KOMINOX, INC.

Patent Trials and Appeals Board

Oct 4, 2021

2021000843 (P.T.A.B. Oct. 4, 2021)

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.
15/077,373 03/22/2016 Bernardus RADEMAKER 073430-0130 4225
20277 7590 10/04/2021
MCDERMOTT WILL & EMERY LLP
THE MCDERMOTT BUILDING
500 NORTH CAPITOL STREET, N.W.
WASHINGTON, DC 20001
EXAMINER
MCMILLIAN, KARA RENITA
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
10/04/2021 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 BENARDUS RADEMAKER1
________________

Appeal 2021-000843
Application 15/077,373
Technology Center 1600
________________

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

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the term “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies Kominox, Inc. as the real party-in-
interest. App. Br. 1.
Appeal 2021-000843
Application 15/077,373

2
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1–5 as unpatentable under 35 U.S.C.
§ 103 as being obvious over the combination of Ellison et al. (WO 99/18798
April 22, 1999) (“Ellison”), Lee et al. (KR-10-0456831, November 2, 2002)
(“Lee”), and N.C. Munshi et al., Clinical Activity of Arsenic Trioxide for the
Treatment of Multiple Myeloma, 16 LEUKEMIA 1835–37 (2002) (“Munshi”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to pharmaceutical
compositions and methods for treatment of urogenital diseases and bone
metastasis in a human. Spec. Abstr.

REPRESENTATIVE CLAIM
Independent claim 1 is representative of the claims on appeal and
recites:
1. A method of treating multiple myeloma in a patient
comprising administering a composition comprising a
therapeutically effective amount of sodium meta arsenite to the
patient.

App. Br. 9.

Appeal 2021-000843
Application 15/077,373

3
ISSUE AND ANALYSIS
We agree with and adopt the Examiner’s findings, reasoning, and
conclusion that the claims would have been obvious over the cited prior art.
We address below the arguments raised by Appellant.

The Examiner’s Findings of Fact and Conclusions of Law
The Examiner finds that Ellison teaches compositions and methods
for the treatment of primary and metastatic neoplastic diseases using arsenic
compounds. Final Act. 9 (citing Ellison Title, Abstr.). The Examiner finds
that Ellison further teaches the novel use of arsenic compounds for treating
primary and metastatic tumors, primary and metastatic tumors of the central
nervous system, refractory primary and metastatic tumors of the central
nervous system, breast, lung, bladder and prostate cancer, and refractory
breast, lung, bladder, and prostate cancer. Id. (citing Ellison, 1). The
Examiner finds that Ellison also teaches the use of arsenic compounds to
treat mammals suffering from hematopoietic disorders, including multiple
myeloma. Id. (citing Ellison, 10).
The Examiner also finds that Ellison teaches that arsenic compounds
in the form of a salt, complex, organic compound or ionic solution, have
broad applicability in the treatment of various cancers. Final Act. 10 (citing
Ellison, 10). The Examiner finds that Ellison teaches that the arsenic
compound can be utilized in a variety of known forms and the preferred
form should be chosen to reduce toxicity and improve efficacy. Id. (citing
Ellison, 14). The Examiner finds that Ellison teaches that the inorganic salt
forms of arsenic are preferred, including, arsenic triiodide, arsenic trioxide,
potassium arsenite, sodium arsenite and calcium arsenite. Id. (citing Ellison,
Appeal 2021-000843
Application 15/077,373

4
14). The Examiner further finds that Ellison specifically teaches that
generally, the skilled artisan will recognize that the form of arsenic to be
used should be therapeutically effective without unreasonable toxicity. Id.
(citing Ellison, 15).
The Examiner acknowledges that Ellison does not specifically teach
administration of sodium meta arsenite, despite Ellison’s teaching the use of
sodium arsenite. Final Act. 12. However, the Examiner finds that Lee
teaches an anticancer drug compositions comprising sodium arsenite,
sodium meta arsenite, and mixtures thereof, which exhibits direct cytotoxic
activity against rapidly proliferating cells, such as tumor cells or other
hyperproliferative cellular disease, which is effective in the treatment of
cancer. Id. (citing Lee, Abstr.). The Examiner finds that Lee expressly
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. (citing Lee Exs. 1, 2). The Examiner further notes that Example 3
of Lee demonstrates that arsenic acid sodium salt and the salt of meta-
arsenite have low toxicity. Id.

Issue 1
Appellant argues that the Examiner erred because Ellison’s teaching
of using arsenic compounds to treat cancers does not render obvious the
claimed subject matter of using the specific compound, i.e., sodium meta
arsenite, for the treatment of the specifically claimed cancer, multiple
myeloma. App. Br. 3.

Appeal 2021-000843
Application 15/077,373

5
Analysis
Appellant initially points to Impax Labs., Inc. v. Lannett Holdings
Inc., 893 F.3d 1372 (Fed. Cir. 2018), as noting that a passing reference in the
prior art to a formulation containing the claimed active ingredient may not
be sufficient to invalidate a claim directed to a formulation comprising the
active ingredient. App. Br. 3 (see Impax, 893 F.3d at 1379 n.4). According
to Appellant, Ellison teaches a “laundry list” of arsenic compounds, in which
sodium meta-arsenite is not specifically mentioned. Id. Appellant argues
that Ellison teaches sodium arsenite as one of the many arsenic compounds,
but, Appellant notes, sodium arsenite can be in either sodium meta arsenite
or sodium ortho arsenite forms. Id. Appellant also argues that Ellison
teaches a large list of cancers for which arsenic compounds can be used to
treat, and that multiple myeloma is referenced only in passing. Id.
Appellant summarizes that Ellison, as a whole, is not about treating
multiple myeloma with any arsenic compounds, much less about treating
multiple myeloma with sodium meta arsenite (which Ellison even fails to
spell out). App. Br. 3. Appellant asserts that Ellison is focused on arsenic
trioxide, and speculates about treatment of varieties of cancers using
varieties of arsenic compounds. Id. at 3–4.
Appellant acknowledges that Lee teaches that arsenic acid sodium salt
and a salt of meta arsenite have anti-cancer activity. App. Br. 4. Appellant
argues that, even assuming the salt of meta arsenite is sodium meta arsenite,
the combination of Lee and Ellison at most teaches that sodium meta
arsenite can be used to treat a large list of cancers. Id.
Appellant acknowledges the Examiner’s finding that claim 18 of
Ellison recites a method of treating seven types of cancer, one of which is
Appeal 2021-000843
Application 15/077,373

6
multiple myeloma. App. Br. 4 (see Final Act. 11). However, Appellant
argues that claim 18 refers generally to treatment with an “arsenic
compound,” but provides no guidance with respect to sodium meta arsenite.
Id.
Appellant further contends that the Examiner’s reliance on KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398 (2007) is misplaced. App. Br. 4 (see, e.g.,
Final Act. 3–4). Appellant argues that KSR is applicable only if the number
of possible solutions are defined and the art is predictable. Id. Appellant
contends that the combination of Ellison and Lee provides an untenable
number of possible arsenic compounds and cancers to be treated, and that
the claimed subject matter is in an unpredictable field of the chemical
sciences. Id. (citing Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.2d
1316, 1330 (Fed. Cir. 2001) (holding that chemistry and biology are
unpredictable arts).
We are not persuaded by Appellant’s arguments that the Examiner
erred in rejecting the claims as obvious. As an initial matter, it is well
known in the chemical arts that sodium meta arsenite is a synonym for
sodium arsenite.2 See, e.g., Millipore Sigma, Sodium (meta)arsenite,
available at: https://www.sigmaaldrich.com/US/en/product/aldrich/s7400
(last visited September 27, 2021) (Sodium arsenite is a synonym for sodium
meta arsenite). Consequently, we find that a person of ordinary skill in the
art would understand that Ellison’s teachings concerning sodium arsenite
refer to sodium meta arsenite. Moreover, even if sodium arsenite referred to

2 Sodium meta arsenite (i.e., sodium arsenite) has the chemical formula
NaAsO3. Sodium ortho-arsenite (also known as trisodium arsenite) has the
chemical formula Na3AsO3.
Appeal 2021-000843
Application 15/077,373

7
the ortho- and meta arsenites, one of ordinary skill in the art would have
envisaged that either compound could be used therapeutically, making the
choice of sodium meta arsenite obvious.
Ellison teaches that inorganic arsenic-based compounds have broad
use as anticancer agents, including against hematopoietic neoplasms.
Specifically, Ellison teaches that:
This invention also encompasses the treatment of hematopoietic
disorders in mammals by the administration of one or more
arsenic compounds to said mammal. The hematopoietic
disorders to be treated include but are not limited to
polycythemia vera, Hodgkin’s Disease, non-Hodgkin’s Disease
including Follicular Lymphoma, Diffuse Lymphoma,
lymphoblastic lymphoma, small lymphocytic lymphoma, acute
lymphocytic leukemia, hairy cell leukemia, myeloid metaplasia,
myeloid dysplastic syndrome, multiple myeloma and
plasmacytoma.

Ellison 10 (emphasis added). Furthermore, Ellison teaches that:
The arsenic compound of the invention may be utilized in … a
variety of known forms; for example, arsenic can be
administered as a salt, an organic or inorganic complex, an
organic chelate, an organic compound or an organic or inorganic
solution.… The inorganic salt forms of arsenic are preferred. For
example, inorganic salts such as arsenic triiodide,
arsenic(III)bromide, arsenic(III)chloride, arsenic pentoxide,
arsenic trioxide, Fowler’s solution (potassium arsenite), sodium
arsenite, and calcium arsenite may be used. Arsenic trioxide is
most preferred.

Id. at 14 (emphasis added). In summary, Ellison expressly teaches the use of
sodium meta arsenite as a preferred inorganic arsenic compound against an
array of neoplasms, including multiple myeloma.
Appeal 2021-000843
Application 15/077,373

8
Lee also teaches that sodium meta arsenite has activity against a
number of tumor cell lines, including the hematopoietic tumor lines
leukemia CCRF-CEM. Lee teaches that sodium meta arsenite not only has
antitumor activity against cancer cell lines, but additionally has a lower
toxicity at the administered doses. See Lee, Ex. 2, 3.
We conclude that, contrary to Appellant’s arguments, the combination
of Ellison and Lee teaches or suggests the limitations of claim 1.

Issue 2
Appellant argues that the Examiner erred because a person of ordinary
skill in the art could have had no reasonable expectation of success in
combining the teachings of Lee and Ellison to arrive at the claimed
invention. App. Br. 5.

Analysis
Appellant first points to the Declaration of Dr. Sujong Kim (the “Kim
Declaration”). According to Appellant, the studies reported in the Kim
Declaration demonstrates that sodium meta arsenite is much more effective
than arsenic trioxide in inhibiting the cellular proliferation in seven multiple
myeloma cell lines. App. Br. 5. Appellant states that the Kim Declaration
reports that the in vivo effectiveness of sodium meta arsenite in treating
multiple myeloma was further confirmed in a human clinical trial. Id.
Appellant asserts that this reported success in treating multiple myeloma
patients with sodium meta arsenite could not have been reasonably expected.
Id.
Appeal 2021-000843
Application 15/077,373

9
Appellant contends that neither Ellison nor Lee provides a reasonable
expectation of success with respect to using sodium meta arsenite for
treating multiple myeloma. App. Br. 5. According to Appellant, it is well
known in the art that the field of cancer therapeutics is highly unpredictable
and that in vitro assays do not serve as a reasonable prediction of the
effectiveness of the tested compound. Id. Appellant argues that the only
arsenic compound for which Ellison provides any data is arsenic trioxide,
and the data are obtained from in vitro assays using cancer cell lines. Id.
Appellant contends that the Examiner has not established if any of the cell
line are related to multiple myeloma. Id. (citing Ellison, 33, 34).
Furthermore, Appellant argues, because Lee is also limited to in vitro data
obtained from cancer cell lines (none of which appears to be multiple
myeloma cell-line), the combination of these two references would offer no
basis for reasonable expectation of success for the claimed “method of
treating multiple myeloma in a patient comprising administering a
composition comprising a therapeutically effective amount of sodium meta
arsenite to the patient.” Id.
Appellant acknowledges the Examiner’s finding that Ellison teaches
that hematopoietic disorders, including multiple myeloma, may be treated by
administering arsenic compounds, including sodium meta arsenite. App. Br.
5. Appellant contends, however, that the evidence of record shows that
Ellison’s teaching of the anti-cancer activity of arsenic compounds is
contradicted by scientific literature at the time of filing of the claimed
invention. Id.
Appellant points, by way of example, to K.B. Kim et al., A Phase II
Trial of Arsenic Trioxide in Patients with Metastatic Melanoma, 104
Appeal 2021-000843
Application 15/077,373

10
CANCER 1687–92 (2005) (“Kim”). Appellant notes that Kim reports that, in
a phase II clinical trial of arsenic trioxide in patients with metastatic
melanoma, arsenic trioxide failed to induce any clinical response. App. Br.
6 (citing Kim, Results). Appellant notes that Kim states 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. Appellant asserts
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 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.E. Gallagher et al., Arsenic Trioxide (ATO)
in Metastatic Hormone-Refractory Prostate Cancer (HRPC): Results of
Phase II Trial T99–0077 22 (14S) J. CLIN. ONCOL. 4638 (2004)
(“Gallagher”). Appellant contends that Gallagher teaches a clinical trial
employing arsenic trioxide in metastatic hormone-refractive prostate cancer
patients, “based on in vitro evidence of anti-prostate cancer cell activity” of
arsenic trioxide, but found that the drug had “limited efficacy” and severe
toxicity.
Appellant also 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 2624–29 (2006) (“Beer”) and J. Vuky et al.,
Phase II Trial of Arsenic Trioxide in Patients with Metastatic Renal Cell
Carcinoma, 20 Invest. New Drugs 327–30 (2002) (“Vuky”), which,
Appellant argues, also found arsenic trioxide to have no clinical efficacy in
Appeal 2021-000843
Application 15/077,373

11
the treatment of tumors and/or metastasis, while exhibiting significant side
effects. App. Br. 6. Appellant contends that these studies, inter alia, show
that in vitro data obtained with arsenicals are not predictive of clinical
efficacy. Id. Appellant further argues that additional studies reported in the
scientific literature demonstrate that another arsenical, Melarsopol, a
trivalent arsenic, disclosed by Ellison to have therapeutic efficacy in the
treatment of cancer including metastasis, is too toxic for clinical use. Id.
(citing, e.g., P. Rousselot et al., A Clinical and Pharmacological Study of
Arsenic Trioxide in Advanced Multiple Myeloma Patients, 18 LEUKEMIA
1518–21 (2004)).
Appellant contends that these studies demonstrate that neither
Ellison’s in vitro data obtained with arsenic trioxide and statements
concerning other arsenicals, nor Lee’s in vitro data with sodium meta
arsenite against primary tumor cell lines (none of which is multiple myeloma
cell line) provides a sufficient basis for 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 multiple myeloma. App.
Br. 7.
Appellant also points to the Declaration of Bernardus Rademaker
submitted in parent application 11/631,962, filed December 11, 2014 (the
“Bernardus Declaration”), which states that neither arsenic acid sodium salt
nor potassium arsenite has anti-cancer activity, although Ellison teaches that
these two compounds have such activity. App. Br. 7.
In summary, Appellant argues that the Examiner has not established
that a skilled artisan, based on the in vitro anti-cancer activity of arsenic
trioxide or sodium meta arsenite against cancer cell lines, none of which
Appeal 2021-000843
Application 15/077,373

12
even appears to be multiple myeloma, could have reasonably expected the
success of the claimed subject matter (i.e., using sodium meta arsenite for
the treatment of multiple myeloma). App. Br. 7. Appellant contends that
the only evidence supporting the Examiner’s findings is Ellison’s
teachingthat a broad range of arsenic compounds can treat a broad range of
cancers, which Appellant asserts is contrary to the scientific research as
discussed above.
We are not persuaded by Appellant’s arguments. Ellison expressly
teaches or suggests the use of inorganic arsenic salts, including sodium meta
arsenite, for the treatment of multiple myeloma. See, e.g., Ellison 1, 10, 14,
16-18. Ellison does not provide any working examples expressly using
sodium meta arsenite. However, 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 9.3 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 position that the related art at the time of Appellant’s
filing of the present application was such that a person of ordinary skill in
the art would not have had a reasonable expectation of success in using

3 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
Appeal 2021-000843
Application 15/077,373

13
sodium meta arsenite as an anticancer drug in vivo against multiple
myeloma, 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 in vivo, and exhibits 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
evidence of the lack of predictive power of in vitro testing for in vivo
efficacy such that a person of ordinary skill in the art would not have had 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 (NaAsO3) and arsenic trioxide (As2O3).
Appellant persuasively argues that certain cited 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. As Lee discussed, sodium meta
arsenite is a metabolite of arsenic trioxide. Appellant did not provide
evidence that the metabolite would be expected to have the same properties
as the unmetabolized compound.
Second, although we agree with Appellant that there is some degree of
unpredictability in the translation of in vitro into in vivo efficacy,
Appeal 2021-000843
Application 15/077,373

14
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
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 both 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 Langi, 759 F.2d 887, 897 (Fed. Cir. 1985); In re Clinton,
527 F.2d 1226, 1228 (C.C.P.A. 1976) (emphasis added). Indeed, the “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
Appeal 2021-000843
Application 15/077,373

15
(Fed. Cir. 2007).
With respect to the Rademaker Declaration, Appellant contends that
Dr. Rademaker attests that neither arsenic acid sodium salt nor potassium
arsenite has anti-cancer activity. See App. Br. 7. That is simply not true.
The Rademaker Declaration expressly states that “[a]rsenic acid sodium salt
was active at the dose range of 10 pg/mL in the leukemia cell line CCRF-
CEM and lymphoma U937, at 30 g/mL in promyelocytic leukemia K562,
lymphoma U937 and melanoma MEXF 462NL (CCRF-CEM was not tested
at this dose) and at 100 μg/mL in 7 of 9 tumour cell lines.” Rademaker
Decl. 5. Dr. Rademaker further attests that “[s]odium meta arsenite was
very active at 1 pg/mL in lymphoma U937, active in leukemia CCRF-CEM
at 3, 10,30 and 100 pg/mL in 2/8 (leukemia K562 and lymphoma U937), 5A,
5/8, 9/9 tumour cell lines respectively,” which correlates with the findings of
Lee. Id.
We conclude that, given the teachings of Ellison and Lee, it would
have been reasonable for a person of ordinary skill in the art to expect that
sodium meta arsenite would be effective as a drug for the treatment of
multiple myeloma. We are consequently not persuaded by Appellant’s
arguments, and we affirm the Examiner’s rejection of claims 1–5.

CONCLUSION
The rejection of claims 1–5 as unpatentable under 35 U.S.C. § 103 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.

Appeal 2021-000843
Application 15/077,373

16
AFFIRMED

Claim(s)
Rejected
35 U.S.C. §  Reference(s)/Basis Affirmed Reversed
1–5 103 Ellison, Lee,
Munshi
1–5