Ulrike Stein et al.

Patent Trials and Appeals Board

Nov 29, 2019

14112521 - (D) (P.T.A.B. Nov. 29, 2019)

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.
14/112,521 06/11/2014 Ulrike Stein HERT4.001APC 2794
20995 7590 11/29/2019
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
LOVE, TREVOR M
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
11/29/2019 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):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ULRIKE STEIN, WOLFGANG WALTHER, ULRIKE SACK,
ROBERT SHOEMAKER, DOMINIC SCUDIERO, PETER M. SCHLAG
__________

Appeal 2018-007430
Application 14/112,5211
Technology Center 1600
__________

Before DONALD E. ADAMS, TAWEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for inhibiting, reducing and/or reducing the risk or cancer metastasis, which
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “Applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real parties in interest as Max-
Delbruckcentrum Für Molekulare Medizin, and The United States Of
America, as represented by the Secretary, Department Of Health And
Human Services. (Appeal Br. 2.)
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STATEMENT OF THE CASE
“Colorectal cancer is one of the most frequent malignant tumors.”
(Spec. 1) This cancer is “often associated with . . . high expression of the
metastasis-inducing gene S100A4.” (Id. at 2.) Indeed, “S100A4 is
overexpressed in many different types of cancer such as gallbladder,
bladder, breast, esophageal, gastric, pancreatic, hepatocellular, non-small
cell lung and especially colorectal cancer.” (Id. at 3.) “The invention relates
to niclosamide and derivate[ive]s thereof, which effectively inhibit
transcription of the S100A4 gene, resulting in inhibition of S100A4-induced
cell motility, invasiveness, metastasis and proliferation of human cancer
cells.” (Id. at 1.)
Claims 19, 20, 22–27, and 30–36 are on appeal.2 Claim 19 is
representative and reads as follows:
19. A method for inhibiting, reducing and/or reducing the risk
of cancer metastasis, comprising:
(a) identifying a subject as in need of inhibiting, reducing
and/or reducing the risk of cancer metastasis, by identifying the
subject as having a cancer with:
(i) an elevated or up-regulated level of expression of
S100A4 compared to an expression level in non-
oncogenic cells,
(ii) a mutated S100A4, or
(iii) an S100A4 that is altered in physiology compared to
non-oncogenic cells, and
(b) administering to the subject a therapeutically effective
amount of niclosamide or a niclosamide derivate, thereby
inhibiting or reducing expression or activity of the S100A4, the

2 Claims 31, 34, and 35 remain pending but are withdrawn from
consideration. (Final Action 2.)
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mutated S100A4 or the S100A4 that is altered in physiology so
as to inhibit, reduce, and/or reduce the risk of cancer metastasis.
(Appeal Br. 17.)

The following ground of rejection by the Examiner is before us on
review:
Claims 19, 20, 22–27, 30, 32, 33, and 36 under 35 U.S.C. § 103(a) as
unpatentable over Khodadoust3 and Boye.4
DISCUSSION
The Examiner finds that Khodadoust teaches a composition “useful
for ‘prophylactic cancer prevention, prevention of cancer recurrence and
metastases after surgery’” which composition includes niclosamide in a
therapeutically effective dose for humans. (Final Action 3 (citing
Khodadoust ¶¶ 90, 114).) The Examiner further finds that Khodadoust
teaches that the niclosamide composition can be used in combination with
other actives that “also prevent metastases in order to achieve a combination
treatment.” (Id. (citing Khodadoust ¶ 91).) In addition, the Examiner finds
that Khodadoust teaches that niclosamide “is useful for inducing an
antiproliferative effect in colon cancer.” (Id. (citing Khodadoust ¶ 143 and
Table 1).)
The Examiner recognizes that Khodadoust does not teach identifying
a subject in need of reducing the risk of cancer metastasis. (Id. at 4.)
However, the Examiner determines that such a step would have been

3 Khodadoust, US 2005/0250709 A1, published Nov. 10, 2005.
4 Boye et al., S100A4 and Metastasis: A Small Actor Playing Many Roles,
176(2) AJP, 528–35 (2010).
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obvious to one of ordinary skill in the art given the teachings of Boye. (Id.)
In particular, the Examiner finds that Boye teaches “S100A4 is
overexpressed in colorectal cancer,” its presence is an indicator of decreased
survival expectancy, and that “patients are able to be identified through the
secretion of S100A4 in vivo in interstitial fluid.” (Id. (citing Boye 529,
531).)
We agree with the Examiner’s factual findings and conclusion that the
method recited by claim 19 would have been obvious to one having ordinary
skill in the art in light of the teachings of Khodadoust and Boye. Appellant’s
primary argument that it repeats throughout to rebut the Examiner’s
rejection is that “Khodadoust does not disclose any specific effect of
niclosamide on the process of metastasis.” (See e.g., Appeal Br. 9; see also
Reply Br. 2, 4). This argument is not persuasive. In particular, we agree
with the Examiner that paragraph 90 of Khodadoust explicitly refers to using
any one of the compounds described alone or in combination with each other
or with other anti-cancer therapeutics and that any of “such methods can be
used in prophylactic cancer prevention, prevention of cancer recurrence and
metastases after surgery, and as an adjuvant of other conventional cancer
therapy.” (Khodadoust ¶ 90 (emphasis added), Ans. 3–4.) Paragraph 91
does not provide a caveat to paragraph 90’s teaching, as Appellant suggests
(Appeal Br. 9–11), but rather explains that combination therapy can result in
synergy and allow a reduction of dosage of each of the treatments.
(Khodadoust ¶¶ 91–92).
We also do not find persuasive Appellant’s argument that Khodadoust
and Boye do not suggest giving niclosamide to cancer patients in which
S100A4 is overexpressed (Appeal Br. 11–13). First, with respect to the
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claim requirement that the subject is identified as being “in need of
inhibiting, reducing and/or reducing the risk of cancer metastasis,” the claim
requires such identification be accomplished “by identifying the subject as
having a cancer with (i) an elevated or up-regulated level of expression of
S100A4 compared to an expression level in non-oncogenic cells.” As the
Examiner noted (Ans. 4–5), Boye teaches that S100A4 is a metastasis-
associated gene marker in human colorectal cancer that is overexpressed in
colorectal cancer. (Boye 531 (“As illustrated in the previous sections,
S100A4 is a well-established marker and mediator of metastatic disease”)
and (“S100A4 is also overexpressed in colorectal cancer”).)5 Boye also
teaches that cells expressing S100A4 are prone to result in metastases. (See
e.g., Boye 531–32.) Thus, to the extent that a colorectal cancer patient is
identified as being S100A4 positive, Boye suggests that such a patient

5 Appellant’s argument made for the first time in the Reply Brief that “not
all colorectal cancers overexpress S100A4 gene transcripts” (Reply Br. 2) is
not considered. “[T]he reply brief [is not] an opportunity to make arguments
that could have been made in the principal brief on appeal to rebut the
Examiner’s rejections, but were not.” Ex parte Borden, 93 USPQ2d 1473,
1474 (BPAI 2010) (informative). Appellant has not demonstrated any
specific Examiner findings presented for the first time in the Answer
necessitating this specific new argument in rebuttal in the Reply Brief.
(Compare Final Action 4, 5 with Ans. 4). Nor do we find any substantial
differences in the Examiner’s initial findings and the Examiner’s findings
stated in the Answer that would warrant the new arguments presented in the
Reply Brief for the first time. Moreover, Appellant’s new argument, which
appears to contradict Boye’s teaching at 531(“S100A4 is also overexpressed
in colorectal cancer” (citing articles)) is not supported by any evidence.
“Attorney argument is not evidence.” Icon Health & Fitness v. Strava, 849
F.3d 1034, 1043 (Fed. Cir. 2017) (citing See, e.g., Gemtron Corp. v. Saint-
Gobain Corp., 572 F.3d 1371, 1380 (Fed. Cir. 2009) (“[U]nsworn attorney
argument . . . is not evidence and cannot rebut . . . other admitted evidence”).
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overexpresses S100A4 and such a patient is at risk of cancer metastasis.
Given Khodadoust’s teaching that a composition including niclosamide can
be administered to prevent cancer metastasis, and Boye’s teaching that
S100A4 is a marker for colorectal cancer and its metastasis and it is
overexpressed in colorectal cancer, we agree with the Examiner that it would
have been obvious to one of ordinary skill in the art to screen a potential
colon cancer patient for S100A4 and, if the patient was found to be positive
for S100A4 and thus necessarily overexpressing S100A4, to administer
niclosamide with a reasonable expectation of success that it would prevent
cancer metastasis in the colorectal cancer patient that was in need of cancer
metastasis prevention. We also agree with the Examiner (Final Action 4–5)
that the administration of the niclosamide composition would thus
necessarily result in the claimed effect of “inhibit[ing], reduc[ing], and/or
reduc[ing] the risk of cancer metastasis.”
Appellant’s argument that there could have been no reasonable
expectation that “niclosamide would be able to reduce metastasis by
specifically inhibiting transcription of the S100A4 gene” (Appeal Br. 12) is
not persuasive as the claim does not require such inhibition.
Appellant’s argument that metastasis is only one risk of colon cancer
and that primary tumor management is treated separately from secondary
tumors formed by metastases (Appeal Br. 11–12) is unavailing for the
reasons discussed. That is, Khodadoust teaches administration of
niclosamide to prevent metastasis (Khodadoust ¶ 90), which Boye teaches is
a risk identified in colon cancer patients expressing the S100A4 gene (Boye
531). We also do not agree with Appellant (Appeal Br. 13, Reply Br. 3) that
it has “demonstrated that the use of niclosamide is unexpectedly
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advantageous in the treatment of cancers that have a high level of S100A4-
expression.” We disagree because, as already discussed above, it is known
that in colorectal cancer patients S100A4 is overexpressed (Boye 531), and
Khodadoust teaches treating colorectal cancer patients to prevent, i.e.,
inhibit, metastasis by administering niclosamide.
Appellant contends that Appellant established with experimental
evidence that niclosamide “specifically inhibits transcription of the S100A4
gene, thereby resulting in inhibition of S100A4-induced cell motility,
invasiveness, metastasis and proliferation of cancer cells,” making
administration of “a therapeutically effective amount of niclosamide . . . the
treatment option of choice for subject having cancer in which there is: (i) an
elevated . . . level of expression of S100A4 compared to an expression level
in non-oncogenic cells.” (Appeal Br. 13.) However, this is not persuasive
evidence of non-obviousness in light of Khodadoust’s teaching that the
compounds disclosed therein, including niclosamide, can be used to prevent
cancer recurrence and metastases after surgery” (Khodadoust ¶ 90). “Mere
recognition of latent properties in the prior art does not render nonobvious
an otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d 388,
392 (Fed. Cir. 1991). That a person of ordinary skill in the art would not
have known of the manner by which metastasis was prevented, thus, does
not preclude a finding of obviousness. See Par Pharm. v. TWi Pharms.,
Inc., 773 F.3d 1186, 1197 (Fed. Cir. 2014), In re Woodruff, 919 F.2d 1575,
1578 (Fed. Cir. 1990). Here, the newly discovered inherent property does
not correspond to a claimed new benefit because the claims require
inhibiting or reducing cancer metastasis by administering niclosamide,
thereby causing a particular activity inherent to the administration of
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niclosamide “so as to inhibit, reduce . . . cancer metastasis.” This inhibiting
or reducing metastases by the administration of niclosamide in a patient with
colorectal cancer is taught by Khodadoust. Boye teaches that colorectal
cancer overexpresses S100A4 and is a marker for metastasis. Thus, by
following Khodadoust’s teaching to treat the colon cancer patient to prevent
or inhibit metastases with niclosamide and Boye’s suggestion that it would
be reasonable to identify the patient as having S100A4 given that it was
known that in colorectal cancer S100A4 is overexpressed (Boye 531) and
that S100A4 is a known metastatic marker (id.), one of ordinary skill in the
art would necessarily arrive at the claimed benefit.
Appellant’s reliance on the Declaration of the inventor Dr. Stein
(Stein Declaration6) (Appeal Br. 14–15) is also unavailing. As Dr. Stein
admits, the new discovery was that niclosamide down-regulates the
expression of the metastasis-inducing gene S100A4. (Stein Declaration
¶¶ 3, 5.) While Dr. Stein may be correct that the prior does not identify
“such an effect” of niclosamide (id. ¶ 6), this does not negate that
Khodadoust teaches the use of niclosamide to prevent cancer metastases
after surgery (Khodadoust ¶ 90) and that niclosamide can be used for
therapeutic effect in colorectal cancer (Khodadoust ¶ 9). In light of
Khodadoust’s teaching regarding preventing cancer metastases with
niclosamide, we do not give substantial weight to Dr. Stein’s statement that
the activity of niclosamide being effective at inhibiting metastasis in cancers
in which S100A4 is overexpressed was surprising (Stein Declaration ¶ 7; see
also id. ¶ 13 (“To the best of my knowledge, niclosamide has never

6 This declaration is dated May 15, 2017.
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previously been disclosed . . . in connection with . . . a direct anti-metastatic
effect in cancer cells.”).) Opinion evidence in declarations has little value
without factual support. In re Beattie, 974 F.2d 1309, 1313 (Fed. Cir. 1992);
see also In re American Acad. of Science Tech Ctr., 367 F.3d 1359, 1368
(Fed. Cir. 2004) (“The Board has broad discretion as to the weight to give to
declarations offered in the course of prosecution. See Velander v. Garner,
348 F.3d 1359, 1371 (Fed. Cir. 2003) (‘[A]ccord[ing] little weight to broad
conclusory statements [in expert testimony before the Board] that it
determined were unsupported by corroborating references [was] within the
discretion of the trier of fact to give each item of evidence such weight as it
feels appropriate.’).” (alterations in original)). Moreover, we note that Dr.
Stein does not attest to having read Khodadoust prior to arriving at his
conclusions.
Dr. Stein’s observation that “tumor cell migration is reduced much
more effectively by niclosamide in S100A4-positive tumors than in S100A4-
negative tumors” and his conclusion that this “demonstrates an unexpected
synergistic effect of these two features of the present invention” (Stein
Declaration ¶¶ 8–12) are also not persuasive to establish non-obviousness
when considering the teachings of Khodadoust and Boye. That is because
Boye teaches that colon cancer overexpresses S100A4 and Khodadoust
teaches treating colon cancer with niclosamide. Consequently, the method
suggested by Boye and Khodadoust is treating S100A4 positive tumors, and
thus the comparison to an S100A4-negative tumor that Dr. Stein identifies is
not a comparison to the closest prior art. “[W]hen unexpected results are
used as evidence of nonobviousness, the results must be shown to be
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unexpected compared with the closest prior art.” Baxter Travenol Labs.,
952 F.2d at 392.
For all of the foregoing reasons, therefore, we affirm the Examiner’s
rejection of claim 19 as being obvious over Khodadoust and Boye.
Claims 20, 22–27, 30, 32, 33, and 36 have not been argued separately
and therefore fall with claim 19. 37 C.F.R. § 41.37(c)(1)(iv).

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
19, 20, 22–
27, 30, 32,
33, 36
103(a) Khodadoust, Boye 19, 20, 22–
27, 30, 32,
33, 36

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

AFFIRMED