RIEDL, Bernd et al.

Patent Trials and Appeals Board

Mar 2, 2020

14333533 - (D) (P.T.A.B. Mar. 2, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/333,533 07/17/2014 Bernd RIEDL BAYER-0018-A-C02 1088
23599 7590 03/02/2020
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON, VA 22201
EXAMINER
RAO, DEEPAK R
ART UNIT PAPER NUMBER
1624
NOTIFICATION DATE DELIVERY MODE
03/02/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte BERND RIEDL, JACQUES DUMAS,
UDAY KHIRE, TIMOTHY LOWINGER,
WILLIAM J. SCOTT, ROGER A. SMITH,
and JILL E. WOOD1
________________

Appeal 2019-002722
Application 14/333,533
Technology Center 1600
________________

Before DONALD E. ADAMS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1We use the word “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies Bayer Healthcare LLC as the real
party-in-interest. App. Br. 1.
Appeal 2019-002722
Application 14/333,533

2
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1, 2, 50, 68, and 70 as unpatentable
under 35 U.S.C. § 112, first paragraph, for lack of enablement.
Claims 1, 2, 50, 69, and 70 also stand rejected as unpatentable under
the nonstatutory doctrine of obviousness-type double patenting over claims
1–21 of US 8,580,798 B2 (the “’798 patent”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s invention is directed to the use of a group of aryl ureas in
treating raf-mediated diseases, and pharmaceutical compositions for use in
such therapy. Abstr.

REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. Method for the treatment of cancerous cell growth
mediated by raf kinase comprising administering 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 moiety of up to 40 carbon atoms of the
formula: -L-(M-L1)q, where L is a 5 or 6 membered cyclic
structure bound directly to D, L1 comprises a substituted cyclic
Appeal 2019-002722
Application 14/333,533

3
moiety having at least 5 members, M is a bridging group having
at least one atom, q is an integer of from 1-–3; and each cyclic
structure of L and L1 contains 0–4 members of the group
consisting of nitrogen, oxygen and sulfur, and

B is substituted or unsubstituted pyrimidinyl,

wherein L1 is substituted by at least one substituent
selected from the group consisting of -SO2Rx, -C(O)Rx and -
C(NRy) Rz,

Ry is hydrogen or a carbon based moiety of up to 24 carbon
atoms optionally containing heteroatoms selected from N, S and
O and optionally halosubstituted, up to per halo,

Rz is hydrogen or a carbon based moiety of up to 30 carbon
atoms optionally containing heteroatoms selected from N, S and
O and optionally substituted by halogen, hydroxy and carbon
based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally
substituted by halogen;

Rx is Rz or NRaRb where Ra and Rb are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of
up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by
halogen, or

-OSi(Rf)3 where Rf is hydrogen or a carbon based moiety
of up to 24 carbon atoms optionally containing heteroatoms
selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O
and are optionally substituted by halogen; or
Appeal 2019-002722
Application 14/333,533

4

b) Ra and Rb together form a 5–7 member heterocyclic
structure of 1–3 heteroatoms selected from N, S and O, or a
substituted 5–7 member heterocyclic structure of 1–3
heteroatoms selected from N, S and O substituted by halogen,
hydroxy or carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O
and are optionally substituted by halogen; or

c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene
group or a substituted C1-C5 divalent alkylene group bound to the
moiety L to form a cyclic structure with at least 5 members,
wherein the substituents of the substituted C1-C5 divalent
alkylene group are selected from the group consisting of halogen,
hydroxy, and carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O
and are optionally substituted by halogen;

where B is substituted, L is substituted or L1 is additionally
substituted, the substituents are selected from the group
consisting of halogen, up to per-halo, and Wn, where n is 0–3;

wherein each W 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, -Q-Ar, and carbon
based moieties of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O and optionally substituted
by one or more substituents independently selected from the
group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7,
-SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7 and halogen
up to per-halo; with each R7 independently selected from H or a
carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally
substituted by halogen,

wherein Q is -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-,
-CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN(R7)-,
-O(CH2)m-CHXa-, -CXa2-, -S-(CH2)m- and -N(R7)(CH2)m-,
where m= 1–3, and Xa is halogen; and
Appeal 2019-002722
Application 14/333,533

5

Ar is a 5- or 6-member aromatic structure containing 0-2
members selected from the group consisting of nitrogen, oxygen
and sulfur, which is optionally substituted by halogen, up to per-
halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and
each Z is independently selected from the group consisting of -
CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, - SR7,
-NR7R7, -NR7C(O)OR7, -NR7C(O)R7, and a carbon based moiety
of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O and optionally substituted by one or
more substituents 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 as defined above.

App. Br. 11–13.

ISSUES AND ANALYSES
We agree with, and adopt the Examiner’s findings, reasoning, and
conclusion that the claims on appeal are not enabled by Appellant’s
Specification. We similarly affirm the Examiner’s conclusion that the
claims are obvious under the doctrine of obviousness-type double patenting
over claims 1–21 of the ’798 patent. We address the arguments raised by
Appellant below.

A. Rejection of claims 1, 2, 50, 68, and 70 under 35 U.S.C. § 112, first
paragraph

Issue
Appellant argues the Examiner erred because the Specification is
enabling for the full scope of the pending claims in that it describes how to
make the compounds of Formula (I), how to prepare pharmaceutical
Appeal 2019-002722
Application 14/333,533

6
compositions with these compounds and how to administer them in treating
cancers mediated by raf kinase. App. Br. 4.

Analysis
The Examiner finds that Appellant’s Specification, although enabling
for a method for the treatment of cancerous cell growth mediated by raf
kinase in carcinoma of the colon, or villous colon adenoma (based on the
provided in vitro treatment of tumor cell lines HCT116 and DLD-1), does
not reasonably provide enablement for a method for the treatment of all
types of cancerous cell growth mediated by raf kinase by administering
compounds of Formula (I). Final Act. 2. The Examiner finds that the
Specification does not enable a person skilled in the art to make and/or use
the invention commensurate in scope with the claims. Id.
Specifically, the Examiner points to page 2 of the Specification, which
discloses that “the compounds of the present invention are inhibitors of raf
kinase and are useful in the treatment of human and animal solid cancers.”
Final Act. 3. The Examiner finds that the Specification provides examples
of the types of cancers, using open ended language, e.g., “such as,” “e.g.,”
etc. Id. The Examiner therefore reasons, employing the broadest reasonable
interpretation of the claims, that the scope of the claimed method of
treatment includes treating several types of solid cancers. Id.
The Examiner further finds that the compounds recited in the instant
claim have a generic formula of A-D-B, in which D is -NHC(O)-NH-; etc.
Final Act. 3. However, the Examiner finds, the Specification does not
disclose a subgenus or species of compounds specifically recited in the
claims, i.e., compounds of formula (I) wherein B is a substituted or
Appeal 2019-002722
Application 14/333,533

7
unsubstituted pyrimidinyl. Id. The Examiner finds that the claims cover
compounds potentially numbering in the millions, based on the many
generic permutations permitted by the definitions of terms A and B of
Formula (I). Id. The Examiner finds that, in Formula (I), B is defined as
including “substituted pyrimidinyl” and A is defined as “a substituted
moiety of up to 40 carbon atoms of the formula -L-(M-L1)q, in which L is a 5
or 6 membered cyclic structure bound directly to D, L1 comprises a
substituted cyclic moiety having at least 5 members, and M is a bridging
group having at least one atom, q is an integer 1–3, etc. Id.
Summarizing, the Examiner concludes that it would require an undue
burden of experimentation by a skilled artisan to practice the method recited
in the claims. Final Act. 3.
Appellant argues that references that are of record in the Application’s
history provide evidence of the broad application of raf kinase inhibitors.
App. Br. 4. Specifically, Appellant points to the following references:
1. P.J. O’Dwyer et al., C-raf-1 Depletion and Tumor Responses in
Patients Treated with the c-raf-1 Antisense Oligodeoxynucleotide ISIS
5132 (CGP 69846A), 5 CLIN. CANCER RES. 3977–82 (1999)
(“Dwyer”);

2. C.M. Rudin et al., Phase I Trial of ISIS 5132, an Antisense
Oligonucleotide Inhibitor of c-raf-1, Administered by 24-hour Weekly
Infusion to Patients with Advanced Cancer, 7 CLIN. CANCER RES.
1214–20 (2001) (“Rudin”);

3. J.P. Stevenson et al., Phase I Clinical/Pharmacokinetic and
Pharmacodynamic Trial of the c-raf-1 Antisense Oligonucleotide ISIS
5132 (CGP 69846A), 17(7) J. CLIN. ONCOL. 2227–36 (1999)
(“Stevenson”);

Appeal 2019-002722
Application 14/333,533

8
4. J. Holmlund et al., Phase I Trial of C-raf Antisense Oligonucleotide
ISIS 5132 (CGP 69846A) By 21-Day Continuous Intravenous Infusion
(CIV) In Patients With Advanced Cancer, ASCO ANN. MEETING,
Abstr. No. 811, (1998) (“Holmlund”);

5. Q.C. Lau et al., Abrogation of C-raf Expression Induces Apoptosis in
Tumor Cells, 16 ONCOGENE 1899–1902 (1998) (“Lau”);

6. B.P. Monia et al., Antitumor Activity of a Phosphorothioate Antisense
Oligodeoxynucleotide Targeted against C-raf Kinase, 2(6) NATURE
MED. 668–75 (1996) (“Monia I”);

7. B.P. Monia et al., Sequence-Specific Antitumor Activity of a
Phosphorothioate Oligodeoxyribonucleotide Targeted To Human C-
raf Kinase Supports and Antisense Mechanism of Action in vivo, 93
PROC. NAT’L. ACAD. SCI. USA 15481–484 (1996) (“Monia II”);

8. National Cancer Institute, Clinical Trials (PDQ®), Phase II Study of
ISIS 5132 in Patients with Advanced Pancreatic Cancer, available at:
www.cancer.gov website (1999) (“NCI I”);

9. National Cancer Institute, Clinical Trials (PDQ®), Phase II
Randomized Study of ISIS 5132 or ISIS 3521 in Women with
Previously Treated Metastatic Breast Cancer, available at:
www.cancer.gov (1998) (“NCI II”);

10. National Cancer Institute, Clinical Trials (PDQ®), Phase II
Randomized Study of ISIS 3521 and ISIS 5132 for Locally Advanced
or Metastatic Colorectal Cancer, available at: www.cancer.gov
(1998) (“NCI III”);

11. National Cancer Institute, Clinical Trials (PDQ®), Phase II
Randomized Study of ISIS 3521 and ISIS 5132 in Patients with
Hormone Refractory Prostate Cancer, available at: www.cancer.gov
(1998) (“NCI IV”);

Appeal 2019-002722
Application 14/333,533

9
12. National Cancer Institute, Clinical Trials (PDQ®), Phase II Study of
ISIS 5132 in Patients with Advanced Pancreatic Cancer, available at:
www.cancer.gov (1999) (“NCI V”).

App. Br. 4–5.
Appellant argues that, the Examiner’s findings to the contrary
notwithstanding, the teachings of O’Dwyer, Rudin, Stevenson, Holmlund,
Lau, and Monia I and II collectively demonstrate the promise and efficacy of
raf kinase inhibitors. App. Br. 5. By way of example, Appellant points to
O’Dwyer’s teaching that progress has been hampered by the “limited
specificity of small molecules” and contends that, nevertheless, O’Dwyer
casts no doubt as to whether small molecules are efficacious or whether the
compounds claimed are efficacious. Id. (quoting O’Dwyer 3980).
Appellant asserts that the quoted language does not detract from the general
teachings of O’Dwyer that inhibition of raf kinase is relevant to cancer
treatment. Id.
Appellant argues that Rudin’s teaching that: “No significant
antitumor activity was observed” must be taken in context, as the study was
a Phase I trial to test patient tolerance to the drug, and not its efficacy. App.
Br. 5. Appellant asserts that, despite this statement, of the 13 evaluable
patients, 5 were reported to have a stable disease. Id. According to
Appellant, the results reported by Rudin, when taken as a whole, do not cast
any doubt that the compounds of Formula (I), as recited in Appellant’s
claims, are efficacious in treating cancers mediated by raf kinase, and
support the concept that inhibiting raf kinase may have some impact on
treating cancer. Id. at 5–6.
Appeal 2019-002722
Application 14/333,533

10
Furthermore, Appellant contends, Stevenson also teaches a Phase I
trial testing toxicity and not efficacy. App. Br. 6. Appellant notes that
Stevenson reports antitumor effects of the drug observed in 2 patients who
had progressive disease. Id. Appellant asserts that the results reported by
Stevenson support the conclusion that the compounds of the claimed
Formula (I) herein are efficacious in treating cancers mediated
by raf kinase. Id.
Furthermore, argues Appellant, the teachings referred to by the
Examiner in Holmlund, Lau, and Mania I and II do not detract from the
concept that inhibiting raf kinase would be effective in treating all cancers
mediated by raf kinase. Id. (citing Final Act. 5–6). Furthermore, Appellant
argues, the Final Office Action makes no mention of the phase II clinical
trials (NCI I–V) which tested the efficacy of raf kinase inhibitors and
provide evidence of the broad applicability of raf kinase inhibitors to treating
specific cancers, viz., advanced pancreatic cancer, metastatic breast cancer,
metastatic colorectal cancer, and refractory prostate cancer. Id.
Appellant also points to V. Khazak et al., Selective raf Inhibition in
Cancer Therapy, 11(12) EXPERT OPIN. THER. TARGETS 1587–609 (2007)
(“Khazak”) (filed July 10, 2017), which, Appellant argues, supports
Appellant’s contention that the claims on appeal are supported by the
Specification. App. Br. 6. Appellant points specifically to section 3.2 of
Khazak, which discusses 7 different raf kinase inhibitors under clinical
development, and sections 5.1 and 5.2 which discuss the then-current state
of the art of raf-involved cancers. Id. Appellant therefore contends that a
person of ordinary skill in the art would have recognized that compounds
Appeal 2019-002722
Application 14/333,533

11
“having raf kinase activity [sic] would be effective in treating cancers
mediated by raf kinase.” Id. at 6–7.
Appellant then points to the Specification, which, Appellant contends,
provides sufficient guidance, and describes the state of the art with respect to
the inhibition of tumor growth by raf kinase inhibitors. App. Br. 7. By way
of example, Appellant points to the background section of the Specification
which, Appellant argues, discloses additional assays such as, the teachings
of Monia I, which demonstrate that inhibition of raf kinase has been
correlated in vitro and in vivo with inhibition of the growth of a variety of
human tumor types. Id. (see Spec. 2). Appellant also points to the
Specification’s disclosures of specific in vitro and in vivo assays. Id. (citing
Spec. 1–2, 94–96).
The Examiner responds that the references cited by Appellant do not
establish the type or class of compounds of instant claims to be useful as
therapeutic agents in the treatment of cancerous cell growth mediated by raf
kinase, in which the cancerous cell growth includes various types of solid
cancers, including those listed in Appellant’s Specification. Ans. 19.
The Examiner finds that O’Dwyer teaches that: “Inhibition of
proliferative pathways has long been a goal of anticancer therapy, but
progress has been hampered by the limited specificity of small molecule
inhibitors.” Ans. 20. The Examiner finds that O’Dwyer teaches the
biological response in patients to ISIS 5132 treatment and indicates that
long-term stability and symptomatic improvement was noted in two patients
- one with colorectal cancer and another with renal cell cancer. Id. The
Examiner finds that O’Dwyer does not sufficiently provide evidence that
pyrimidine urea compounds, such as those recited in instant claims, are
Appeal 2019-002722
Application 14/333,533

12
effective in the treatment of all types of cancerous cell growth mediated by
raf kinase. Id.
With respect to the teachings of Rudin, the Examiner finds that Rudin
describes Phase I trial of ISIS 5132 (an antisense oligonucleotide inhibitor of
c-raf-1) administered to cancer patients. Ans. 20. The Examiner finds that
Rudin teaches specific primary tumor sites in patients in Table I. Id. (citing
Rubin 1216). The Examiner finds that Rudin teaches that: “This trial
evaluated the administration of ISIS 5132 as a weekly 24-h infusion …. No
significant antitumor activity was observed, and no significant suppression
of PBMC c-raf-1 mRNA level was evident by quantitative RT-PCR …. This
finding warrants additional study before firm conclusions can be made.” Id.
(quoting Rudin 1218–19). The Examiner finds that Rudin also teaches that:
It is difficult to correlate the plasma levels reached in this and
other similar antisense oligonucleotide trials to an in vitro IC50 of
these agents. Intracellular uptake of ISIS 5132 and other
phosphorothioate oligonucleotides in cell culture has required
addition of cationic lipids, which are not required for
oligonucleotide uptake and suppression of target genes in vivo,
for reasons that are not fully understood.

Id. (quoting Rudin 1219). The Examiner therefore reasons that Rudin does
not provide sufficient evidence of enablement of Appellant’s claimed
method. Id.
The Examiner then turns to Stevenson, finding that its teachings are
also limited to specific types of primary tumor sites, listed in Table 1. Ans.
21 (citing Stevenson 2230). The Examiner further find that Stevenson
teaches that: “[T]hese results define a regimen suitable for phase II testing in
specific tumor sites.” Id. at 20–21 (citing Stevenson 2228). The Examiner
finds that there is no indication or conclusion in the reference that c-raf-1
Appeal 2019-002722
Application 14/333,533

13
inhibitors can be used for the treatment of all types of cancerous cell growth
mediated by raf kinase. Id. at 21.
With respect to the teachings of Holmlund, the Examiner finds that
Holmlund teaches that: “ISIS 5132 (CGP 69846A) inhibits human C-raf
expression in vitro and is active in human xenograft models, where
prolonged exposure increases activity.” Ans. 21. The Examiner finds that
there is no conclusive evidence in the reference that the C-raf inhibitor was
effective in the treatment of all types of cancerous cell growth mediated by
raf kinase. Id.
Similarly, the Examiner finds that Lau teaches that: “an anti-sense
phosphorothioate oligonucleotide (ODN) specifically targeted against c-raf
mRNA (ISIS5132) had profound effects on the growth of the human lung
adenocarcinoma cell line A549 both in culture and on xenografts in nude
mice. The underlying mechanisms remained, however, unclear.” Id.
(quoting Lau 1899). The Examiner finds that Lau also teaches that:
At least for the carcinoma cells analyzed in the current study, c-
raf appears to have a protective role. It is unclear at present what
the cellular pathways involved in this response are …. Based on
the results obtained in the present study, these open questions can
be addressed in future studies.

Id. (quoting Lau 1902).
Finally, with respect to Monia I, the Examiner finds that the reference
teaches:
The recent discovery that raf kinases function in part as
downstream mediators of ras oncogene action suggests that
inhibitors of raf gene expression may prove useful in the
treatment of ras-dependent tumors. Of the three tumor types
shown here to be responsive to the antitumor effects of ISIS 5132
(A549 lung, T24 bladder, MDA-MB-231 breast), two (T24 and
Appeal 2019-002722
Application 14/333,533

14
A549) have been reported to contain ras mutations, supporting
the premise that C-raf inhibition may be useful for the treatment
of human tumors that are associated with these mutations….
Consistent with this possibility are our findings that antisense
ODNs targeted against ras gene products display potent
antitumor activity against A549 and T24 tumor xenografts at a
level that is nearly equal to that of the antitumor activity
displayed by ISIS 5132, but show relatively poor activity against
MDA-MB-231 tumor xenografts. Despite the positive outlook
for antisense inhibitors targeted against C-raf for the treatment
of cancer, some potential limitations may exist for this approach.
For example, little is known about the potential for development
of resistant tumor cell populations that lose their sensitivity
toward C-raf inhibition over time. One possible mechanism by
which such resistance may be acquired is through the recruitment
of alternate signaling pathways, possibly involving the activity
of other raf kinase isotypes.

Ans. 21–22 (quoting Monia I 673). The Examiner finds that Monia I thus
teaches the unpredictable nature of the activity and role of raf inhibitors in
tumor suppression. Id. at 22.
Summarizing, the Examiner finds that these references cited by
Appellant do not provide any conclusive supporting evidence to Appellant’s
contention that a person of ordinary skill in the art would have understood
that inhibiting raf kinase activity would be effective in treating all cancers
mediated by raf kinase, and that the Specification would therefore be
enabling for a person of ordinary skill in the art. Ans. 22. To the contrary
the Examiner finds, the references teach the complex and unpredictable
nature of the raf inhibitor activity, and the requirement of future studies and
experimentation. Id.
Turning to Appellant’s Specification, the Examiner finds that it fails
to disclose a validated marker or method for predicting a benefit from the
Appeal 2019-002722
Application 14/333,533

15
instantly claimed compounds. Ans. 22. With respect to Appellant’s
argument that the Specification’s disclosure of specific cell and in vivo
assays, the Examiner notes that Appellant’s Specification does not disclose
any compounds in these examples that correspond to Formula (I) of instant
claims, in which “B is substituted or unsubstituted pyrimidinyl.” Id. at 24.
The Examiner points out that all of the compounds exemplified in the
Specification have a substituted or unsubstituted phenyl or pyridinyl as the B
group for Formula (I). Id. at 24–25.
The Examiner emphasizes that the major contributing factors to this
rejection are: (1) the lack of predictability in the art regarding treatment of
cancerous cell growth mediated by raf kinase due to an insufficient number
of validated biomarkers; (2) the lack of guidance provided to one of skill in
the art regarding treatment of all types of cancerous cell growth mediated by
raf kinase, particularly the lack of guidance and working examples regarding
the claimed raf inhibitor’s activity in a broad spectrum of cancers mediated
by raf kinase. Ans. 22–23. The Examiner finds that neither the
Specification nor the prior art of record effectively provides to one of skill in
the art that the instantly claimed raf kinase inhibitors can be applied in the
treatment of cancerous cell growth mediated by raf kinase. Id. at 23.
We agree with the Examiner. As an initial matter, claim 1 requires
that Formula (I) consists of components: A-D-B, or a pharmaceutically
acceptable salt thereof, in which B “is substituted or unsubstituted
pyrimidinyl.” Appellant’s Specification discloses, with respect to B, that:
“B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety
of up to 30 carbon atoms with at least one 6-member cyclic structure bound
directly to D containing 0–4 members of the group consisting of nitrogen,
Appeal 2019-002722
Application 14/333,533

16
oxygen and sulfur.2” Spec. 3. This genus includes a veritable host of
possible substituted pyrimidinyl constituents, and none of the embodied
compositions listed as examples 1–103 in Tables 1–5 of the Specification
depict a compound for which B “is substituted or unsubstituted
pyrimidinyl.” Spec. 80–92. Rather, the Specification names but a single
unsubstituted species:
In formula I, suitable hetaryl groups include, but are not limited
to, 5–12 carbon atom aromatic rings or ring systems containing
1-3 rings, at least one of which is aromatic, in which one or more,
e.g., 1–4 carbon atoms in one or more of the rings can be replaced
by oxygen, nitrogen or sulfur atoms. Each ring typically has 3–7
atoms. For example, B can be… 2-, 4-, 5- or 6- pyrimidinyl, ….
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy,
etc. throughout include methyl, ethyl, propyl, butyl, etc.,
including all straight-chain and branched isomers such as
isopropyl, isobutyl, sec-butyl, tert-butyl, etc. Suitable aryl
groups which do not contain heteroatoms include, for example,
phenyl and 1- and 2-naphthyl.

Id. at 5–6 (emphasis added).
Moreover, the Examples provided on pages 94–96 of Appellant’s
Specification disclose methods of conducting in vitro and in vivo assays of
raf kinase activity, but there are no examples provided that employ the
claimed compounds.
In summary, the Specification does not disclose sufficient examples of
B as recited in claim 1, such that a person of ordinary skill would understand

2 We note, however, that neither these substituents, nor the ones in the
subsequent quoted passage, are limiting on the claims with respect to “B”.
See In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993) (holding that
although the claims are interpreted in light of the specification, limitations
from the specification may not be read into the claims).
Appeal 2019-002722
Application 14/333,533

17
which species of the claimed genus of B might reasonably be expected to
have inhibitory activity against raf kinase.
“Section 112 requires that the patent specification enable ‘those
skilled in the art to make and use the full scope of the claimed invention
without ‘undue experimentation’ in order to extract meaningful disclosure of
the invention and, by this disclosure, advance the technical arts.” Invitrogen
Corp. v. Clontech Labs. Inc., 429 F.3d 1052, 1070 (Fed. Cir. 2005) (quoting
Koito Mfg. Co. v. Turn-Key-Tech, LLC, 381 F.3d 1142, 1155 (Fed. Cir.
2004)). Because Appellant’s Specification does not sufficiently define the
contours of what constitutes a “substituted or unsubstituted pyrimidinyl”
such that it possesses raf kinase inhibitory activity, we conclude that a
person of ordinary skill in the art would not have been able to practice the
claimed invention without performing undue experimentation to determine
which compounds with component B, as defined in the claim, would
perform that function.
Furthermore, claim 1 is directed to a “[m]ethod for the treatment of
cancerous cell growth mediated by raf kinase,” but Appellant’s Specification
discloses such cancerous cell growths only in the broadest terms.
Specifically, the Specification discloses that: “The p21ras oncogene is a
major contributor to the development and progression of human solid
cancers and is mutated in 30% of all human cancers.” Spec. 1. The
Specification further discloses that:
The present invention provides compounds which are inhibitors
of the enzyme raf kinase. Since the enzyme is a downstream
effector of p21ras, the inhibitors are useful in pharmaceutical
compositions for human or veterinary use where inhibition of the
raf kinase pathway is indicated, e.g., in the treatment of tumors
and/or cancerous cell growth mediated by raf kinase. In
Appeal 2019-002722
Application 14/333,533

18
particular, the compounds are useful in the treatment of human
or animal solid cancers, e.g., murine cancer, since the
progression of these cancers is dependent upon the ras protein
signal transduction cascade and therefore susceptible to
treatment by interruption of the cascade, i.e., by inhibiting raf
kinase. Accordingly, the compounds of the invention are useful
in treating cancers, including solid cancers, such as, for example,
carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or
colon), myeloid disorders (e.g., myeloid leukemia) or adenomas
(e.g., villous colon adenoma).

Id. at 2. We find that these disclosures are insufficient to guide a person of
ordinary skill as to which cancers are mediated by raf kinase, because the
Specification teaches that the underlying oncogene is mutated in “30% of all
human cancers,” but does not specify in which types of cancer, specifically,
a mutation of the p21 ras oncogene occurs, and whether that mutation is the
underlying cause of cancerous cell growth in the broad categories of solid
tumors recited in the passage supra. Indeed, Monia I, at least, teaches that
not all types of solid tumors demonstrate mutation of the oncogene. See
Monia I 673:
Of the three tumor types shown here to be responsive to the
antitumor effects of ISIS 5132 (A549 lung, T24 bladder, MDA-
MB-231 breast), two (T24 and A549) have been reported to
contain ras mutations, supporting the premise that C-raf
inhibition may be useful for the treatment of human tumors that
are associated with these mutations.

Nor are we persuaded that the prior art references provided by
Appellant are sufficient to guide the skilled artisan in practicing the
invention. We agree with the Examiner, for the reasons given, that the prior
art teaches that employing inhibition of raf kinase to prevent cancerous
growth is uncertain and unpredictable. Furthermore, we are not persuaded
Appeal 2019-002722
Application 14/333,533

19
that the references in particular, and the state of the art in general, would
provide sufficient guidance to a person of ordinary skill in the art how to use
the claimed compositions to inhibit raf kinase or that such an approach
would be feasible for preventing cancerous cell growth.
Specifically, O’Dwyer, Rudin, Stevenson, Holmlund, Lau, and Monia
I and II all teach the use of antisense oligonucleotides to inhibit expression
of the raf kinase enzyme: none of these references teaches the use of the
claimed compositions, or any other composition, to directly inhibit activity
of the raf-kinase enzyme itself. Nor does Appellant present any argument or
evidence that NCI I–IV employ compounds as raf kinase inhibitors that
correspond to the claimed compound. As such, we conclude that there was
not sufficient guidance in the prior art, at the time of invention, to guide a
person of ordinary skill in that art to use Appellant’s invention without
undue experimentation.
Khazak, also cited by Appellant, teaches:
At present, 7 independent raf kinase inhibitors have been
preclinically or clinically evaluated (Table 3).…. In general, in
evaluating the action of these Raf-targeted kinase inhibitors, it is
very important to consider some of the efficacy of these
compounds may arise from activity against non-Raf-kinases. In
one extensive study, it was shown that sorafenib blocks the
activity of over 60 kinases at clinically relevant concentrations.
Broadly speaking, all uses of such compounds represent an
unselected “combination therapy” approach. At present, it is an
open question whether increasing or decreasing the specificity
of raf kinase inhibitors would increase therapeutic value. While
combinatorial inhibition of multiple oncogenic kinases
may increase potency, the downside of this approach may be that
low potency of blockade of essential kinases contributes to
therapy-related toxicity. Hence, while antisense and SiRNA-
based approaches unequivocally seek to act “on-target”, with
Appeal 2019-002722
Application 14/333,533

20
kinase inhibitors, it is an open question as to restricting or
exploiting “off-target” activities of the compounds is a
better strategy.

Khazak 1604 (emphasis added, internal citation omitted). In short, Khazak
teaches that it is by no means obvious to a person of ordinary skill that
inhibition of raf kinase alone, sensu strictori, is efficacious in preventing cell
growth, or whether the effects of the drugs under review in Khazak have
their effectiveness in a broader scale action. See Khazak 1605 (internal
citation omitted):
The mechanism of apoptosis induction in sensitive cell lines by
sorafenib is largely independent of raf activity in caspase
activation and BAD dephosphorylation, but rather involves
nuclear translocation of AIF (apoptosis inducing factor). It is not
yet clear whether this represent Raf-directed or off-target
activities of sorafenib.

In summary, we agree with the Examiner that the prior art cited by
Appellant reflects the fact that the use of raf kinase inhibitors to prevent
cancerous cell growth was in an early phase and that the state of the art was
still uncertain and unpredictable, such that the extant prior art failed to
provide guidance to a skilled artisan such that the invention could be
practiced without undue experimentation. We consequently affirm the
Examiner’s rejection upon this ground.

Appeal 2019-002722
Application 14/333,533

21
B. Rejection of claims 1, 2, 50, 69, and 70 under the doctrine of
obviousness-type double patenting

Issue
Appellant argues that the Examiner erred because the claims on
appeal are patentably distinct over the cited claims of the ’798 patent. App.
Br. 9.

Analysis
Appellant argues that the claims of the ’798 patent on appeal are
directed to pyrimidinyl urea compounds, but are silent with respect to
methods of treatment. App. Br. 10. Specifically, Appellant asserts that the
claims of the ’798 patent are silent regarding the treatment of cancerous cell
growth mediated by raf kinase, comprising administering a compound of
Formula (I). Id.
Appellant argues further that the compositions claimed by the ’798
patent only partially overlap the compounds recited in the methods of
Appellant’s present claims 1, 2, and 50: they provide no direction to select
the compounds of Formula (I) for the claimed methods. App. Br. 10.
According to Appellant, there is no direction to select compounds with the
substituents required of Formula (I) of the present claims. Id.
Appellant also argues that the compounds recited by the claims of the
’798 patent are optionally substituted and do not include the sulfides and
imide substituents of Formula (I) of the present claims. App. Br. 10.
Appellant acknowledges that the compounds of the ’798 patent optionally
include carboxy substituents, which overlap the compounds of Formula (I )
in which L1 is substituted by with C(O)Rx. Id. However, argues Appellant,
Appeal 2019-002722
Application 14/333,533

22
based on the distinct compounds and the selections made for the compounds
of Formula (I), the methods claimed in the claims on appeal are not obvious
in view of compounds claimed in the ’798 patent. Id.
Finally, Appellant argues that claims 69 and 70, which do not define
compounds claimed in the ’798, were not rejected for nonstatutory double
patenting. App. Br. 10.
The Examiner acknowledges that the compounds claimed by the ’798
patent partially overlap the compounds used in the present method claims on
appeal. Ans. 28. However, the Examiner finds that the compositions of the
’798 patent are disclosed as being useful as pharmaceutical agents and,
further, also useful in methods for the treatment of hyper-proliferative
disorders and angiogenesis disorders, including solid tumors such as cancers
of the breast, thyroid, etc. Id. (citing ’798 patent col. 6, ll. 35–39, col. 17, ll.
56–64).
The Examiner also finds that the compositions of the ’798 patent are
also disclosed to be raf inhibitors and that: “C-raf and B-raf are preferred
targets for compounds of the present invention.” Ans. 28–29 (quoting ’798
patent col. 18, ll. 48–62). The Examiner finds that the ’798 patent discloses
c-raf biochemical assays, and further discloses that: “Compounds of
examples 1–13 showed significant inhibition (IC50 < 10 μM) in either or both
the c-raf and flk-1 biochemical assays.” Id. at 29 (citing ’798 patent Ex. 15;
quoting col. 32, ll. 43–45).
The Examiner notes that Appellant’s claims on appeal are directed to
a “method for the treatment of … cancerous cell growth mediated by raf
kinase comprising administering a compound of Formula I,” and that the
types of cancerous cell growth within the scope of instant claims includes
Appeal 2019-002722
Application 14/333,533

23
those of solid cancers, such as, for example, carcinomas of the lung, thyroid,
etc. Ans. 29. Accordingly, the Examiner reasons, the reference claims teach
the use of same compounds in a method of treating the same patient
population as recited in instant claims. Id.
With respect to the compositions recited in the ’798 patent and
Appellant’s claims on appeal, the Examiner finds that the claims of the ’798
patent are directed to compound represented by Appellant’s Formula (I), and
the dependent claims provide subgeneric embodiments of Formula (I). Ans.
29 (citing, e.g., claims 7, 8, 9, 14). The Examiner points out that dependent
claim 21 of the ’798 patent provides species within the structural Formula (I)
of claim 1, e.g., the first compound in claim 21 has the following structure:
4-{3-fluoro-4-[3-(6-trifluoromethylpyrimidin-4-yl)ureido]phenoxy}
pyridine-2-carboxylic acid methylamide:

which the Examiner finds is encompassed within Formula (I) of the claims
on appeal. Id.
With respect to claims 69 and 70, the Examiner notes that claim 70
was entered into the application on September 11, 2017 with the Request for
Continued Examination and claim 70 was included in the nonstatutory
double patenting rejection in the subsequent office action mailed on January
26, 2018. Ans. 30.
We are not persuaded by Appellant’s arguments. An obviousness-
type double patenting analysis generally involves two steps:
Appeal 2019-002722
Application 14/333,533

24
First, as a matter of law, a court construes the claim in the earlier
patent and the claim in the later patent and determines the
differences. Second, the court determines whether the
differences in subject matter between the two claims render the
claims patentably distinct. A later claim that is not patentably
distinct from an earlier claim in a commonly owned patent is
invalid for obvious-type double patenting. A later patent claim
is not patentably distinct from an earlier patent claim if the later
claim is obvious over, or anticipated by, the earlier claim.

Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 968 (Fed. Cir. 2001).
Claim 1 of the ’798 patent recites, in relevant part:
1. A compound of formula (I), a salt thereof, an oxidized
derivative thereof, wherein one or more of the nitrogens are
substituted with a hydroxy group, or a diastereoisomeric form
thereof, either as an isolated stereoisomer or in a mixture of
stereoisomers

’798 patent col. 32, ll. 47–59.
In short, the claims of the ’798 patent are directed to compositions,
whereas Appellant’s claims on appeal are directed to a method of using
those compositions, i.e., a “[m]ethod for the treatment of cancerous cell
growth mediated by raf kinase comprising administering a compound of
Formula I.” App. Br. 11. The Examiner cites to the disclosures of the
specification of the ’798 patent as evidence of the raf kinase activity and
intended potential uses of the compositions claimed therein.
Although there is a general prohibition on using the disclosures of the
reference patent’s specification as prior art in an obviousness-type double
patenting analysis:
Appeal 2019-002722
Application 14/333,533

25
We have repeatedly approved examination of the disclosed
utility of the invention claimed in an earlier patent to address the
question of obviousness. As we explained in Geneva
Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, “[t]he
[reference] patent’s claim describes a compound, and [the
reference patent’s] written description discloses a single utility
of that compound.... The [later expiring] patent claims nothing
more than [the reference patent’s] disclosed utility as a method
of using the [reference patent’s] compound. Thus, the claims of
the [reference patent] and [later expiring] patents are not
patentably distinct.”

Abbvie Inc. v. Mathilda and Terence Kennedy Inst. of Rheumatology Trust,
764 F.3d 1366, 1381 (Fed. Cir. 2014) (alterations in original) (quoting
Geneva Pharms, 349 F.3d 1373, 1386 (Fed. Cir. 2003)). The Examiner
finds, and we agree, that the specification of the ’798 patent discloses that
the compositions claimed in the ’798 patent have utility as raf kinase
inhibitors and may be used in the treatment of various types of solid tumor
cancers. We consequently find, despite Appellant’s argument that the
claims are necessarily patentably distinct because the claims of the ’798
patent are directed to compositions, whereas the claims on appeal are
directed to a method of using those compositions, in light of the utility
described by the disclosure of the ’798 patent for the compositions claimed
in the ’798 patent, that the difference in statutory class of invention (i.e.,
composition versus method of use) is not sufficient, standing alone, to render
the claims on appeal patentably distinct from the claims of the ’798 patent.
We therefore turn to whether the compositions of the present claims
are obvious over those of the ’798 patent. Both Appellant and Examiner
acknowledge that there is substantial overlap between the compositions
claimed in the ’798 patent and Appellant’s claims. Appellant’s principal
Appeal 2019-002722
Application 14/333,533

26
contention of nonobviousness of the claims on appeal over the ’798 patent is
that “[t]he compounds [recited by the claims of the ’798 patent] are
optionally substituted and do not include the sulfides and imide substituents
of Formula [(I) of the present claims].” See App. Br. 10. We find this
argument, as such, is insufficient to overcome the Examiner’s prima facie
conclusion of obviousness. Both the claims of the ’798 patent and
Appellant’s present claims contain within their scope a large number of
potential species for the claimed genus. In claim 1 of the ’798 patent, both
constituents A and M (which correspond to the present claims’ constituents
A and B) can be “optionally substituted” pyrimidines, which also naturally
includes within its scope, unsubstituted pyrimidines. As we have explained
supra, constituent B of the present claims recites simply: “B is substituted or
unsubstituted pyrimidinyl” without further limitations and “A is a
substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L1 )q,
where L is a 5 or 6 membered cyclic structure bound directly to D, ….” In
the latter case, L can be a pyrimidinyl in a manner similar to A in claim 1 of
the ’798 patent.
We conclude that, given the breadth of the claims, and the significant
overlap between the claimed compositions in the ’798 patent and the claims
on appeal, Appellant’s argument that “[t]he compounds [recited by the
claims of the ’798 patent] are optionally substituted and do not include the
sulfides and imide substituents of Formula [(I) of the present claims]” is not
sufficient to overcome the Examiner’s conclusion that Appellant’s claims on
appeal are obvious over claims 1–21 of the ’798 patent, not least because
both claims contemplate within their scope unsubstituted pyrimidines. Our
conclusion that the claims are obvious is further supported by the
Appeal 2019-002722
Application 14/333,533

27
Examiner’s finding that dependent claim 21, at least, of the ’798 patent
recites a compound that falls squarely within Formula (1) of the claims on
appeal. Appellant does not contest this finding by the Examiner.3
We consequently conclude that Appellant’s arguments, as presented
in the Appeal Brief, are insufficient, without further evidence, to overcome
the Examiner’s conclusion that the claims on appeal are obvious over claims
1–21 of the ’798 patent. We consequently affirm the Examiner’s rejection
upon this ground.

DECISION
The Examiner’s rejection of claims 1, 2, 50, 68, and 70 under 35
U.S.C. § 112, first paragraph, is affirmed.
The Examiner’s rejection of claims 1, 2, 50, 69, and 70 under the
nonstatutory doctrine of obviousness-type double patenting is affirmed.
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).

AFFIRMED

3 Appellant also argues, in the Reply Brief, that because the present
application was filed before the application which issued as the ’798
patent, the ’798 patent is not an earlier patent, and that the methods
claimed in the claims on appeal could not therefore be claimed in the ’798
patent. Reply Br. 15. However, because Appellant failed to raise this new
argument in the Appeal Brief, we do not consider it in our Decision. See
37 C.F.R. § 41.37(c)(1)(vii); see also Ex parte Borden, 93 USPQ2d 1473,
1474 (BPAI 2010) (informative) (holding that arguments not raised in the
Appellate Brief are considered waived).
Appeal 2019-002722
Application 14/333,533

28
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 2, 50,
68, 70
112, first
paragraph
Lack of
enablement
1, 2, 50, 68,
70

1, 2, 50,
68, 70
Obviousness-
type double
patenting
Claims 1–21 of US
8,580,798 B2
1, 2, 50, 69,
70

Overall
Outcome
1, 2, 50, 68,
69, 70