Ex Parte Stuhler et al

Board of Patent Appeals and Interferences

Oct 29, 2010

10961320 (B.P.A.I. Oct. 29, 2010)

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UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte GERNOT STUHLER and HELMUT SALIH
__________

Appeal 2009-008002
Application 10/961,320
Technology Center 1600
__________

Before TONI R. SCHEINER, DEMETRA J. MILLS, and
MELANIE L. MCCOLLUM, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for lack of written description, lack of enablement and
obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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The invention demonstrates that on a single cell level, intracellular
molecules, such as factors of the signal transduction cascade, appear
essentially simultaneously in transformed or infected biological cells, but not
in normal, nontransformed or uninfected cells. (Spec. 19, 30.) Thus, the
claimed method involves a step of correlating the finding of simultaneous
activities of a substrate of the CDK2 signal pathway and a substrate of the
ras/raf signal pathway in said single cells with a positive diagnosis of tumor
disease or infection.

STATEMENT OF THE CASE
The following claims are representative:
43. Method for diagnosing a tumor disease and/or an infection in a living
being in vitro, comprising:
(a) providing leucocytes to be analyzed from said living being,
(b) analyzing in said leucocytes the phosphorylation state of a
retinoblastoma protein involved in the regulation of the cell cycle and the
phosphorylation state of a MAP kinase involved in the regulation of the cell
cycle, wherein said retinoblastoma protein is involved in the regulation of
the cell cycle at a first time in normal cells and said MAP kinase is
involved in the regulation of the cell cycle at a second time in normal cells,
and
(c) correlating the finding of simultaneous phosphorylation states
of said retinoblastoma protein and said MAP kinase in said leucocytes with a
positive diagnosis.

44. Method for diagnosing a tumor disease and/or an infection in a living
being in vitro, comprising:
(a) providing single cells to be analyzed from said living being,
(b) analyzing in said single cells the activity of a substrate of the
CDK2 signal pathway involved in the regulation of the cell cycle and the
activity of a substrate of the ras/raf signal pathway involved in the regulation
of the cell cycle, wherein said substrate of the CDK2 signal pathway is
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involved in the regulation of the cell cycle at a first time in normal cells and
said substrate of the ras/raf signal pathway is involved in the regulation of
the cell cycle at a second time in normal cells, and
(c) correlating the finding of simultaneous activities of said
substrate of the CDK2 signal pathway and said substrate of the ras/raf signal
pathway in said single cells with a positive diagnosis.

Cited References

The Examiner relies on the following evidence:

Perez et al. (hereinafter Perez I) US 2005/0112700 A1 May 26, 2005
Perez et al. (hereinafter Perez II) US 2006/0073474 A1 Apr. 6, 2006

Cell Signaling Technology, Catalog #2181, Phospo-Rb (Ser608) Antibody,
http://www.cellsignal.com/product.asp?catalog%5Fname=CellSignal&categ
ory%5Fname= (2006).

Irish et al., Single Cell Profiling of Potentiated Phospho-Protein Networks in
Cancer Cells, 118 Cell 217-228 (2004).

Appellants rely on the following evidence:

Declaration of Dr. Gernot Stuhler, submitted under the provisions of 37
C.F.R. § 1.131, dated August 7, 2006 (“1st Decl.”).

Declaration of Dr. Gernot Stuhler, submitted under the provisions of 37
C.F.R. § 1.132, dated May 4, 2007 (“2nd Decl.”).

Grounds of Rejection
1. Claim 44 is rejected under 35 U.S.C. § 112, first paragraph for failing
to comply with the written description requirement.
2. Claims 43-47 are rejected under 35 U.S.C. § 112, first paragraph for
failing to comply with the enablement requirement.
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3. Claims 43-47 are rejected under 35 U.S.C. § 103(a) over Perez I in
view of Cell Signaling.

FINDINGS OF FACT

1. The Examiner finds that “claim [44] encompasses a method for
diagnosing any tumor disease and any type of an infection in a living being,
comprising (a) providing any type of single cells to be analyzed from
anywhere within the subject and (b) analyzing the activity of any of the
possible substrates of the entire CDK2 signal pathway, and any of numerous
substrates of the entire ras/raf signal pathway.” (Ans. 3.)
2. The Specification states that on a single cell level, the intracellular
molecules, such as factors of the signal transduction cascade, appear
essentially simultaneously in transformed or infected biological cells, but not
in normal, nontransformed or uninfected cells. (Spec. 19, 30.)
3. According to the Specification, the two molecules with which the cell
substance reacts refers to “cell-owned” compounds such as, for example,
enzymes, which differ from each other in their activity or/and specificity
or/and affinity for or/and accessibility to reactants or in other characteristics.
These molecules do not appear simultaneously in normal, i.e. in non-
transformed or non-infected cells. These differences in the chronological
order of appearance of the two molecules, which can be observed in single
normal cells, can, for example, be the result of cell cycle-specific regulatory
mechanisms. It is known, for example, that cyclin-dependent kinases (CDK)
are regulated both in their activity as well as their availability over the cell
cycle, so that these proteins only appear at times in the cell cycle. The
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phenomenon of the non-simultaneous appearance of the molecules in
question in single normal cells can be traced back to other regulatory intra-
and extra-cellular phenomena, such as for example time-coordinated
mitogenic impulses. (Spec. 7-8.)
4. According to the Specification, “non-simultaneous appearance
of the two molecules means that these two molecules either are not present
at the same time in one normal single cell, or are not active at the same time,
or do not display their activity at the same time or in the same manner. That
is to say, that simultaneously on the contrary means that in a transformed or
infected cell these two molecules are present or active in one single cell
essentially at the same time, i.e. over longer times within the cell cycle or in
the arrested state of the cell (GO phase) and not just punctiform.” (Spec. 8.)
“This concurrence in transformed or/and infected cells means, that the two
molecules appear essentially simultaneously in each single cell.” (Id.)
5. According to the Specification, it is shown “on a single cell level, that in
transformed and infected cells, both the ras/raf as well as the CDK2 signal
transduction cascade is largely proceeding simultaneously over longer times,
resulting in the simultaneous appearance of the activities of the single factors
of the corresponding two signal cascades, such as of, for example, the MAP
kinase and the CDK2 kinase, in transformed or infected cells.” (Spec. 14.)
5. According to the Specification, the substance which is a substrate for the
at least two molecules “can also be designed in such a way, that the property
in question is induced, when a reaction with an enzymes occurs, which are
involved in at least two other such signal transduction cascades which do not
proceed simultaneously in normal or healthy cells. Examples of such
enzymes can be found under:
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http://www.infobiogen.fr/services/chromcancer/ or http : / / www.ncbi.nlm.
nih.gov/antrez/que~ = searc&DB=omim (enter: "cancer"), the content of
these web pages is incorporated into the present application by reference.
Further examples are given in the article of Hahn and Weinberg. (2002)
. . . According to a preferred embodiment, the substance
according to the invention is a substrate for the at least two molecules.”
(Spec. 15.)
6. According to the 2nd Declaration of Dr. Stuhler, “[t]he fact that certain
tumors are associated with defined and described alterations of signaling
molecule activities simplifies the selection of further suitable molecule pairs
for a person skilled in the art.” (Decl. 4.) For example, in the case of colon
carcinoma, potential candidate molecules would be selected which are
published in the literature and a publically available under Vogelstein et al.
(2004) or http://atlasgeneticsoncology.org or www.infobiogen.fr./services/
chromcancer/ (id.).
7. The Specification states that the ras/raf signal transduction pathway
results in an activation of the MAP kinase (mitogen-activated protein kinase,
also called ERK1) via a cascade of phorphorylation events. The CDK2
signal transduction pathway results in an activation of the cyclin-dependent
kinase 2 via the stimulation of transcription. “According to the invention,
the CDK2 kinase can consist of the catalytic subunit cdk2 and the regulatory
subunit cyclin A, as well as of the cdk2 subunit and cyclin E. subunit.
Furthermore, any active CDK2 kinase is considered.” (Spec. 13-14.)

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Discussion
Written Description
ISSUE
The Examiner concludes with respect to claim 44 that:
The claim encompasses a method for diagnosing any tumor
disease and any type of an infection in a living being, comprising (a)
providing any type of single cells to be analyzed from anywhere
within the subject and (b) analyzing the activity of any of the possible
substrates of the entire CDK2 signal pathway, and any of numerous
substrates of the entire ras/raf signal pathway.
The claims encompass an enormous number of molecules that
may appear in single cells and given the guidance of the specification
and state of the art, whose activity must additionally be correlated
with the presence of a tumor or infection. The claims thus constitute a
claimed genus that encompasses cellular molecules whose activities
relative to each other and disease or infection has not been
established, and constitutes a reach through to an enormous number of
embodiments that have yet to be established or discovered.

(Ans. 3.)

Appellants argue that:
In their current form … the claims are not applicable to any
arbitrary pair of molecules. Specifically, claim 43 recites a particular
molecule pair: a MAP kinase and retinoblastoma protein. Similarly,
claim 44 recites molecule pairs from only two signal pathways: the
CDK2 and ras/raf signal pathways. The recited proteins and pathways
encompass the experimental results for which the diagnosis of specific
tumor cells has already been demonstrated to be enabled (i.e., in both
Example 1 of the specification and the additional declaration of Dr.
Stuhler ("second Stuhler declaration") accompanying Amendment
“B”). Further, the second Stuhler declaration sets forth a general
procedure that would have only required routine experimentation by a
skilled artisan to identify other suitable molecule pairs in the CDK2
and ras/raf signal pathways.

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(App. Br. 14.)

The issue is: Does the written description support the pending claim
scope?

ANALYSIS

1. Claim 44 is rejected under 35 U.S.C. § 112, first paragraph for failing
to comply with the written description requirement.
We are persuaded by Appellants’ argument with respect to claim 44.
“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).
Claim 44 recites molecule pairs from two signal pathways: the CDK2
and ras/raf signal pathways. In the present case the description evidences
that the Appellants were in possession of substrates of the CDK2 and ras/raf
pathways known in the art or could determine such substrates without undue
experimentation. See 2nd Declaration of Dr. Stuhler, May 14, 2007, pages 3-
6; FF6. Upon reading the disclosure and selecting substrates of the CDK2
and ras/raf pathways known in the art, one of ordinary skill in the art could
readily correlate the finding of simultaneous activities of said substrate of
the CDK2 signal pathway and said substrate of the ras/raf signal pathway in
said single cells with a positive diagnosis in a tumor or infected cell. The
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evidence in the Dr. Stuhler’s 2nd Declaration supports a finding that one of
ordinary skill in the art had possession of a genus of substrates of the CDK2
and ras/raf pathways known in the art. Thus, one of ordinary skill in the art
was in possession of the invention as claimed.
The written description rejection of claim 44 is reversed.

Enablement
2. Claims 43-47 are rejected under 35 U.S.C. § 112, first paragraph for
failing to comply with the enablement requirement.
“[A]s part of the quid pro quo of the patent bargain, the applicant's
specification must enable one of ordinary skill in the art to practice the full
scope of the claimed invention… That is not to say that the specification
itself must necessarily describe how to make and use every possible variant
of the claimed invention, for the artisan's knowledge of the prior art and
routine experimentation can often fill gaps, interpolate between
embodiments, and perhaps even extrapolate beyond the disclosed
embodiments, depending upon the predictability of the art.” AK Steel Corp.
v. Sollac, 344 F.3d 1234, 1244 (Fed. Cir. 2003). “The specification need not
explicitly teach those in the art to make and use the invention; the
[enablement] requirement is satisfied if, given what they already know, the
specification teaches those in the art enough that they can make and use the
invention without ‘undue experimentation.’” Amgen, Inc. v. Hoechst Marion
Roussel, Inc., 314 F.3d 1313, 1334 (Fed. Cir. 2003).
We are not convinced by the Examiner’s fact finding with respect to
the Wands factors and the enablement rejection. We conclude that upon
reading the disclosure and selecting substrates of the CDK2 and ras/raf
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pathways known in the art, one of ordinary skill in the art could readily
correlate the finding of simultaneous activities of said substrate of the CDK2
signal pathway and said substrate of the ras/raf signal pathway in said single
cells with a positive diagnosis in a tumor or infected cell. Such selection and
correlation would not require undue experimentation, especially in view of
the Dr. Stuhler’s assertion that substrates of the CDK2 and ras/raf pathways
were known in the art at the time of filing of the application. (2nd Decl.;
FF6.)
The rejection of the claims for lack of enablement is reversed.

Obviousness

3. Claims 43-47 are rejected under 35 U.S.C. § 103(a) over Perez I in
view of Cell Signaling.

ISSUE

• The Examiner finds that Perez I with Cell Signaling supports
the rejection of the claims.

• Appellants argue that Perez I is not available as a reference and
the obviousness rejection should be reversed.

FINDINGS OF FACT
8. The present application was filed October 8, 2004.
9. Appellants filed a Declaration under 37 CFR §1.131 indicating that
the claimed invention was made before July 22, 2004. (1st Decl.
1.)10. Perez I has a publication date of May 26, 2005 and filing date
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of July 21, 2004. Perez I is a continuation in part of Application No
10/193,462 (Perex II.)
11. Perez II has a publication date of April 6, 2006 and a filing date
of July 10, 2002.

Appellants submit a Declaration under 37 CFR 1.131 swearing behind
the date of the Perez I reference, thus “Perez I is not available as a
reference”, except under 35 U.S.C. §102(e) and only if Perez II supports the
relied upon disclosure of Perez I. (Ans. 14.) The Examiner further
acknowledges that Perez I and II do not “describe the retinoblastoma protein
as the first molecule involved in the regulation of cell cycle,” as claimed in
claim 43 (Ans. 13).
Upon review of the evidence before us, we conclude that Perez II does
not support the relied upon disclosure of Perez I under 35 USC §112, first
paragraph. Thus, we agree with Appellants that the Examiner has not set
forth a prima facie case of a disclosure or suggestion in the prior art, Perez
II, of a step of (c) “correlating the finding of simultaneous activities of said
substrate of the CDK2 signal pathway and said substrate of the ras/raf signal
pathway in said single cells with a positive diagnosis” found in claim 44 or a
step of (c) “correlating the finding of simultaneous phosphorylation states of
said retinoblastoma protein and said MAP kinase in said leucocytes with a
positive diagnosis” of claim 43.
The obviousness rejection over Perez I in view of Cell Signaling is
reversed.

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REVERSED
alw

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