Bernardus Rademaker

Patent Trials and Appeals Board

Aug 30, 2019

11631962 - (D) (P.T.A.B. Aug. 30, 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.
11/631,962 09/04/2008 Bernardus Rademaker 073430-0052 1472
20277 7590 08/30/2019
MCDERMOTT WILL & EMERY LLP
THE MCDERMOTT BUILDING
500 NORTH CAPITAL STREET, N.W.
WASHINGTON, DC 20001
EXAMINER
MCMILLIAN, KARA RENITA
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
08/30/2019 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):
ipdocketmwe@mwe.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte BERNARDUS RADEMAKER1
________________

Appeal 2018-005307
Application 11/631,962
Technology Center 1600
________________

Before RICHARD M. LEBOVITZ, JOHN G. NEW, and
TAWEN CHANG, Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 Appellant identifies Kominox, Inc., as the real party-in-interest. App. Br.
1.
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Application 11/631,962

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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 7, 20, and 34–37 as unpatentable under
35 U.S.C. § 103(a) as being obvious over the combination of Ellison et al.
(WO 99/18798, April 22, 1999) (“Ellison”) and Lee et al. (KR-10-0456831,
November 3, 2004) (“Lee2”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s invention is directed to pharmaceutical compositions and
methods for treatment of urogenital diseases and bone metastasis in a
human. The pharmaceutical composition contains an effective amount of
arsenous acid alkaline or earth alkaline metal salt and/or a pharmaceutically
acceptable adjuvant. Abstr.

REPRESENTATIVE CLAIM
Claim 7 is representative of the claims on appeal and recites:
7. A method of treating genitourinary metastatic cancer in a
patient, comprising administering a composition comprising a
therapeutically effective amount of sodium meta arsenite to the
patient

App. Br. 8.

2 An English translation of Lee, dated August 20, 2012, is of record in this
appeal.
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ISSUES AND ANALYSES
We adopt the Examiner’s findings, reasoning, and conclusions that the
claims are obvious over the combined cited prior art. We address the
arguments raised by Appellant in the following analyses.

Issue 1
Appellant argues that the Examiner erred in finding that a person of
ordinary skill in the art would have had a reasonable expectation of success
for using any arsenic compound, let alone sodium meta arsenite, to treat
genitourinary metastatic cancer. App. Br. 3.

Analysis
The Examiner finds that Ellison teaches novel uses of arsenic
compounds for treating primary and metastatic tumors of the central nervous
system, breast, lung, bladder and prostate cancer, and refractory breast, lung,
bladder and prostate cancer. Final Act. 9 (citing Ellison 1, ll. 13–20). The
Examiner finds that Ellison further teaches that arsenic compounds such as
arsenic in the form of a salt, complex, organic compound, or ionic solution,
have broad applicability in the treatment of various cancers, including solid
tumors and blood disorders such as tumors of epithelial tissue, connective
tissue, central nervous system, lymphoid tissue, hematopoietic cells and
tumors associated with oncogenic viruses. Id. (citing Ellison 10, ll. 5–15).
The Examiner finds that Ellison teaches that arsenic compounds are
effective in the treatment of cancer through several mechanisms of action
including inhibition of angiogenesis (which would explain its effect on
metastases), sensitizing cancer cells to radiation and/or chemotherapy. Id.
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(citing Ellison 11–12, ll. 3–6; 12 ll. 14–17). The Examiner finds that Ellison
expressly teaches using arsenic compounds for the treatment of metastatic
cancer. Id. at 10 (citing Ellison 27 l. 10).
The Examiner finds further that Ellison teaches that the inorganic salt
forms of arsenic are preferred, including, arsenic triiodide, arsenic trioxide,
potassium arsenite, sodium arsenite, and calcium arsenite. Final Act. 10
(citing Ellison 14 ll. 31–35). However, the Examiner finds that Ellison does
not teach specific examples of the administration of sodium meta arsenite.
Id. at 11.
The Examiner finds that Lee teaches an anticancer drug composition
comprising an arsenic acid sodium salt, a meta-arsenite salt, or mixtures
thereof. Final Act. 11 (citing Lee Abstr.). The Examiner finds that Lee
specifically teaches that both arsenic acid sodium salt and meta-arsenite
sodium salt have antitumor effects against numerous tumor cell lines,
including prostate cancer cells. Id. at 11–12 (citing Lee Exs. 1, 2). The
Examiner also finds that Example 3 of Lee demonstrates that sodium meta
arsenite is a potent anticancer agent because the tumor cells were about 2 to
20 times more sensitive to the meta arsenite compound than to the arsenate
sodium salt, but it is not toxic at the administered concentrations. Id. at 12.
The Examiner concludes that a person of ordinary skill in the art
would have been motivated to administer any of the arsenic compounds
taught by Ellison, including sodium meta arsenite, for the treatment of
metastatic cancer with a reasonable expectation of similar success. Final
Act. 11. The Examiner further concludes that a person of ordinary skill
would have been further motivated to choose sodium meta arsenite for the
treatment of metastatic lung cancer with a reasonable expectation of success
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because Lee expressly teaches that sodium meta arsenite has antitumor
activity against various tumor cell lines including prostate cancer cells. Id.
at 12.
Appellant argues that the field of cancer therapeutics is highly
unpredictable and an in vitro assay does not serve as a reasonable prediction
of the effectiveness of a test compound. App. Br. 3. Appellant contends
that the only arsenic compound for which Ellison provides data is arsenic
trioxide, and the data are obtained from in vitro assays using cancer cell
lines, which provide no information with respect to the effect of the test
compound on metastatic cells. Id. Appellant asserts that Ellison provides no
evidence concerning the effective treatment of metastatic cancer using any
arsenic compound, particularly sodium meta arsenite, as recited in the claims
on appeal. Id.
Appellant argues further that Lee is also limited to in vitro data
obtained from cancer cell lines. App. Br. 3. According to Appellant, the
combination of these two references offers no basis for a skilled artisan to
have had a reasonable expectation of success for the claimed “method of
treating genitourinary metastatic cancer in a patient, comprising
administering a composition comprising a therapeutically effective amount
of sodium meta arsenite to the patient.” Id.
Appellant argues that the scientific literature at the time of invention
with respect to clinical trials of arsenic trioxide in the treatment of various
metastatic cancers contradicts Ellison’s extrapolation of arsenic trioxide’s in
vitro anti-cancer activity into the effectiveness of arsenic trioxide in treating
cancers. App. Br. 4. By way of example, Appellant points to K.B. Kim et
al., A Phase II Trial of Arsenic Trioxide in Patients with Metastatic
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Melanoma, 104 CANCER, 1687–92 (2005) (“Kim”), which teaches that a
phase II clinical trial of arsenic trioxide in patients with metastatic
melanoma failed to induce any clinical response. App. Br. 4. Appellant
points to Kim as stating that: “The discrepancy between the in vitro activity
and the clinical efficacy of an anticancer drug is a recurring dilemma in new
drug development for patients with advanced [metastatic] melanoma, and
this situation calls for more thorough approaches to preclinical drug
testing.…” Id. (quoting Kim 1691). Appellant contends that Kim’s clinical
data demonstrate that in vitro data obtained with arsenic trioxide has limited
value in predicting its efficacy, or that of any other arsenical in the treatment
of metastasis, or in predicting whether side effects may prohibit a drug’s use
in vivo. Id.
Appellant next points to R. Gallagher et al., Arsenic Trioxide (ATO) in
Metastatic Hormone-Refractory Prostate Cancer (HRPC): Results of Phase
II Trial T99–0077, ASCO ANN. MEET. PROC., 22(14S) J. CLIN. ONCOL. 4638
(2004) (“Gallagher”). Appellant contends that Gallagher teaches that:
“based on in vitro evidence of anti-prostate cancer cell activity” of ASO and
found that the drug had ‘limited efficacy’ and severe toxicity.” App. Br. 4
(quoting Gallagher 4638).
Appellant further points to T.M. Beer et al., Southwest Oncology
Group Phase II Study of Arsenic Trioxide in Patients with Refractory Germ
Cell Malignancies, 106 CANCER 2624–2629 (2006) (“Beer”)3 and J. Vuky et

3 Beer was published on September 4, 2008 and is a continuation of
PCT/KR06/01731, filed May 9, 2006, of which it claims the priority
benefit. Beer was published on May 10, 2009 and is consequently not
prior art for the purposes of this application.
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al., Phase II Trial of Arsenic Trioxide in Patients with Metastatic Renal Cell
Carcinoma, 20(3) INVEST. NEW DRUGs 327–30 (2002) (“Vuky”) as both
teaching that arsenic trioxide had no clinical efficacy in the treatment of
tumors and/or metastasis, although exhibiting significant side effects. App.
Br. 4. Appellant argues that the teachings of these references demonstrate
that data from in vitro studies with arsenicals are not predictive of clinical
efficacy. Id.
Appellant next points to P. Rousselot et al., A Clinical and
Pharmacological Study of Arsenic Trioxide in Advanced Multiple Myeloma
Patients, 18 LEUKEMIA 1518–21 (2004) (“Rousselot”) and S.L. Soignet et
al., Clinical Study of an Organic Arsenical, Melarsoprol, in Patients with
Advanced Leukemia, 44 CANCER CHEMOTHER. PHARMACOL. 417–21 (1999)
(Soignet) as teaching that melarsoprol, a trivalent arsenic compound
different from arsenic trioxide, and also taught by Ellison as having
therapeutic efficacy in the treatment of cancer including metastatic cancers,
is too toxic for clinical use. App. Br. 4–5.
Appellant summarizes these studies as demonstrating that neither
Ellison’s in vitro data obtained with arsenic trioxide, and statements
concerning other arsenical compounds, nor Lee’s in vitro data with sodium
meta arsenite against primary tumor cell lines, is sufficient such that a
person of ordinary skill would have had a reasonable expectation of success
concerning the use of arsenic trioxide, let alone other arsenic compounds
such as sodium meta arsenite, in the treatment of metastatic cancer. Id.
Appellant provides a Declaration by Yi Geun Park, filed March 9,
2012 (the “Park Declaration”). App. Br. 5. Appellant asserts that Dr. Park
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states that neither arsenic acid sodium salt nor potassium arsenite has anti-
cancer activity. Id.
Appellant accordingly argues that the prior art cited by the Examiner
is, at most, mere speculative concerning the successful use of arsenic
compounds to treat cancer and metastasis. App. Br. 5. Appellant contends,
however, that such speculation has proven to be incorrect, and that a skilled
practitioner would not have had a reasonable expectation of success for
using any particular arsenic compound to treat metastatic cancer.
We are not persuaded by Appellant’s arguments. Ellison expressly
teaches the use of inorganic arsenic salts, including sodium meta arsenite,
for the treatment of various metastatic cancers, including genitourinary
metastatic cancers. See, e.g., Ellison 1, 10, 14, 16–18. Ellison does not
provide any working examples expressly using sodium meta arsenite.
Lee teaches that: “This invention is based on [the] anticancer effect of
arsenic acid sodium salt and salt of meta arsenite which are the metabolite of
arsenic trioxide, or mixture[s] containing these. This has a direct
cytotoxicity to cure [sic] the tumor cell, [and] has an excellent effect as an
anticancer drug.” Lee 9.4 Lee also provides working examples
demonstrating that sodium meta arsenite is effectively cytotoxic against
various cancer lines in vitro, but has generally low toxicity in vivo at a dose
of 20 mg/kg body mass. See Lee Exs. 2–3.
It is Appellant’s contention that the related art at the time of
Appellant’s filing of the instant application was such that a person of

4 The English translation of Lee in the record is without page numbers. The
number referred to is the consecutive page number of the English
translation.
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ordinary skill in the art would not have had a reasonable expectation of
success in using sodium meta arsenite as an anticancer drug in vivo against
metastatic cancers, the teachings of Ellison and Lee notwithstanding.
Appellant points to a number of studies showing that arsenic trioxide, which
Ellison demonstrates as having in vitro cytotoxicity against cancer cell lines,
is inefficacious when used as a drug used in vivo, and demonstrates
significant toxicity. Appellant argues that the failure of arsenic trioxide as
an in vivo anticancer drug, despite the encouraging results presented in vitro
in Ellison, is such that the lack of predictive power of in vitro testing for in
vivo efficacy would not lead a person of ordinary skill in the art to have a
reasonable expectation of success that sodium meta arsenite would
demonstrate in vivo efficacy, despite the teachings of Ellison and Lee.
We do not agree. First, there are the obvious structural differences
between sodium meta arsenite (NaAsO2) and arsenic trioxide (As2O3).
Appellant persuasively argues that the prior art shows that Ellison’s teaching
that arsenic trioxide’s promising effectiveness as an anticancer agent in vitro
is not borne out by a similar in vivo efficacy as an anticancer drug. But
Appellant adduces no direct evidence that a person of ordinary skill in the art
would recognize or understand that sodium meta arsenite must also
necessarily be similarly ineffective in vivo when it is a different compound
and different structurally from the trioxide.
Second, although we agree with Appellant that there is some degree of
unpredictability in the translation of in vitro into in vivo efficacy,
nevertheless, it is generally understood within the art of drug discovery that
in vitro screening of cancer cell cytotoxicity is a commonly practiced and
effective way of selecting candidate chemical compounds for further testing
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as in vivo anticancer drugs. Certainly, in vitro effectiveness is a
considerably more reliable indicator of potential in vivo success than the lack
thereof.
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill in the art has good reason to
pursue the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense.

KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 402–403 (2007). Certainly
there is “design need or market pressure” in the development of new drugs
for the treatment of metastatic cancers, and Ellison and Lee teach that
sodium meta arsenite has significant anticancer cell activity in vitro and at
least suggest that it is a potent anticancer drug in vivo.
Furthermore, “[o]bviousness does not require absolute predictability
of success. Indeed, for many inventions that seem quite obvious, there is no
absolute predictability of success until the invention is reduced to practice.”
In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). For obviousness under
Section 103, “all that is required is a reasonable expectation of success.” Id.
at 904 (citing In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985); In re Clinton,
527 F.2d 1226, 1228 (C.C.P.A. 1976) (emphasis added). Indeed, “case law
is clear that obviousness cannot be avoided simply by a showing of some
degree of unpredictability in the art so long as there was a reasonable
probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364
(Fed. Cir. 2007).
With respect to the Park Declaration, we find no evidence presented
within the Declaration to support Appellant’s contention that, at the time of
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invention, a person of ordinary skill would not have had, at the time of
Appellant’s filing, a reasonable expectation of success that sodium meta
arsenite would not act as an effective chemotherapeutic agent against
metastatic cancers.
We conclude that, given the teachings of Ellison and Lee, it would it
would have been reasonable for a person of ordinary skill in the art to expect
that sodium meta arsenite could be effective as a drug for the treatment of
metastatic cancer. We are consequently not persuaded by Appellant’s
arguments.

Issue 2
Appellant argues that their demonstration of unexpected results
overcomes the Examiner’s prima facie conclusion of obviousness. App. Br.
5–6.

Analysis
Appellant points to the Park Declaration as asserting that sodium meta
arsenite is extremely effective in the treatment of metastasis regardless of the
origin of the primary tumor. App. Br. 5. Specifically, Appellant contends
that the Park Declaration states that metastatic tumors were observed to
disappear (patients 10 and 11) or shrink in size after only a short period of
treatment (patients 4, 8, and 9), or pain associated with bone metastasis was
significantly reduced (patient 6). App. Br. 5. Significantly, asserts
Appellant, Mr. Park attests that these results were obtained in patients where
other treatments had failed. Id. Further, Appellant argues, the Park
Declaration states that, in the clinical trial involving prostate cancer patients,
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sodium meta arsenite treatment of patients who had bone metastasis showed
a higher degree of treatment efficacy for the secondary bone tumors (86%)
than for the primary prostate tumor (66%). Id. at 5–6. Appellant contends
that these results could not have been expected on the basis of effect
achieved on the primary tumor. Id. at 6.
Appellant next points to the Declaration of Mr. Sujong Kim, filed
September 17, 2015 (the “Kim Declaration”). According to Appellant, the
Kim Declaration describes significantly enhanced retention of sodium meta
arsenite in the blood and widespread tissue distribution and high
concentration of sodium meta arsenite in various tissues, which are
unexpected and enable sodium meta arsenite to reach sites of metastasis that
other arsenic compounds, e.g., arsenic trioxide, cannot reach at therapeutic
level. App. Br. 6. Appellant contends that these unexpected properties are
partially responsible for the significantly better efficacy of sodium meta
arsenite observed in treatment of metastatic cancers. Id. Appellant asserts
that the Kim Declaration further demonstrates that the amount of arsenic
trioxide administered intravenously was comparable to the amount of
sodium meta arsenite administered orally. Id. In other words, argues
Appellant, the observed enhanced serum retention and tissue distribution
obtained with sodium meta arsenite in comparison to arsenic trioxide are not
attributable to the amount of drug administered. Id.
Appellant contends that the Kim Declaration also states that even
though the amount of orally administered sodium meta-arsenite is twice the
amount of intravenously administered arsenic trioxide, they are considered
to be comparable. App. Br. 6. Appellant states that the Kim Declaration
suggests that this is because orally administered sodium meta arsenite needs
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to go through hepatic absorption and metabolism before reaching blood flow
while intravenously administered arsenic trioxide reaches blood flow
directly. Id. (citing Kim Declaration ¶ 13).
We are not persuaded by Appellant’s arguments. Appellant contends
that sodium meta arsenite is an effective chemotherapeutic agent for treating
metastatic secondary tumors. However, this entirely consistent with the
teachings of Ellison and Lee, that sodium meta arsenite “has an excellent
effect as an anticancer drug.” Lee 9. See Iron Grip Barbell Co. v. USA
Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (holding that unexpected
results that are probative of nonobviousness are those that are “different in
kind and not merely in degree from the results of the prior art” (citation
omitted)).
Nor are we persuaded by the Kim Declaration’s statement that
significantly enhanced retention of sodium meta arsenite in the blood and its
widespread tissue distribution and high concentration in various tissues are
unexpected. See Kim Declaration ¶ 17. This enhanced retention is a
property of the sodium meta arsenite that, even if previously unknown, is a
latent property of that compound and, therefore, inherent to that compound.
See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991)
(holding that “[m]ere recognition of latent properties in the prior art does not
render nonobvious an otherwise known invention”) (citing In re Prindle, 297
F.2d 251, 254 (C.C.P.A. 1962).
Appellant adduces no evidence to demonstrate that sodium meta
arsenite does not inherently persist in body tissues longer than arsenic
trioxide, to which the Kim Declaration compares it. We consequently are
not persuaded by Appellant’s argument that sodium meta arsenite has
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demonstrated unexpected properties, and we affirm the Examiner’s rejection
of the claims.

DECISION
The Examiner’s rejection of claims 7, 20, and 34–37 as unpatentable
under 35 U.S.C. § 103(a) 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