Ex Parte Huang et al

Patent Trial and Appeal Board

Apr 20, 2017

13989016 (P.T.A.B. Apr. 20, 2017)

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.
13/989,016 10/11/2013 Peng Huang UTSC.P1056US 3042
108197 7590 04/24/2017
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
EXAMINER
MATOS NEGRON, TAINA DEL MAR
ART UNIT PAPER NUMBER
1621
NOTIFICATION DATE DELIVERY MODE
04/24/2017 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):
docket @ phiplaw .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PENG HUANG, WAN ZHANG, and MICHAEL J. KEATING
Appeal 2016-004023
Application 13/989,0161
Technology Center 1600
Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims 1, 3, 8-10, 12,
and 13 (Final Act.2 2).3 Examiner entered rejections under 35 U.S.C.
§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify the real party in interest as the “Board of Regents, The
University of Texas System” (Br. 3).
2 Examiner’s November 19, 2014 Final Office Action.
3 Pending claims 5-7 and 11 stand withdraw from consideration (Final Act.
2).
Appeal 2016-004023
Application 13/989,016
STATEMENT OF THE CASE
Appellants disclose “cancer therapy of hematologic malignant cells,
including chronic lymphocytic leukemia cells, using selenium-containing
compositions” (Spec. ^ 2). Claim 1 is representative and reproduced below:
1. A method of treating chronic lymphocytic leukemia (CLL)
in a human individual having CLL in a stromal tissue
microenvironment, comprising the step of administering to the
individual an amount of a selecticine[4] that is effective to kill
CLL cells in said stromal tissue microenvironment, wherein the
selecticine is selected from the group consisting of
selenocystine, a combination of selenocystine and 2-
mercaptoethanol, a combination of selenocystine and
dithiothreitol, and a combination of selenocystine and
hydrochloric acid.
(Br. 17.)
4 According to Appellants “[t]he term ‘selecticine’ [] refers to chemical
compositions comprising selenocystine or selenocysteine and agents that
make these selenium-containing compounds soluble and stable, thereby
suitable for therapeutic applications. Examples of such agents include
hydrochloric acid, 2-mercaptoethanol, and dithiothreitol” (Spec. ^ 54).
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Application 13/989,016
The claims stand rejected as follows:
Claims 1, 3, and 13 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Milner,5 Last,6 and
Caligaris-Cappio.7’8
Claims 1, 3, 8-10, 12, and 13 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over the combination of Milner, Last, Caligaris-Cappio, and
Stiefel.9’10
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
5 J.A. Milner and C. Y. Hsu, Inhibitory Effects of Selenium on the Growth of
LI210 Leukemic Cells, 41 Cancer Res. 1652-1656 (1981).
6 K. Last et al., The activity of methylated and non-methylated selenium
species in lymphoma cell lines and primary tumours, 17 Annals of Oncology
773-779 (2006).
7 Caligaris-Cappio, Role of the Microenvironment in Chronic Lymphocytic
Leukaemia, 123 British Journal of Haematology 380-388 (2003).
8 Appellants included cancelled claim 2 in their discussion of the rejection
over Milner, Last, and Caligaris-Cappio (see, e.g., Br. 4; cf Final Act. 2).
We did not include cancelled claim 2 in our deliberations.
9 Stiefel et al., US 6,656,509 Bl, issued Dec. 2, 2003.
10 Appellants included cancelled claims 2 and 4 in their discussion of the
rejection over Milner, Last, Caligaris-Cappio, and Stiefel (see, e.g., Br. 15;
cf. Final Act. 2). We did not include cancelled claims 2 and 4 in our
deliberations.
3
Appeal 2016-004023
Application 13/989,016
FACTUAL FINDINGS (FF)
FF 1. Etet11 discloses:
In the ongoing efforts to develop therapies against chronic
lymphocytic leukemia (CLL), stromal factors allowing
malignant cells to escape spontaneous and chemotherapy-
mediated apoptosis, giving way to relapses, have been
abundantly investigated. Bone marrow [(BM)] adherent cell
types, collectively referred to as stromal cells, appear to be key
players in such escape, mainly because CLL malignant cells,
which rapidly undergo spontaneous apoptosis when cultured in
vitro, survive, migrate, and resist cytotoxic agents in co-culture
with bone marrow stromal cells.
(Etet, Abstract.)
FF 2. Etet discloses that “BM stroma derives from mesenchymal stromal
cells (MSCs)” and “[c]o-culture studies have revealed that BM MSCs and
other stromal cell types confer CLL cells the ability to resist both
spontaneous and anticancer drug-induced apoptosis, as well as maintenance
and proliferation abilities” (Etet 24: col. 1,11. 13-14 and 29: col. 2,11. 7-11;
see also Niedermeier12 5555: col. 1,11. 8-14 (“[interactions between CLL
cells and the microenvironment are critical for maintenance and expansion
of the neoplastic B-cell clone. These interactions occur in tissue
compartments, such as the marrow and secondary lymphatic tissues, where
CLL cells interact with a variety of nonmalignant accessory cells
collectively referred to as stromal cells,” wherein “[tjhese interactions
provide growth and survival signals and also confer drug resistance”)).
11 Etet et al., Stromal control of chronic lymphocytic leukemia cells, 4
Research and Reports in Biology 23-32 (2013).
12 Niedermeier et al., Isoform-selective phosphoinositide 3 ’-kinase inhibitors
inhibit CXCR4 signaling and overcome stromal cell-mediated drug
resistance in chronic lymphocytic leukemia: a novel therapeutic approach,
113 Blood 5549-5557 (2009).
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Application 13/989,016
FF 3. Caligaris-Cappio discloses “that [] direct physical contact between
BM stromal cells and leukaemic cells extends the survival of CLL cell[s]”
and that “[i]n vitro, it has been shown that malignant CLL cells interact with
BM stromal cells via [31 and [32 integrins,” wherein “[t]his binding rescues
CLL cells from apoptosis and extends their lifespan, suggesting a potential
mechanism for the preferential in vivo accumulation and survival of CLL
cells within the BM” (Caligaris-Cappio 384: col. 2,11. 28-42; Ans. 4).
FF 4. Milner discloses that “[sjelenium has been shown to inhibit [growth
of] L1210 [Leukemic] cells both in vitro and in vivo,” wherein “[s]elenium
administration as sodium selenite was shown to be more effective in
increasing the longevity of L1210-inoculated mice than was treatment with
sodium selen[i]te, selenocystine, or selenomethionine” (Milner Abstract;
Ans. 3).
FF 5. Milner discloses that “L1210 cells incubated [in vitro] with selenium
(0.5 pg.ml) in various forms were [] found to have decreased viability,”
wherein “[t]he order of relative toxicity of the selenium compounds after 3
hr of incubation [with L1210 cells in vitro] was selenium dioxide > sodium
selenite > selenocystine > sodium selen[i]te, based on trypan blue exclusion”
(Milner 1653: col. 2,11. 1-6; Ans. 3).
FF 6. Milner found that “[s]elenium administration [to mice inoculated
with varying quantities of L1210 tumor cells] significantly increased the
longevity of the mice, regardless of the initial cell number” used to inoculate
the mice (Milner 1654: col. 1,11. 22-27; see also id. at 1653: col. 1,11. 3-12
(Milner discloses the use of “i.p. injection[]” to administer selenium
compounds to mice); Ans. 3).
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Application 13/989,016
FF 7. Milner discloses that “[t]he order of efficacy for the forms of
selenium tested was sodium selenite » selenocystine > selenomethionine =
sodium selenate” (Milner 1654: col. 1,11. 36-39; Ans. 3).
FF 8. Milner discloses that “selenium can alter the growth of L1210
leukemic cells,” wherein “sodium selenite is one of the most efficient
compounds both in vitro and in vivo against L1210 cells,” while “[sjodium
selenate and selenocystine are less effective in altering the growth of this
tumor cell line” (Milner 1655: col. 1,11. 1-14; Ans. 3).
FF 9. Milner discloses that the “[t]ypes of tumors as well as [the] form of
selenium administered may [] be important factors in the efficacy of
selenium therapy” (Milner 1655: col. 1,11. 16-18; see generally Ans. 3).
FF 10. Milner discloses that “[t]he response to selenium was at least
additive when given in conjunction with the chemotherapeutic agent,
methotrexate” (Milner 1655: col. 2,11. 2—4; Ans. 3—4).
FF 11. Examiner finds that Milner fails to disclose the treatment of “chronic
lymphocytic leukemia [(CLL)] in a human [] having CLL in a stromal tissue
microenvironment [], administering to the individual an amount effective to
kill CLL cells[, or] the step of diagnosing chronic lymphocytic leukemia”
(Ans. 4).
FF 12. Last discloses “a study of the effects of methylseleninic acid (MSA)
and selenodiglutathione (SDG), representing methylated and non-methylated
selenium species, respectively, in a lymphoma cell line panel and in a
primary lymphoma culture system,” which included “CHO cells transfected
to express CD40 ligand” that were “irradiated to prevent further
proliferation,” and, thereby, “provide[d] a stromal layer supporting B-cell
proliferation” (Last 773: col. 2,11. 19-23; id. at 774: col. 1,11. 31-33; see
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Application 13/989,016
generally Ans. 4). The selenium species used in the in vitro studies were
“activated selenium species,” which would mimic dietary forms of selenium,
such as L-selenomethionine, a selenium compound which is activated in vivo
and has little in vitro activity. (Last 776: col. 1,11. 17-24.)
FF 13. Last discloses that “[t]he activity of a 48-h exposure to SDG or MSA
was [] investigated in primary B-cell malignancy samples from patients with
mantle cell lymphoma [], follicular lymphoma [], chronic lymphocytic
leukemia [] and a normal B-cell sample from a healthy blood donor” and
Last’s results demonstrated that “[a]ll samples showed a concentration-
dependent decrease in percentage viability with MSA and SDG” (Last 775-
776, bridging paragraph (emphasis added); see also id. at 777: col. 2,11. 10-
13 (Last’s “studies were conducted to determine the activity of different
selenium species as single agents, prior to examining the role of selenium in
mediating chemosensitivity in vitro and in vivo in the lymphoma setting”);
Ans. 4).
FF 14. Last found that “[b]oth MSA and SDG induced cytostasis and
cytotoxicity in the lymphoma cell line panel studied, in a concentration and
time-dependent manner,” wherein “cells appeared more sensitive to SDG []
than MSA” (Last 776: col. 2,11. 3-6; id. at col. 1,11. 6-7). Last further
suggests that other selenium compounds may be appropriate for clinical use.
(Last 777: col. 2,11. 17-21.)
FF 15. Last discloses that “[djiffuse large B-cell lymphoma patients with
low serum selenium concentration at presentation have a lower response rate
and overall survival than patients with higher serum selenium. The co­
administration of selenium with conventional chemotherapy may be useful
in these patients” (Last, Abstract).
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Application 13/989,016
FF 16. Examiner finds that the combination of Milner, Last, and Caligaris-
Cappio fails to disclose the administration of a selenium compound with “an
additional anticancer therapy []; anticancer therapy that comprises
chemotherapy []; chemotherapy comprising] [] cyclophosphamide”; or the
oral or intravenous delivery of a selenium compound, such as a selecticine
(Ans. 7).
FF 17. Stiefel “relates to the use of selenium and/or a derivative thereof in
combination with a cytostatic or a mixture of cytostatics” (Stiefel 1: 3-5; see
generally Ans. 7).
FF 18. Stiefel discloses “[t]he use of organic selenium compounds [] to
reduce toxicity in comparison with inorganic selenium compounds with
simultaneous or improved antitumor efficiency,” wherein “[particularly
preferred are the selenium amino acids selenomethionine and selenocysteine
as well as the compound phenylenebis(methylene)selenocyanate as well as
derivatives thereof’ (Stiefel 5: 1-7; Ans. 7).
FF 19. Stiefel discloses the use of selenium or a selenium compound
together with, inter alia, “a mitosis-inhibiting cytostatic . . ., a cytostatic
inhibiting nucleic acid synthesis, for example methotrexate and fluorouracil,
which belong to the group of antimetabolites, or the topisomerase [sic]
inhibitor topotecan, mRNA synthesis inhibitors such as doxorubicin, or
alkylating agents such as cyclophosphamide and chlorambucil” (Stiefel 6: 3-
13; Ans. 7).
FF 20. Stiefel discloses the administration “of a selenium compound and a
cytostatic or several cytostatics ... in [a] solid or liquid form” for, inter alia,
oral or intravenous administration (Stiefel 9: 29-34; Ans. 7).
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Appeal 2016-004023
Application 13/989,016
ANALYSIS
The combination of Milner, Last, and Caligaris-Cappio:
Based on the combination of Milner, Last, and Caligaris-Cappio,
Examiner concludes that, at the time Appellants’ invention was made, it
would have been prima facie obvious
to develop a method of treating chronic lymphocytic leukemia
in an individual by administering selenocystine with [a]
reasonable expectation of success because Milner []
demonstrates that selenocystine inhibits L1210 leukemic cells
in vitro and in vivo and Last [] demonstrates that selenium
compounds induced cytostasis and cytotoxicity in B-cell
malignancy samples from patients with chronic lymphocytic
leukemia,
wherein the B-cell malignancy samples were co-cultured in the presence of a
stromal cell surrogate (i.e., “CHO cells transfected to express CD40 ligand”
that were “irradiated to prevent further proliferation,” and, thereby,
“provide[d] a stromal layer supporting B-cell proliferation”) (Ans. 4-5; FF
12; see generally FF 3-15).
The prior art relied upon by Examiner makes clear that the serum
selenium concentration of patients with diffuse large B-cell lymphoma, i.e.,
CFF, affects the patient’s response rate and overall survival (FF 15). The
prior art of record establishes that a selenium compound is capable of
treating, inter alia, CFF in a concentration dependent manner, when the
CFF cells are in a stromal tissue microenvironment (FF 12-13; see also FF
1-3). The prior art relied upon by the Examiner also suggests that selenium
concentration can be provided by other selenium species besides MSA or
SDG for treating CFF cells in a stromal microenvironment (FF 14). The
prior art relied upon by Examiner expressly suggests “[t]he co­
administration of selenium with conventional chemotherapy” to patients
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Application 13/989,016
with diffuse large B-cell lymphoma, such as CLL (id.; see also FF 10). The
prior art of record discloses a number of selenium based compounds that are
suitable for administration to a mammal, including selenocystine (FF 4-8
and 12-14).
For the foregoing reasons, we are not persuaded by Appellants’
contention that Appellants have “surprisingly shown that selenocystine, can
preferentially kill primary chronic leukemia cells isolated from CLL
patients, but only [] efficiently in the presence of stromal cells as now
required by [Appellants’] claims” (Br. 5; cf. FF 1-8, 10, and 12-15). Last
established that selenium based compounds were capable of killing primary
CLL cells in the presence of stromal cells and suggested that selenium based
compounds be used in the treatment of patients with CLL (FF 12-15), not
just the selenium species tested in the specific in vitro tests performed.
Milner established that a person of ordinary skill in this art was aware of a
number of different selenium based compounds, including selenocystine (FF
4-8). Thus, notwithstanding Appellants’ contention to the contrary,
Appellants appear to have, at best, performed the method suggested by the
prior art relied upon by Examiner and observed the result. “Scientific
confirmation of what was already believed to be true may be a valuable
contribution, but it does not give rise to a patentable invention.”
Pharmastem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1363-64
(Fed. Cir. 2007). See KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1732
(2007) (“Granting patent protection to advances that would occur in the
ordinary course without real innovation retards progress”). Further,
Appellants failed to establish that their evidence of surprising or unexpected
results were compared against the closest prior art.
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Appeal 2016-004023
Application 13/989,016
For the same reasons we are not persuaded by Appellants’ contentions
that their Specification established unexpected results for the use of a
selenium compound, i.e., selenocysteine, to provide an anti-CLL effect when
administered to CLL cells in a stromal tissue microenvironment (see Br. 6-
8; cf. FF 13). That is, Appellants’ Specification does not account for the
teaching of treating CLL with a selenium species already taught by Last.
Selenocysteine was known and used in the art prior to Appellants’
claimed invention (FF 4-8). Therefore, we are not persuaded by Appellants’
contentions regarding the stability and manufacture of selenocysteine, or
their use of the term “selecticines” (Br. 5-6; see also Spec. ^ 54).
For the reasons discussed above, it was known in the art prior to
Appellants’ claimed invention that serum selenium concentration of patients
with diffuse large B-cell lymphoma, i.e., CLL, affects the patient’s response
rate and overall survival (FF 15). The prior art of record also establishes that
a selenium compound is capable of treating, inter alia, CLL in a
concentration dependent manner, when the CLL cells are in a stromal tissue
microenvironment (FF 12-13). Therefore, we are not persuaded by
Appellants’ contentions regarding Milner’s failure to “know[] the
mechanism of action” for the use of selenium or selenium based compounds
in the treatment of cancer (Br. 8).
In addition, Milner establishes that selenium based compounds exhibit
differences in relative toxicity and efficacy, suggesting that a person of
ordinary skill in this art would have found it prima facie obvious to optimize
the selenium source and dosage for administration to CLL patients, where,
as here, the prior art teaches that CLL cells in a stromal cell
microenvironment can be effectively treated with a selenium compound and
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Application 13/989,016
the “[t]ypes of tumors as well as [the] form of selenium administered may []
be important factors in the efficacy of selenium therapy” (see FF 5, 7, 9, and
12-15). See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir.
2007) (“[T]he discovery of an optimum value of a variable in a known
process is usually obvious”). Therefore, we are not persuaded by
Appellants’ contention that “Milner [] teaches away from therapy with
selenoamino acids, teaching instead to use inorganic selenium, not the
organic selenium found in selenoamino acids” (Br. 9). For the same reasons
we are not persuaded by Appellants’ contention that Last “is [of] little
relevance [] to the present invention,” because Last used SDG and MSA to
“represent[] methylated and non-methylated selenium species” instead of
selenocystine (Br. 12; see also id. at 13 (Last’s use of compounds
representative of methylated and non-methylated selenium species “teaches
away from selenocystine and instead directs [an artisan] in quite another
direction, Se-Methylselenocysteine”); id. at 14 (“As for Last [], it is entirely
unclear why it is even being cited since it says nothing about
selenocystine”); FF 12).
We are not persuaded by Appellants’ contentions regarding Milner’s
use of “murine L1210 cells without stromal cell co-culture,” which fails to
account for the contribution of Last and Caligaris-Cappio to the combination
of references relied upon by Examiner (Br. 9; see generally id. at 9-11 and
14, citing Kessel13 and Bichi;14 cf. FF 3 and 12-15).
13 David Kessel and H. Bruce Bosmann, Studies on a Cell Line Derived from
the LI210 Murine Leukemia with Altered Surface Properties and Decreased
Capacity for Tumor Production, 34 Cancer Research 603-608 (1974).
14 Bichi et al., Human chronic lymphocytic leukemia modeled in mouse by
targeted TCL1 expression, 99 PNAS 6955-6960 (2002).
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Application 13/989,016
Last established that selenium compounds, representative of selenium
species were effective to treat CLL cells in a stromal microenvironment (FF
12-15). We recognize, but are not persuaded by, Appellants’ contention that
“CHO cells are ovary cells unrelated to bone marrow stromal cells” and
assertion that Last’s “studies were [] not carried out in the presence of bone
marrow stromal cells” (Br. 12). Notwithstanding Appellants’ contention to
the contrary, Last modifies CHO cells in such a way that Last expressly
characterizes the modified CHO cells as “providing] a stromal layer
supporting B-cell proliferation” (FF 12). Appellants failed to establish an
evidentiary basis on this record to support a conclusion that Last’s modified
CHO cells, which Last characterizes as “providing] a stromal layer
supporting B-cell proliferation,” represent a materially different stromal
tissue microenvironment than is required by Appellants’ claimed invention
(FF 12; cf Br. 17).
Appellants do not appear to dispute that Caligaris-Cappio discloses
“that [] direct physical contact between BM stromal cells and leukaemic
cells extends the survival of CLL cell[s]” and that “[/]/? vitro, it has been
shown that malignant CLL cells interact with BM stromal cells via [31 and
[32 integrins,” wherein “[t]his binding rescues CLL cells from apoptosis and
extends their lifespan, suggesting a potential mechanism for the preferential
in vivo accumulation and survival of CLL cells within the BM” (FF 3; cf. Br.
13).
The combination of Milner, Last, Caligaris-Cappio, and StiefeT.
Based on the combination of Milner, Last, Caligaris-Cappio, and
Stiefel, Examiner concludes that, at the time Appellants’ invention was
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Application 13/989,016
made, it would have been prima facie obvious to treat CLL patients with a
combination of selenocystine and an additional anti-cancer therapy, such as
cyclophosphamide (Ans. 8-9; FF 3-20).
Having found no error in the combination of Milner, Last, and
Caligaris-Cappio, as it relates to Appellants’ claim 1, we are not persuaded
by Appellants’ contention “that Stiefel adds nothing of relevance to the
teachings of Milner,” Last, and Caligaris-Cappio (Br. 16).
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Milner, Last, and Caligaris-Cappio is affirmed.
Claims 3 and 13 are not separately argued and fall with claim 1.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Milner, Last, Caligaris-Cappio, and Stiefel is
affirmed. Claims 3, 8-10, 12, and 13 are not separately argued and fall with
claim 1.
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
14