the compound,
wherein the ARE comprises bases 1197 to 1350 of the
polynucleotide with the GenBank accession number X02611
(SEQ ID NO: 2).

The Examiner rejected the claims as follows:
• claims 1-3, 22, 23, 25 and 30-34 under 35 U.S.C. §102(a) as
anticipated by Blackshear;1 and
• claims 24, 27-29 and 35-37 under 35 U.S.C. § 103(a) as
unpatentable over Blackshear and Grotendorst.2

ANTICIPATION
The Examiner found that Blackshear taught the methods for screening
a compound for its ability to enhance tumor necrosis factor-α (TNFα)
production by inhibiting and/or reversing the binding of tristetraprolin
(TTP) to TNFα mRNA as recited by the rejected claims. (Ans. 4.) In
particular, the Examiner found that Blackshear’s method comprised
contacting an agent with a cell line comprising TTP protein, and expressing
a part of the TNFα mRNA comprising AU-rich element (ARE) fragments
known to bind to TTP, fused to a reporter gene, and comparing the
expression level of the reporter protein in the presence and absence of the
test agent in order to identify agents that have the ability to inhibit TTP

1Patent Application Publication No. WO 01/12213 A2 by Perry J.
Blackshear et al., published Feb. 22, 2001.
2 US Patent No. 6,069,006 issued to Gary R. Grotendorst et al., May 30,
2000.
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activity, i.e., TTP binding to the AREs present in the reporter construct.
(Ans. 4.) The Examiner also found that Blackshear taught that TNFα and
granulocyte-macrophage stimulating factor (GM-CSF) comprise AREs in
their 3´ untranslated regions (UTR) to which TTP can bind and thereby
target the molecules for destruction. (Id.)
Appellants contend that Blackshear “is directed to methods for
curbing TNFα production…[and] is absolutely silent about methods of
enhancing TNFα production or inhibiting the degradation of TNFα mRNA,
and the potential utility thereof, for example, in treatment of cardiac diseases
and/or cardiac injury.” (App. Br. 6-7.)
The Examiner responds that Blackshear expressly disclosed in an
eighth aspect of the invention wherein its method screens an agent “for the
ability to inhibit an activity of TTP,” i.e., binding to an ARE of a nucleic
acid, which activity results in enhanced TNFα production, as recited by the
claimed invention. (Ans. 6-7.)
Appellants also contend that “Blackshear expressly teaches that
[pharmaceutically useful] compounds either stimulate the activity of TTP
(i.e., are TTP-like) or inhibit the activity of TTP…[and] that methods for
identifying stimulatory compounds rely on detection of TNF-α mRNA
degeneration, whereas methods for identifying inhibitory compounds rely on
the detection of GM-CSF or IL-3 mRNA degeneration.” (App. Br. 9.)
Therefore, according to Appellants, “in the context of screening for
compounds inhibiting the activity of TTP, Blackshear points directly and
only to GM-CSF or IL-3 mRNA degradation, not to TNFα mRNA
degradation.” (Id.)
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The Examiner responds that while Blackshear’s eleventh aspect of the
invention is directed to mRNA encoding GM-CSF or IL-3, the eighth aspect
of the invention is directed to any nucleic acid that includes an ARE
downstream of a nucleic acid sequence encoding a reporter, which
Blackshear expressly discloses being present within the 3´ UTR of a TNF-α
mRNA molecule. (Ans. 8, 4.)
Regarding claims 22 and 23, Appellants assert that “[n]either
Blackshear nor the Office Action provides any evidence that a
polynucleotide which meets the structural elements recited in Applicants’
claims was utilized therein.” (App. Br. 11.) According to Appellants, “[i]t
is not expressly understood what ARE sequences were utilized in
Blackshear.” (Id.)
The Examiner responds that Blackshear disclosed using mouse TNF-α
mRNA ARE to construct its probes, similar to the instant Specification,
which disclosed using mouse TNF-α mRNA comprising a 3´ UTR (bp 1110-
1627 of GenBank accession number X02611) to prepare its probes. (Ans. 9,
citing Blackshear 14; Spec. 65.)
After considering the evidence and arguments, we find that
Blackshear anticipates the claimed invention. We adopt the Examiner’s
explicit findings regarding the scope and content of Blackshear as our own.
(See Ans. 4, 6-8.) In particular, we agree with the Examiner that Blackshear
taught an eighth embodiment of its invention that comprises a method of
selecting a compound which inhibits the binding activity of TTP to a nucleic
acid that includes an ARE downstream of a nucleic acid sequence encoding
a reporter, such as TNF-α mRNA, which activity enhances TNF-α
production. Moreover, to the extent Appellants assert that Blackshear did
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not disclose “the potential utility [of enhanced TNF-α production], for
example, in treatment of cardiac disease and/or cardiac injury” (see App. Br.
6-7) we note that the rejected claims do not recite such utility.
Regarding claims 22 and 23, we find that the Examiner has provided a
sound basis for believing that the polynucleotide used in the method of the
applicant and the prior art were the same (see Ans. 9) and Appellants have
not established otherwise with evidence. See In re Spada, 911 F.2d 705, 709
(Fed. Cir. 1990).
Accordingly, we affirm the rejection of claims 1, 22 and 23 under 35
U.S.C. §102(a) as anticipated by Blackshear. Appellants have not raised
separate arguments regarding claims 2, 3, 25 and 30-34, therefore, these
claims fall with claims 1, 22 and 23. 37 C.F.R. § 41.37(c)(1)(vii).

OBVIOUSNESS
The Examiner’s position is that Blackshear taught the limitations of
the independent claims from which the instantly rejected claims depend, as
discussed regarding the anticipation rejection. (Ans. 5.) The Examiner
further found that the difference between Blackshear and the rejected
dependent claims is that Blackshear did not disclose the recited cell lines and
reporter genes. (Id.) However, the Examiner found that Grotendorst
disclosed that the cell lines recited in the instant claims, e.g., HeLa, CHO,
BHK, HEK 293 are standard and well known cell lines useful for reporter
assays. (Id.) The Examiner also found that Grotendorst taught that reporter
molecules, such as beta-galactosidase, CAT, and luciferase, are useful and
commonly used in reporter assays. (Id.) According to the Examiner, it
would have been obvious to a person of ordinary skill in the art at the time
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the invention was made to have used well known cell lines, promoters and
reporter genes for assaying expression in the method disclosed by
Blackshear because they were well known and standardly used for such
purposes, as taught by Grotendorst, due to their ease of assay, transfection
and maintenance, as well as their ability to provide controllable high levels
of expression. (Id. at 5-6.)
Appellants contend, as discussed regarding the anticipation rejection,
that “Blackshear is absolutely silent about methods of enhancing TNFα
production or inhibiting the degradation of TNFα mRNA.” (App. Br. 9.)
According to Appellants, Blackshear therefore does not provide motivation
to screen compounds which increase TNF-α levels and to use them to treat
cardiac disorders. (Id.) Additionally, Appellants assert that Blackshear
teaches away from the claimed invention by teaching that TNF-α mRNA
degradation is observed with TTP-like or a TTP-stimulatory compound. (Id.
at 11.) Further, according to Appellants, “Grotendorst does nothing to add
to the disclosure in Blackshear.” (Id. at 10.)
We are not persuaded by these arguments for the same reasons
discussed regarding the anticipation of the independent claims from which
the instantly rejected claims depend.
Accordingly, we affirm the rejection of claims 24, 27-29 and 35-37
under 35 U.S.C. § 103(a) as unpatentable over Blackshear and Grotendorst.

SUMMARY
We affirm both the anticipation and obviousness rejections.

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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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