Ex Parte Dumas et al

Board of Patent Appeals and Interferences

Feb 10, 2009

09838286 (B.P.A.I. Feb. 10, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JACQUES DUMAS, BERND RIEDL, UDAY KHIRE,
ROBERT N. SIBLEY, HOLIA HATOUM-MOKDAD,
MARY-KATHERINE MONAHAN, DAVID E. GUNN,
TIMOTHY B. LOWINGER, WILLIAM J. SCOTT,
ROGER A. SMITH, and JILL E. WOOD
__________

Appeal 2008-3379
Application 09/838,286
Technology Center 1600
__________

Decided1: February 10, 2009
__________

Before DEMETRA J. MILLS, ERIC GRIMES, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 CFR § 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 2008-3379
Application 09/838,286

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating diseases mediated by p38. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.

Statement of the Case
Background
“The mitogen-activated protein (MAP) kinase family is made up of a
series of structurally related proline-directed serine/threonine kinases which
are activated either by growth factors . . . and phorbol esters . . . or by IL-1,
TNFα or stress (p38 . . .)” (Spec. 1:32-34). The Specification teaches that
“inhibition of p38 has been shown to inhibit both cytokine production (eg.,
TNFα, IL-1, IL-6, IL-8) and proteolytic enzyme production (eg., MMP-1,
MMP-3) in vitro and/or in vivo” (Spec. 2, ll. 11-13). According to the
Specification,
Inhibitors of p38 are active in animal models of TNFα
production, including a muirne [sic, murine]
lipopolysaccharide (LPS) model of TNFα production.
Inhibitors of p38 are active in a number of standard animal
models of inflammatory diseases, including carrageenan-
induced edema in the rat paw, arachadonic acid-induced
edema in the rat paw, arachadonic acid-induced peritonitis in
the mouse, fetal rat long bone resorption, murine type II
collagen-induced arthritis, and Fruend's [sic, Freund’s]
adjuvant-induced arthritis in the rat.

(Spec. 5, ll. 20-26).
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The Claims
Claims 50 and 52-56 are on appeal. We will focus on claim 50, which
is representative and reads as follows:

50. A method of treating a disease mediated by p38
within a host, said method comprising administering to said
host a compound of Formula I:
A- D- B (I)
or a pharmaceutically acceptable salt thereof, wherein
D is -NH-C(O)-NH-,
A is a substituted t-butylpyridinyl, unsubstituted
t-butylpyridinyl, substituted (trifluoromethyl)pyridyl,
unsubstituted (trifluoromethyl)pyridyl, substituted
isoquinolinyl, unsubstituted isoquinolinyl, substituted
quinolinyl or unsubstituted quinolinyl, and
B is a substituted or unsubstituted, phenyl naphthyl,
pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl or a bridged
cyclic structure of the formula -L(ML1)q, wherein q is an
integer of 1-3, and L1 and L are each independently
thiophene, substituted thiophene, phenyl, substituted phenyl,
naphthyl, substituted naphthyl, pyridinyl, substituted
pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl
substituted quinolinyl, isoquinolinyl or substituted
isoquinolinyl and M is -O-, -CH2-, -S-, -NH-, -C(O)-,
-O-CH2-or -CH2-O-, with cyclic structure L bound directly
to D,
wherein the substituents for A are selected from the
group consisting of halogen, up to per-halo, and Wn, where
n is 0-3 and each W is independently selected from the
group consisting of
C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having at
least a five cyclic members and 0-3 heteroatoms selected
from N, S and O; C2-10 alkenyl, CH1-10 alkenoyl, C6-C14 aryl,
C7-C24 alkaryl, C7-C24 aralkyl, C3-C12 heteroaryl having at
least 5 cyclic members and 1-3 heteroatoms selected from
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Application 09/838,286

O, N and S, C4-C24 alkheteroaryl having at least 5 cyclic
members and 1-3 heteroatoms selected from O, N and S;
substituted C1-10 alkyl, substituted C1-10 alkoxy,
substituted C3-10 cycloalkyl having at least 5 cyclic members
and 0-3 heteroatoms selected from N, S and O; substituted
C2-10 alkenyl, substituted C1-10 alkenoyl, substituted C6-C14
aryl, substituted C7-C24 alkaryl, substituted C7-C24 aralkyl,
substituted C3-C12 heteroaryl having at least 5 members and
1-3 heteroatoms selected from O, N and S, substituted C4-
C24 alkheteroaryl having at least 5 members and 1-3
heteroatoms selected from O, N and S,
-CN, -CO2R7, -C(O)NR7R7', -C(O)-R7, -NO2, -OR7,
-SR7, -NR7R7', -NR7C(O)OR7', -NR7C(O)R7', with each R7
and R7' independently selected from hydrogen, C1-10 alkyl,
CH1-10 alkoxy, C2-10 alkenyl, C1-10 alkenoyl, up to per
halosubstituted C1-10 alkyl, up to per halosubstituted C1-10
alkoxy, up to per halosubstituted C2-10 alkenyl and up to per
halosubstituted CH1-10 alkenoyl, C3-C10 cycloalkyl having at
least 5 cyclic members and 0-3 heteroatoms selected from
O, S and N, C6-C14 aryl, C3-C10 hetaryl having at least 6
cyclic members and 0-3 heteroatoms selected from O, S and
N, up to per halo substituted C3-C10 cycloalkyl having at
least 5 cyclic members and 0-3 heteroatoms selected from
O, S and N, up to per halo substituted C6-C14 aryl and up to
per halo substituted C3-C10 hetaryl having at least 6 cyclic
members and 0-3 heteroatoms selected from O, S and N,
where W is a substituted group, it is substituted by
halogen, up to per halo, or by one or more substituents
independently selected from the group consisting of -CN,
-CO2R7, -C(O)NR7R7', -C(O)-R7, -NO2, -OR7, -SR7,
-NR7R7', -NR7C(O)OR7', and -NR7C(O)R7', wherein R7 and
R7' are independently as defined above;
wherein the substituents for B are selected from the
group consisting of halogen, up to per-halo, and Jn, where n
is 0-3 and each J is independently selected from the group
consisting of -CN, -CO2R7, -C(O)NR7R7', -C(O)-R7, -NO2, -
OR7, -SR7, -NR7R7', -NR7C(O)OR7', -NR7C(O)R7', with each
R7 and R7' independently as defined for W above, C1-10 alkyl,
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Appeal 2008-3379
Application 09/838,286

CH1-10 alkoxy, C3-10 cycloalkyl having at least five cyclic
members and 0-3 heteroatoms, C2-10 alkenyl, C1-10 alkenoyl,
C6-14 aryl, C3-12 hetaryl having at least a five cyclic members
and 1-3 heteroatoms selected from N, S and O, C7-24 aralkyl,
C7-24 alkaryl, C4-C23 alkylheteroaryl having at least six
members and 1-3 heteroatoms selected from O, N and S,
substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted
C3-10 cycloalkyl having at least a five-members and 0-3
heteroatoms selected from N, S and O, substituted C2-10
alkenyl, substituted C1-10 alkenoyl, substituted C6-C14 aryl,
substituted C3-12 hetaryl having at least five cyclic members
and 1-3 heteroatoms selected from N, S and O, substituted
C7-24 alkaryl, substituted C7-24 aralkyl and substituted C4-C23
alkylheteroaryl having at least six members and 1-3
heteroatoms selected from O, N and S,
where J is a substituted group, it is substituted by
halogen, up to per halo, or by one or more substituents
independently selected from the group consisting of-CN,
-CO2R7, -COR7, - C(O)NR7R7', -OR7, -SR7, -NO2, -NR7R7', -
NR7C(O)R7', and -NR7C(O)OR7', with R7 and R7' as defined
above for W.

The Art

Chialda et al., Inhibitors of mitogen-activated protein
kinases differentially regulate costimulated T cell cytokine
production and mouse airway eosinophilia, 6 RESPIRATORY RES.
1-19 (2005).
Kapoun et al., TGFβR1 kinase activity, but not p38
activation is required for TGFβR1-induced myofibroblast
differentiation and pro-fibrotic gene expression, MOLECULAR
PHARMACOLOGY FAST FORWARD (2006) (Abstract only).
Marc Feldmann, Pathogenesis of arthritis: recent research
progress, 2 NATURE IMMUNOLOGY 771-773 (2001).
Joseph V. Simone, Oncology – Introduction, in CECIL
TEXTBOOK OF MEDICINE 1004-1010 (J. Claude Bennett and Fred
Plum ed., 1997).
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Application 09/838,286

Goodman & Gilman’s THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS 51, 57, 58 (1996).
Dumas et al., Discovery of a New Class of p38 Kinase
Inhibitors, 10 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
2047-2050 (2000).
Blink et al., p38 Mitogen-Activated Protein Kinase
Inhibition Increases Cytokine Release by Macrophages In Vitro
and During Infection In Vivo, 166 J. IMMUNOLOGY 582-587
(2001).
Trisha Gura, Systems for Identifying New Drugs are Often
Faulty, 278 SCIENCE 1041-42 (1997).
Johnson et al., Relationships between drug activity in NCI
preclinical in vitro and in vivo models and early clinical trials, 84
BRITISH J. CANCER 1424-1431 (2001).

The Issues

A. The Examiner rejected claims 50 and 52-56 under 35 U.S.C. § 112,
first paragraph as enabled for treating rheumatoid arthritis, osteoarthritis and
septic arthritis with the compound of formula I but not reasonably enabled
for “a method of treating a disease mediated by p38 within a host” with the
compound of formula I (Ans. 4-16).
B. The Examiner rejected claims 50 and 52-56 under the judicially
created doctrine of double patenting over claims 17-24, 26, and 30-32 of
copending U.S. Application No. 09/776,935, and over claims 1, 3, 4, and
7-11 of copending U.S. Application No. 10/086,417 (Ans. 16-17).
A. 35 U.S.C. § 112, first paragraph enablement
The Examiner finds that:
the specification, while being enabling for treating the
specific disease mediated by p38 (e.g., rheumatoid arthritis,
osteoarthritis and septic arthritis) by administration of the
specific compounds of the Formula I (e.g., 4-ter-Butyl-2-
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Application 09/838,286

pyridyl ureas), does not reasonably provide enablement for
“a method of treating a disease mediated by p38 within a
host" or "the treatment of a disease other than cancer” with
the administration of “a compound of Formula I”.

(Ans. 4.)
Appellants contend “[n]o evidence has been presented which even
suggests that any compounds of this invention, as inhibitors of p38, would
not be effective in treating the diseases defined by the functional language.
Furthermore, no evidence has been presented of the ‘undue experiment-
tation,’ allegedly necessary to practice the invention commensurate in scope
with the claims” (App. Br. 3). Appellants contend that “one of ordinary
skill in the art, by performing the same or similar tests, can, by routine
experimentation, determine the activity levels of each of the claimed
compounds in treating various p38 mediated diseases” (App. Br. 5).
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Did the Examiner err in finding that it would have required undue
experimentation to treat a disease mediated by p38 by administering a
compound of formula I?
Findings of Fact (FF)
Breadth of the Claims
1. The Examiner finds that the “claimed invention is directed to a
method for the therapeutic treatment of all types of diseases mediated by p38
including cancer (claims 50, 52-54) or all types of diseases mediated by p38
other than cancer (claim 55), comprising administering said compounds
represented by the Formula I” (Ans. 9).
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2. The Examiner finds that invention comprises treating “multiple
complex disorders having unrelated manifestations” (Ans. 9-10). The
Examiner finds that “the scope of the instant claims encompasses over 100
different types of diseases that may be related to p38 pathway mechanism”
(Ans. 13). Among the many diseases listed in the Specification are
inflammatory diseases (Spec. 2, l. 17), asthma (Spec. 2, l. 31), and
tuberculosis (Spec. 4, l. 15).
Presence of Working Examples
3. The Specification teaches that the “in vitro inhibitory properties
of compounds were determined using a p38 kinase inhibition assay” (Spec.
74, ll. 9-10). The Specification states that “[a]ll compounds exemplified
displayed p38 IC50s of between 1 nM and 10 µM” (Spec. 75, l. 3).
4. The Specification teaches that the “in vivo inhibitory properties
of selected compounds were determined using a murine LPS induced TNFα
production in vivo model” (Spec. 75, ll. 6-7). However, no specific
information regarding the values of inhibition for any specific compound is
present in the Specification.
Amount of Direction or Guidance Presented
5. The Specification teaches that “[b]ecause inhibition of p38
leads to inhibition of TNFα production, p38 inhibitors will be useful in
treatment of the above listed diseases” (Spec. 4:30-31).
6. The Examiner finds that the “specification does not provide any
competent evidence or disclosed tests that are highly predictive for the
pharmaceutical use of the instant compounds for the treatment of all of [the]
disease condition[s] encompassed by the instant claim” (Ans. 13).
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State of the Art and Unpredictability of the Art
7. The Examiner finds that “the efficacy of the claimed
compounds in treating all complex disease[] condition[s] by all of [the]
compounds encompassed by the instant invention cannot be predicted . . . a
priori” (Ans. 16).
8. Chialda teaches that “the MAPKs ERK and JNK may be
suitable targets for anti-inflammatory therapy of asthma, whereas inhibition
of p38 seems to be an unlikely target” (Chialda, abstract).
9. Chialda teaches that “[w]e found, that the p38 inhibitor was not
effective . . . . The p38 inhibitor SB203580 did not affect airway
inflammation in our model. Conflicting data about the action of p38
inhibitors in asthma models have been reported in the literature” (Chialda
16, col. 2).
10. Kapoun teaches that “SD-208, but not SD-282, [the p38
inhibitor] inhibited TGFβ-induced: SMAD signaling, myofibroblast
transformation, and collagen gel contraction. Furthermore, we extended our
findings to a rat bleomycin-induced lung fibrosis model, demonstrating a
significant decrease in the number of myofibroblasts at fibroblastic foci in
SD-208, but not SD-282 treated animals” (Kapoun, abstract).
11. Blink teaches that “we observed increased cytokine production
in mouse models of pneumococcal pneumonia and tuberculosis
accompanied by severely reduced bacterial clearance. This apparent
inefficacy of p38 MAPK kinase inhibition in reducing cytokine release in
infectious disease, as well as its immune-compromising action, suggest that
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Application 09/838,286

targeting p38 MAPK may not be a suitable anti-cytokine strategy in patients
with such disease or at risk for infection” (Blink, abstract).
12. Blink teaches that “these findings highlight the uncertainty with
respect to the role of p38 MAPK in cytokine production in general and
emphasize the need for in vivo assessment of the usefulness of p38 MAPK
inhibition as an anti-cytokine inflammatory strategy” (Blink 582, col. 2).
13. Feldmann teaches that “[d]espite the fact that drugs blocking
p38 are effective in animal models, human studies so far have been hindered
by drug toxicity” (Feldman 772, col. 3).
14. Gura teaches that “‘[t]he fundamental problem in drug
discovery for cancer is that the model systems are not predictive at all,’ says
Alan Oliff” (Gura 1041, col. 1).
Quantity of Experimentation necessary
15. The Examiner finds that “one of skill in the art would be forced
to perform an exhaustive search for the embodiments of any drugs having
the function recited in the instant claim suitable to practice the claimed
invention” (Ans. 13).
Principles of Law
“In order to satisfy the enablement requirement of section 112, an
applicant must describe the manner of making and using the invention “in
such full, clear, concise, and exact terms as to enable any person skilled in
the art ... to make and use the same ....” 35 U.S.C. § 112, para. 1.”
Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1323 (Fed. Cir.
2005).
Factors to be considered in determining whether a disclosure
would require undue experimentation . . . include (1) the
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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 predictability or unpredictability of the art, and (8)
the breadth of the claims.

In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
The Examiner has the initial burden to establish a reasonable basis to
question the enablement provided for the claimed invention and no such
evidence or scientific reasoning is present in the instant rejection. See In re
Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993) (Examiner must provide a
reasonable explanation as to why the scope of protection provided by a
claim is not adequately enabled by the disclosure).
Analysis
Applying the Wands analysis, the claim is broadly drawn to the
treatment of any disease mediated by p38, including asthma, tuberculosis,
and general inflammatory diseases (FF 1-2). The Specification has two
examples: a first example which shows that the compounds of formula I
inhibit the p38 kinase and a second example which states, but does not
provide any discussion or evidence of, an impact on TNFα (FF 3-4). The
Specification does not explain or exemplify any specific p38 inhibitor which
will function to treat any one of the specific conditions encompassed by
claim 50 (FF 5-6).
The art cited by the Examiner provides extensive evidence of the
unpredictability of p38 inhibitors in treating diseases, including diseases
expressly listed in the Specification (FF 7-14). In particular, Chialda teaches
that the effect of p38 on asthma is disputed in the literature, which is the
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essence of unpredictability (FF 9). Feldman teaches that the p38 inhibitors
have toxicity issues (FF 13). Blink states that “these findings highlight the
uncertainty with respect to the role of p38 MAPK in cytokine production in
general and emphasize the need for in vivo assessment of the usefulness of
p38 MAPK inhibition as an anti-cytokine inflammatory strategy” (Blink
582, col. 2; FF 12). The Examiner notes that large quantities of
experimentation would be required to determine efficacy (FF 15).
Balancing the Wands factors, we agree with the Examiner that undue
experimentation would have been required to use the invention of claim 50
over the entire scope of treating any disease mediated by p38 within a host.
The Specification only teaches methods of making the compounds of
formula I with no teaching or examples of specific diseases on which the
compounds are predicted to function (FF 1-4). There is significant evidence
of unpredictability (FF 7-14) and little guidance in the specification (FF 5-
6). We find that using the method of the claim reasonably requires undue
experimentation.
We are not persuaded by Appellants’ argument that “no evidence has
been presented of the ‘undue experimentation’ allegedly necessary to
practice the invention commensurate in scope with the claims” (App. Br. 3).
In fact, the Examiner has provided abundant evidence that treatment of
disease with p38 inhibitors is unpredictable (FF 7-14) and that the
Specification provides insufficient guidance to address the concerns of the
art (FF 1-4). While Appellants attempt to specifically rebut the teachings of
each of the references cited by the Examiner, the references demonstrate the
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unpredictability of the art. In fact, the conflict between Chialda and Duane23
regarding whether p38 inhibitors treat asthma (see App. Br. 4) supports the
conclusion of unpredictability, since the art shows different results for
different p38 inhibitors (FF 8-9).
We also do not find persuasive Appellants’ argument that “it would at
most involve routine experimentation if any at all, for one of ordinary skill
in the art to treat any one of the recited diseases with a compound of this
invention” (App. Br. 5). In fact, as shown by the Examiner, it would require
undue experimentation to determine which compound within the scope of
the thousands or millions of compounds of Formula I would function to treat
any of over a hundred different diseases in any specific organism without
significant toxicity to that organism (FF 1-15).
Appellants have simply conjectured that every disease associated with
TNFα production will be susceptible to treatment by p38 inhibitors (Spec. 2,
ll. 10-15). “If mere plausibility were the test for enablement under section
112, applicants would obtain patent rights to ‘inventions’ consisting of little
more than respectable guesses as to the likelihood of their success. When
one of the guesses later proved true, the ‘inventor’ would be rewarded the
spoils instead of the party who demonstrated that the method actually
worked. That scenario is not consistent with the statutory requirement that
the inventor enable an invention rather than merely proposing an unproved
hypothesis.” Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318,

2 Appellants do not list Duane in the Evidence appendix.
3 Duane et al., Inhaled p38a Mitogen-Activated Protein Kinase
Antisense Oligonucleotide Attenuates Asthma in Mice, 171 AM. J.
RESPIRATORY CRITICAL CARE MEDICINE 571-578 (2005)
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1325 (Fed. Cir. 2005). Additionally, the Examiner has demonstrated that for
several specific diseases, including asthma, tuberculosis and inflammatory
diseases, p38 inhibitors do not function as therapeutic treatments (FF 7-14).
We are not persuaded by Appellants argument that “Appellants need
not illustrate the activity of every embodiment to enable the subject matter
of claims 50 and 52-56” (App. Br. 8). The amount of guidance or direction
needed to enable the invention is inversely related to the amount of
knowledge in the state of the art as well as the predictability in the art. In re
Fisher, 427 F.2d 833, 839 (CCPA 1970). The evidence of record shows the
unpredictability of the relevant art. (FF 7-14).
Moreover, while a claim may encompass some inoperable subject
matter, it must encompass some operable matter. As the Federal Circuit has
explained, "if the number of inoperative combinations becomes significant,
and in effect forces one of ordinary skill in the art to experiment unduly in
order to practice the claimed invention, the claims might indeed be invalid."
Atlas Powder Co. v. E.I. du Pont de Nemours, 750 F.2d 1569, 1576-77 (Fed.
Cir. 1984)).
Here, as explained, the Specification does not provide persuasive
evidence that even a single compound encompassed by formula I is
operative in treating a disease other than those found to be within the
enabled scope by the Examiner. Additionally, the laboratory data provided
does not satisfy the enablement requirement, since the Specification does not
provide any laboratory data indicating that the assayed compounds treat any
of the specified diseases.
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Conclusions of Law
The Examiner did not err in finding that it would have required undue
experimentation to treat a disease mediated by p38 by administering a
compound of formula I.
B. Provisional Double Patenting rejection
The two U.S. patent applications, 09/776,935 and 10/086,417,
regarding which the Examiner applied the provisional obviousness type
double patenting rejection, are both currently abandoned. Thus, the double
patenting rejection is moot.
SUMMARY
In summary, we affirm the rejection of claim 50 under 35 U.S.C.
§ 112, first paragraph enablement. Pursuant to 37 C.F.R.
§ 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 52-56 as
these claims were not argued separately.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).
AFFIRMED

LP

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