Ex Parte Dorsch et al

Board of Patent Appeals and Interferences

Jul 13, 2010

10486238 (B.P.A.I. Jul. 13, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DIETER DORSCH,
BERTRAM CEZANNE, CHRISTOS TSAKLAKIDIS,
WERNER MEDERSKI, JOHANNES GLEITZ,
and CHRISTOPHER BARNES

__________

Appeal 2009-012567
Application 10/486,238
Technology Center 1600
__________

Before CAROL A. SPIEGEL, DEMETRA J. MILLS, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL1

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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2
This appeal under 35 U.S.C. § 134 involves claims to methods of
inhibiting the activity of coagulation factors Xa and VIIa, as well as methods
of treating disorders involving those coagulation factors. The Examiner
rejected the claims as lacking written description and enablement.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
STATEMENT OF THE CASE
Claims 1, 6, 7, 9, 10, 12, 13-20, 22, and 24-34 are pending (App. Br.
1). Claim 14 stands objected to as depending from a rejected base claim
(Final Rejection 5). However, the Examiner withdrew the enablement
rejection of claims 1, 6, 7, 9, 10, 12, 13, 15, 18, 19, and 28-32 (Ans. 16).
Thus, the only rejections before us for review are the Examiner’s
rejections of claims 16-20, 22, 33, and 34 under 35 U.S.C. 112, first
paragraph, for lack of written description and enablement (id. at 4).
Claims 1, 16-18, and 20 illustrate the appealed subject matter and read
as follows:
Claim 1. A compound of the formula I

wherein
D is -CO-NH-CO, -CO-NH-CH2-, -NH-CH=CH-, -O-CH=CH-,
-N=CH-O-, -N=CH-NH-, -NH-NH-CO-, -NH-N=N-, -NH-CO-CH2-,
-NH-CO-O-, -N=CH-S-, -NH-CO-S-, -NH-CO-NH-, -O-NH-CO-,
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-NH-O-CO-, -N=CH-CH=CH-, -CH=N-CH=CH-, -N=N-CH=CH-,
-N=CH-N=CH-, -N=CH-CH=N-, -N=N-N=CH-, -NH-CO-CH=CH-,
-NH-CH=CH-CO-, -NH-CO-CH2-CH2-, -NH-CH2-CH2-CO-,
-NH-CO-N=CH-, -N=CH-NH-CO-, -NH-CO-NH-CO-,
-NH-CO-NH-CH2-, -CH=N-N=CH-, -N--S+=-N-, -O-CH2-O-,
-CH=N-NH-CO-, -CH=CH-NH-, -NH-N=CH-, -O-CH2CH2-O-,
-CO-NH-NH-CO-, -N=N-NH-CO-, -O-CO-NH-CH2-,
-O-CO-NH-CO-, -(CH2)3-, -CO-(CH2)2-,-(CH2)4-or-CO-(CH2)3-,
and wherein, the alkylene chain and/or a nitrogen located therein is
optionally mono-, di- or trisubstituted by A or NH2,
R1 is H,
R2 is H, A, -[C(R3)2]n-Ar,- [C(R3)2]n-Het or - [ C(R3)2]n- cycloalkyl,
R3 is H or A,
W is -C(R2)2-, -[C(R2)2]2-, -OC(R2)2- or –NR2C(R2)2-,
X is CONR2, CONR2 C(R3)2- C(R3)2NR2 or -C(R3)2NR2C(R3)2,
Y is alkylene, Het-diyl or Ar-diyl,
T is a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring
having 1 or 2 N and/or O atoms, which is optionally monosubstituted
or disubstituted by carbonyl oxygen, OH or OA,
A is unbranched or branched alkyl having 1-6 carbon atoms, in which
one or two CH2 groups may be replaced by O or S atoms and/or by -
CH=CH- groups and/or in addition 1-7 H atoms may be replaced by
F,
Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or
monosubstituted, disubstituted or trisubstituted by Hal, A, OR3,
N(R3)2, NO2, CN, COOR3,CON(R3)2, NR3COA, NR3C0N(R3)2,
NR3SO2A,COR3, SO2N(R3)2 or S(O)mA,
Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic
heterocyclic ring having from 1 to 4 N, O and/or S atoms, which may
be unsubstituted or monosubstituted, disubstituted or trisubstituted by
carbonyl oxygen, Hal, A, -[C(R3)2],-Ar, -[C(R3)2]n,-Het1,-[C(,R3)2]n,-
cycloalkyl, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA,
NR2C0N(R2)2, NR2SO2A, C0R2, SO2NR2 and/or S(O)mA,
Het1 is a monocyclic or bicyclic, saturated, unsaturated or aromatic
heterocyclic ring having 1 or 2 N, O and/or S atoms, which may be
unsubstituted or monosubstituted or disubstituted by carbonyl oxygen,
Hal, A, OR2, N(R2)2, NO2, CN, COOR2,CON(R2)2,NR2COA,
NR2C0N(R2)2, NR2SO2A, C0R2, SO2NR2 and/or S(O)mA,
Hal is F, C1, Br or I,
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n is 0, 1 or 2,
m is 0, 1 or 2,

or a pharmaceutically usable derivative, solvate or stereoisomer thereof, or a
mixture thereof.

Claim 16. A method of inhibiting the activity of coagulation factor
Xa comprising contacting said coagulation factor Xa with a
compound of claim 1.

Claim 17. A method of inhibiting the activity of coagulation factor
VIIa comprising contacting said coagulation factor VIIa with a
compound of claim 1.

Claim 18. A medicament comprising at least one compound of
Claim 1 and optionally comprising an excipient and/or an assistant.

Claim 20. A method for treating thromboses, myocardial infarction,
arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis
after angioplasty, claudicatio intermittens, migraine, tumours, tumour
diseases and/or tumour metastases comprising administering to a host
in need thereof an effective amount of a compound of claim 1.

The claims were subject to a restriction requirement in which
Appellants elected “compounds, compositions, process of making and
methods of treatment of the claims of formula (I) wherein D is
i.e. wherein D together with the
phenyl ring [is] a quinoline or quinolone moiety” (Ans. 2-3).

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WRITTEN DESCRIPTION
ISSUE
The Examiner finds that claims 16-20, 22, 33, and 34 lack descriptive
support because the Specification “does not adequately describe the nexus
between the modulation of the factor Xa receptor and a useful treatment of a
disease/condition” (Ans. 4).
Specifically, the Examiner reasons that modulating a receptor
“involves antagonism, inhibition, agonism and others. These modulations
are sometimes opposite reactions to the same receptor. It is not seen where
the instant specification adequately describes the nexus between the
modulation of the factor Xa receptor and a useful treatment of a single
disease or condition” (id.).
Appellants contend that none of their claims recite modulating factor
Xa, but instead recite methods of inhibiting coagulation factors Xa and VIIa
with compounds according to claim 1, as well as medicaments containing
the claimed compounds, and methods of treating disorders using the claimed
compounds (App. Br. 5). Appellants argue that the Specification discloses
the relationship between factors Xa and VIIa and thrombin formation, and
the fact that methods of assaying for inhibition of those factors were known
in the art (id. at 6).
Moreover, Appellants argue, the Specification discloses examples of
two compounds according to claim 1 that bind to those coagulation factors’
receptors in micromolar concentrations (id. at 7-8). Further, Appellants
urge, the Specification discloses that the correlation between the claim-
recited coagulation factors and related disorders was recognized in the art
(id. at 8).
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In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether the evidence of record
supports the Examiner’s finding that claims 16-20, 22, 33, and 34 lack
adequate descriptive support in the Specification.
FINDINGS OF FACT (“FF”)
1. The Specification discloses:
Factor Xa is one of the proteases involved in the complex
process of blood coagulation. Factor Xa catalyses the
conversion of prothrombin into thrombin. Thrombin cleaves
fibrinogen into fibrin monomers, which, after crosslinking,
make an elementary contribution to thrombus formation.
Activation of thrombin may result in the occurrence of
thromboembolic diseases. However, inhibition of thrombin may
inhibit the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for example, by
the method of G. F. Cousins et al. in Circulation 1996, 94,
1705-1712.

(Spec. 4.)
2. The Specification discloses:
The inhibition of factor Xa by the compounds according to the
invention and the measurement of the anticoagulant and
antithrombotic activity can be determined by conventional in-
vitro or in-vivo methods. A suitable method is described, for
example, by J. Hauptmann et al. in Thrombosis and
Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example, by
the method of T. Hara et al. in Thromb. Haemostas. 1994, 71,
314-319.

(Spec. 4.)

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3. The Specification discloses:
Coagulation factor VIIa initiates the extrinsic part of the
coagulation cascade after binding to tissue factor and
contributes to the activation of factor X to give factor Xa.
Inhibition of factor VIIa thus prevents the formation of factor
Xa and thus subsequent thrombin formation.

The inhibition of factor VIIa by the compounds according to
the invention and the measurement of the anticoagulant and
antithrombotic activity can be determined by conventional in-
vitro or in-vivo methods. A conventional method for the
measurement of the inhibition of factor VIIa is described, for
example, by H. F. Ronning et al. in Thrombosis Research 1996,
84, 73- 81.

(Spec. 4-5.)
4. The Specification discloses that the “antithrombotic and anticoagulant
effect of the compounds according to the invention is attributed to the
inhibitory action against activated coagulation protease, known by the name
factor Xa, or to the inhibition of other activated serine proteases, such as
factor VIIa, factor IXa or thrombin” (id. at 3).
5. Based on the antithrombotic/anticoagulant properties of the
compounds according to formula I, the Specification provides an extensive
list of “thromboembolic diseases, such as thrombosis, myocardial infarction,
arteriosclerosis, inflammation,” and other disorders, treatable using the
compounds (id. at 5-6).
6. The Specification states that the disclosed compounds “are
furthermore used in diseases in which blood coagulation makes a crucial
contribution to the course of the disease or represents a source of secondary
pathology, such as, for example, in cancer, including metastasis,
inflammatory diseases, including arthritis, and diabetes” (id. at 6).
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7. The Specification discloses:
The compounds according to the invention may furthermore be
used for the treatment of tumours, tumour diseases and/or
tumour metastases. A correlation between tissue factor TF /
factor VIIa and the development of various types of cancer has
been indicated by T. Taniguchi and N.R. Lemoine in Biomed.
Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic
Cancer), 57-59.
The publications listed below describe an antitumoral action of
TF-VII and factor Xa inhibitors in various types of tumour:
K.M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-
1047;
E.G. Fischer et al. in J. Clin. Invest. 104:1213-1221 (1999);
B.M. Mueller et al. in J. Clin. Invest. 101:1372-1378 (1998);
M.E. Bromberg et al. in Thromb. Haemost. 1999; 82:88-92

(Spec. 5.)
8. The Specification discloses that the “compounds according to the
invention are furthermore used for the treatment of migraine (F. Morales-
Asin et al., Headache, 40, 2000, 45-47)” (Spec. 6).
9. The Specification also discloses the following “[p]harmacological
data” (Spec. 34):

10. The Specification identifies compound AA as “N-[4-(2- oxopiperidin-
1-yl)phenyl]-2-(1-aminoisoquinolin-7-yloxy)pentanamide” and compound
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AB as “N-[4-(2- oxopiperidin-1-yl)phenyl]-2-(1-aminoisoquinolin-7-yloxy)-
2-phenylacetamide” (Spec. 32).
11. The Specification states that the compounds according to formula I
“can be converted here into a suitable dosage form together with at least one
solid, liquid and/or semi-liquid excipient or assistant and, if desired, in
combination with one or more further active ingredients” (Spec. 26).
12. The Specification provides a list of suitable excipients for the
disclosed compounds, as well as dosages suitable for “combating and
preventing thromboembolic diseases, such as thromboses, myocardial
infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris,
restenosis after angioplasty, claudicatio intermittens, tumours, tumour
diseases and/or tumour metastases” (Spec. 26-27).
13. The Specification discloses:
In the treatment of the diseases described, the compounds
according to the invention are also employed in combination
with other thrombolytically active compounds, such as, for
example, with “tissue plasminogen activator” t-PA, modified t-
PA, streptokinase or urokinase. The compounds according to
the invention are administered either at the same time as or
before or after the other substances mentioned.

(Spec. 6).
PRINCIPLES OF LAW
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . . 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.

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To meet the initial burden of establishing a prima facie case of
unpatentability based on a lack of written description, the Examiner must
“present[] evidence or reasons why persons skilled in the art would not
recognize in the disclosure a description of the invention defined by the
claims.” In re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996).
Thus, as the Federal Circuit recently stated in Ariad Pharmaceuticals,
Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010), the “test for
sufficiency is whether the disclosure of the application relied upon
reasonably conveys to those skilled in the art that that the inventor had
possession of the claimed subject matter as of the filing date.”
Beyond simple possession, however, the court explained that the “test
requires an objective inquiry into the four corners of the specification from
the perspective of a person of ordinary skill in the art. Based on that inquiry,
the specification must describe an invention understandable to that skilled
artisan and show that the inventor actually invented the invention claimed.”
Id.
The Court further noted that, “[f]or generic claims, we have set forth a
number of factors for evaluating the adequacy of the disclosure, including
‘the existing knowledge in the particular field, the extent and content of the
prior art, the maturity of the science or technology, [and] the predictability
of the aspect at issue.’” Id. (quoting Capon v. Eshhar, 418 F.3d 1349, 1359
(Fed. Cir. 2005).
Accordingly:
A claim will not be invalidated on section 112 grounds
simply because the embodiments of the specification do not
contain examples explicitly covering the full scope of the claim
language. That is because the patent specification is written for
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a person of skill in the art, and such a person comes to the
patent with the knowledge of what has come before. Placed in
that context, it is unnecessary to spell out every detail of the
invention in the specification; only enough must be included to
convince a person of skill in the art that the inventor possessed
the invention and to enable such a person to make and use the
invention without undue experimentation.

Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006) (quoting
LizardTech, Inc. v. Earth Resource Mapping, PTY, Inc., 424 F.3d 1336,
1345 (Fed.Cir.2005)); see also Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed.
Cir. 2005) (“It is not necessary that every permutation within a generally
operable invention be effective in order for an inventor to obtain a generic
claim, provided that the effect is sufficiently demonstrated to characterize a
generic invention.”)
ANALYSIS
We agree with Appellants that a preponderance of the evidence of
record does not support the Examiner’s finding that claims 16-20, 22, 33,
and 34 lack adequate descriptive support in the Specification.
We first note that the Examiner focuses principally on the therapeutic
treatments recited in claims 20, 22, 33, and 34. Claims 16 and 17, however,
do not recite treatment methods, but instead only require “inhibiting the
activity of coagulation factor Xa” (claim 16) and “inhibiting the activity of
coagulation factor VIIa” (claim 17) by contacting the factors with a
compound of claim 1.
As noted above, the Specification discloses that two compounds,
which the Examiner does not dispute as being within the scope of claim 1,
inhibit binding of factors Xa and VIIa to their respective receptors at
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micromolar concentrations (FF 9). The Examiner concedes that this
amounts to “in vitro inhibitory data” (Ans. 11). The Examiner argues,
however:
[T]he two compounds tested have only a phenyl vs. propyl
difference and their activities for FXa-IC50(M) are the same
but their activities for TF/FVIIa-IC50(M) differ by 0.2x10-7.
The markush of compounds encompassed by the instant
formula I have a much wider variance than just phenyl vs.
propyl. This shows the unknown and experimental nature of
what is being instantly claimed.

(Id.)
We are not persuaded. The Specification provides examples of two
compounds the Examiner concedes as capable of inhibiting the coagulation
factors recited in claims 16 and 17, and further asserts that other compounds
encompassed by the claims will act the same way. In contrast, the Examiner
provides no specific evidence suggesting that an ordinary artisan would
consider this assertion to be erroneous.
The fact that every compound encompassed by the claims might not
inhibit the coagulation factors does not demonstrate absence of description.
See Capon v. Eshhar, 418 F.3d at 1359 (“It is not necessary that every
permutation within a generally operable invention be effective in order for
an inventor to obtain a generic claim, provided that the effect is sufficiently
demonstrated to characterize a generic invention.”).
As the Examiner does not point to any specific evidence suggesting
that the claimed compounds will not function as required by claims 16 and
17, a preponderance of the evidence does not support the Examiner’s finding
that claims 16 and 17 lack descriptive support. We therefore reverse the
Examiner’s written description rejection of those claims.
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Claims 18 and 19 also do not recite the treatment methods the
Examiner focuses on. Rather, those claims recite medicaments that contain
a compound according to claim 1 in combination with an excipient (claim
18) or a further active ingredient (claim 19).
As noted above, the Specification provides examples of two
compounds according to formula I conceded by the Examiner as capable of
inhibiting factors Xa and VIIa (FF 9), and also discloses suitable excipients
and additional antithrombotic agents that may be combined with those
compounds, as well as dosages that may be used to treat thromboembolic
diseases (FF 12-13). Given these disclosures, and the absence of any
specific evidence showing that the medicaments would fail to inhibit
thrombosis formation, a preponderance of the evidence supports Appellants’
position that claims 18 and 19 are adequately described in the Specification.
We therefore reverse the Examiner’s rejection of claims 18 and 19 for lack
of written description.
Claims 20, 22, 33, and 34, as the Examiner points out, recite treating a
number of disorders, including, for example, “thromboses, myocardial
infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris,
restenosis after angioplasty, claudicatio intermittens, migraine, tumours,
tumour diseases and/or tumour metastases” (claim 20) by administering an
effective amount of a compound of claim 1.
The Examiner finds that claims 20, 22, 33, and 34 lack descriptive
support, given the breadth of compounds encompassed by claim 1 (Ans. 12).
Moreover, the Examiner argues:
[P]age 8 [of the Specification] last line states that
activation of thrombin may result in the occurrence of
thromboembolic diseases. The specification cannot state that
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activation of thrombin results in the occurrence of
thromboembolic diseases. This has not been positively linked
in the instant specification or in the prior art of record. The art
knows that thrombus formation relates to many diseases
instantly claimed. However, the instant compounds have not
been shown to inhibit thrombus formation.

(Id.)
We are not persuaded. The Examiner points to no specific evidence
suggesting that an ordinary artisan would have failed to recognize that
Appellants invented the treatment methods recited in claims 20, 22, 33, and
34.
To the contrary, the Examiner does not dispute that the Specification
describes two compounds that inhibit factors Xa and VIIa, nor does the
Examiner dispute, as described in the Specification, that those factors are
critical to thrombus formation. The Examiner further concedes that
thrombus formation “relates to many diseases instantly claimed” (id.).
Moreover, as Appellants point out, the Specification discloses the link
between inhibiting factors Xa and VIIa and thromboembolic diseases (FF 4-
5), as well as disorders in which blood coagulation represents a source of
secondary pathology (FF 6), and also discloses the art-recognized link
between factor VIIa and Xa inhibitors and antitumor activity (FF 7), as well
as migraine treatment (FF 8).
Given the lack of specific evidence presented by the Examiner,
contrasted with the Specification’s disclosure of compounds that inhibit
factors Xa and VIIa, the disclosure of the link between inhibition of factors
Xa and VIIa and thrombus formation, as well as the art-recognized capacity
of inhibitors of those factors to treat a number of disorders, we find that a
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preponderance of the evidence does not support the Examiner’s position that
claims 20, 22, 33, and 34 lack descriptive support. Accordingly, we reverse
the Examiner’s rejection of those claims for lack of written description.

ENABLEMENT
ISSUE
Applying the oft-cited factors set forth in In re Wands, 858 F.2d 731,
737 (Fed. Cir. 1988), the Examiner concludes that practicing the subject
matter recited in claims 16-20, 22, 33, and 34 would have required undue
experimentation (Ans. 5-9).
Specifically, the Examiner finds that, despite a high skill level, the
pharmaceutical arts are highly unpredictable, and therefore,
in the absence of a showing of a nexus between any and all
known diseases and the modulation of factor Xa receptors, one
of ordinary skill in the art is unable to fully predict possible
results from the administration of the compound of claim 1 due
to the unpredictability of the role of modulation of Factor Xa
receptors.

(Id. at 6.)
The Examiner further contends that in vitro tests generally do not
correlate with clinical activity, as evidenced by Freshney2 and Dermer,3 and
that given the absence of working examples of treating thromboses,
inflammation, migraine, or cancer, and the lack of guidance regarding
thrombus inhibition, “[o]ne skilled in the art would need to determine what

2 R. IAN FRESHNEY, CULTURE OF ANIMAL CELLS, A MANUAL OF BASIC
TECHNIQUE 4 (1983).
3 Gerald B. Dermer, Another Anniversary for the War on Cancer, 12
BIO/TECHONOLOGY 320 (1994).
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diseases out of all known diseases would be benefited by the mediation of
factor Xa receptors and then would further need to determine which of the
claimed compounds would provide treatment of the disease” (id. at 8).
Appellants contend that the PTO must consider a specification to be
enabling “unless there is reason to doubt the objective truth of statements
contained therein relied on for enabling support” (App. Br. 10 (quoting In re
Marzocchi, 439 F.2d 220, 223 (CCPA 1971)). Thus, Appellants argue, the
“rejection fails to present sufficient evidence to doubt the objective
enablement provided in Appellants' specification that claimed compounds
exhibit inhibitory activity with respect to factor Xa and factor VIIa” (id.).
Appellants argue that the Freshney and Dermer publications are not
adequate to show that in vitro assays fail to predict in vivo activity, given the
ages of the references at the time the instant application was filed, and given
the Fiebig4 disclosure, which is asserted to show the current view of the
predictability of in vitro tests vis-à-vis in vivo treatments (id. at 13).
Moreover, Appellants argue, the Federal Circuit has recognized that in vitro
results are generally predictive of pharmacological activity (id. at 14 (citing
Cross v. Iizuka, 753 F.2d 1040, 1050 (Fed. Cir. 1985) and Fujikawa v.
Wattanasin, 93 F.3d 1559, 1564 (Fed. Cir. 1996).
In view of the positions advanced by Appellants and the Examiner,
the issue with respect to this rejection is whether the Examiner has
adequately explained why an ordinary artisan would have doubted the

4 H.H. Fiebig et al., Clonogenic assay with established human tumour
xenografts: correlation of in vitro to in vivo activity as a basis for anticancer
drug discovery, 40 European Journal of Cancer 802-820 (2004).
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assertions in the Specification, and would instead have expected that
practicing the claimed processes would require undue experimentation.
FINDINGS OF FACT
14. Freshney discloses:
Many of the differences in cell behavior between
cultured cells and their counterparts in vivo stem from the
dissociation of cells from a three-dimensional geometry and
their propagation on a two-dimensional substrate. Specific cell
interactions characteristic of the histology of the tissue are lost,
and, as the cells spread out, become mobile, and, in many cases,
start to proliferate, so the growth fraction of the cell population
increases. When a cell line forms, it may represent only one or
two cell types, and many heterotypic cell-cell interactions are
lost.

(Freshney 4.)

15. Freshney discloses:
The [cell] culture environment also lacks the several
systemic components involved in homeostatic regulation in
vivo, principally those of the nervous and endocrine systems.
Without this control, cellular metabolism may be more constant
in vitro than in vivo, but may not be truly representative of the
tissue from which the cells were derived. Recognition of this
fact has led to the inclusion of a number of different hormones
in culture media . . ., and it seems likely that this trend will
continue.

(Id.)

16. Freshney discloses:

It is not difficult to find many more differences between
the environmental conditions of a cell in vitro and in vivo . . . ,
and this disparity has often led to tissue culture being regarded
in a rather skeptical light. Still, although the existence of such
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differences cannot be denied, many specialized functions are
expressed in culture, and as long as the limits of the model are
appreciated, tissue culture can become a very valuable tool.

(Id.)
17. Dermer discloses that the reason no cancer cure has yet been
discovered is because the “cell lines in which cancer is usually studied are
unsuitable for the job. They do not mimic conditions in the human body”
(Dermer 320).
18. Dermer discloses that cell lines “have become the standard for
determining what cancer should be like. The facts indicate, however, that
petri dish cancer is really a poor representation of malignancy, with
characteristics profoundly different from the human disease” (id.).
PRINCIPLES OF LAW
The Examiner bears the burden of establishing that practicing the full
scope of the claimed subject matter would have required undue
experimentation. In re Wright, 999 F.2d 1557, 1561-62, 27 USPQ2d 1510,
1513 (Fed. Cir. 1993) (“[T]he PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of protection
provided by that claim is not adequately enabled by the description of the
invention provided in the specification of the application.”) .
Enablement is not precluded by the necessity for some
experimentation such as routine screening. However,
experimentation needed to practice the invention must not be
undue experimentation. . . . The test is not merely quantitative,
since a considerable amount of experimentation is permissible,
if it is merely routine, or if the specification in question
provides a reasonable amount of guidance with respect to the
direction in which the experimentation should proceed.

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In re Wands, 858 F.2d at 736-37 (citations omitted).
Moreover, “[working] examples are not required to satisfy section
112, first paragraph.” In re Strahilevitz, 668 F.2d 1229, 1232 (CCPA 1982).
For example, in Falko-Gunter v. Inglis, the court affirmed this Board’s
conclusion that claims to a modified pox virus vaccine were enabled, despite
the fact that the specification focused on viruses other than pox virus,
provided no examples directed to pox virus, and discussed pox virus only in
general terms relating to the inventive disclosure. Falko-Gunter, 448 F.3d at
1365.
Also, a claim does not lack enablement merely because it
encompasses inoperative embodiments. Atlas Powder Co. v. E.I. du Pont
De Nemours & Co., 750 F.2d 1569, 1576 (Fed. Cir. 1984); see also In re
Angstadt, 537 F.2d 498, 502-503 (CCPA 1976).
ANALYSIS
We agree with Appellants that a preponderance of the evidence does
not support the Examiner’s position that an ordinary artisan would have
doubted the assertions in the Specification and would have expected that
practicing the claimed processes would require undue experimentation.
The Examiner’s position is essentially that the Specification fails to
meet the “how to use” element of 35 U.S.C. 112, first paragraph. Claims 16
and 17, however, only require “inhibiting the activity of coagulation factor
Xa” (claim 16) and “inhibiting the activity of coagulation factor VIIa”
(claim 17) by contacting the factors with a compound of claim 1.
As noted above, the Specification discloses that two compounds,
which the Examiner does not dispute as being within the scope of claim 1,
inhibit binding of factors Xa and VIIa to their respective receptors at
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micromolar concentrations (FF 9). As also noted above, the Examiner
concedes that this amounts to “in vitro inhibitory data” (Ans. 11).
Moreover, the Specification discloses, and the Examiner does not
dispute, that processes for determining inhibition of factors Xa and VIIa
were known in the art (FF 2, 3). Given that processes of assaying for
inhibition of the claim-designated coagulation factors were known in the art,
and given data in the Specification conceded by the Examiner as showing
that compounds encompassed by the claims in fact inhibit those factors, we
are not persuaded that an ordinary artisan would have expected that undue
experimentation would be required to practice the processes recited in
claims 16 and 17. We therefore reverse the Examiner’s enablement
rejection of those claims.
As noted above, claims 18 and 19 recite medicaments that contain a
compound according to claim 1 in combination with an excipient (claim 18)
or a further active ingredient (claim 19). As also noted above, claims 20, 22,
33, and 34 recite methods of treating a variety of disorders including, for
example, “thromboses, myocardial infarction, arteriosclerosis, inflammation,
apoplexia, angina pectoris, restenosis after angioplasty, claudicatio
intermittens, migraine, tumours, tumour diseases and/or tumour metastases”
(claim 20) by administering an effective amount of a compound of claim 1.
We agree with Appellants that the Examiner has not advanced
sufficient specific evidence to cast doubt on Appellants’ presumptively
enabling disclosure with respect to these claims. As Appellants point out,
the Specification discloses that methods of assaying thrombin inhibition
were known in the art (FF 1), and that the claimed compounds have
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antithrombotic and anticoagulant properties rendering them useful in treating
a number of conditions (FF 4-5)
We acknowledge, as the Examiner argues, that cell culture might not
precisely mimic the conditions under which cells exist in vivo, and that
results obtained from testing cultured cells might not necessarily correlate
with results that would be obtained clinically (FF 14-18). However, the
Examiner has not explained how or why the potential predictive
shortcomings of cell culture vis-à-vis in vivo treatments relate to treating the
specifically claimed disorders, which, according to Appellants’ Specification
involve only disrupting the blood’s coagulation cascade (FF 4).
In this regard, we note Freshney’s statement that “as long as the limits
of the model are appreciated, tissue culture can become a very valuable tool”
(FF 15). We are therefore not persuaded that a skilled artisan would view
Freshney as representing a categorical refutation of the predictive value of in
vitro testing methods, much less a refutation of the value of testing methods
that would be relevant to the claimed disorders.
We also acknowledge that Dermer takes issue with the approach of
using cell lines to investigate cancer (FF 17, 18). The Examiner has not
adequately explained, however, how this generalized teaching would have
led a skilled artisan to question the specific disclosures cited in the
Specification as support for treating tumors and migraines (FF 7-8).
In sum, the Specification discloses generally that the claimed
compounds possess antithrombotic activity, and in support of that,
specifically demonstrates that two of those compounds inhibit two of the
coagulation factors involved in thrombus formation. The Specification also
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discloses that methods of assaying inhibition of those factors, as well as
thrombus inhibition, were known in the art.
The Specification also contains art-supported disclosure that
compounds with such inhibitory properties are useful in treating a number of
the claimed disorders. The Examiner provides no evidence specifically
disputing the veracity of these disclosures.
We are therefore not persuaded that the Examiner has made a prima
facie case of lack of enablement with respect to claims 18, 19, 20, 22, 33,
and 34. As a preponderance of the evidence does not support the
Examiner’s position, we reverse the Examiner’s enablement rejection of
those claims.

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SUMMARY
We reverse the Examiner’s rejection of claims 16-20, 22, 33, and 34
under 35 U.S.C. § 112, first paragraph, as failing to comply with the written
description requirement.
We also reverse the Examiner’s rejection of claims 16-20, 22, 33, and
34 under 35 U.S.C. § 112, first paragraph, for lack of enablement.

REVERSED

alw

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