Ex Parte Lejeune et al

Patent Trial and Appeal Board

Nov 27, 2018

13130867 (P.T.A.B. Nov. 27, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/130,867 11/14/2011
89300 7590 11/29/2018
Sanofi/Genzyme c/o Morrison & Foerster LLP
755 Page Mill Road
Palo Alto, CA 94304
FIRST NAMED INVENTOR
Pascale Lejeune
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
183952028600 1544
EXAMINER
DUFFY, BRADLEY
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
11/29/2018 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):
EOfficeP A@mofo.com
PatentDocket@mofo.com
pair_mofo@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PASCALE LEJEUNE and PA TRICIA VRIGNAUD
Appeal2017-001518
Application 13/130,867
Technology Center 1600
Before MICHAEL J. FITZPATRICK, ULRIKE W. JENKS, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal under 35 U.S.C. § 134(a) involving
claims to a pharmaceutical combination comprising cytarabine and an
antibody recognizing CD38. The Examiner rejected the claims as obvious
and for obviousness-type double patenting. We have jurisdiction under 35
U.S.C. § 6(b ).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Sanofi. App. Br. 3.
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Application 13/130,867
STATEMENT OF THE CASE
Appellants' "invention relates to combinations of monoclonal
antibodies directed against CD3 8 and cytarabine which are therapeutically
useful in the treatment of neoplastic diseases." Spec. 1:4---6. CD38 is a
transmembrane glycoprotein that "is upregulated and has been implicated in
many hematopoietic malignancies." Id. at 1 :8-12. The Specification notes
that "[ m ]onoclonal antibodies ... which specifically recognize CD3 8, are
described in PCT application W02008/047242 [Park]2" and that these
"antibodies are capable of killing CD3 8+ cells" by several mechanisms ( e.g.,
induction of apoptosis and antibody-dependent cell-mediated cytotoxicity
(ADCC)). "Cytarabine is an anti-metabolic agent used in chemotherapy."
Id. at 1 :20-21. Cytarabine converts into a compound that damages DNA
during DNA synthesis and also damages other enzymes required for DNA
synthesis, which most affects rapidly dividing (e.g., cancerous) cells that
require DNA replication for mitosis. Id. at 6:25-30.
According to the Specification:
It has now been found, and for this invention, that the efficacy of
the humanized anti-CD38 antibodies may be considerably
improved when it is administered in combination with at least
one substance which is therapeutically useful in anticancer
treatments and has a mechanism identical to or different from the
one of the humanized anti-CD38 antibodies and which is limited
in the present invention to cytarabine.
Id. at 1 :24--28.
2 Park et al., WO 2008/047242 A9, published Apr. 24, 2008.
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Claims 1, 2, 11, and 30-32 are on appeal. Claim 1 is illustrative and
is reproduced below:
1. A pharmaceutical combination comprising an antibody
specifically recognizing CD3 8 and at least cytarabine, wherein
said antibody comprises at least one heavy chain and at least one
light chain, wherein said heavy chain comprises three sequential
complementarity determining regions comprising the amino acid
sequences of SEQ ID NOs: 13, 81 and 15, and wherein said light
chain comprises three sequential complementarity determining
regions comprising the amino acid sequences of SEQ ID NOs:
16, 17 and 18, and wherein the antibody and cytarabine
constituents of the combination are physically separate.
App. Br. 29 (Claims App'x).
The claims stand rejected3 as follows:
I. Claims 1, 2, 11, and 30-32 under 35 U.S.C. § I03(a) as obvious
over Weers, 4 Park, Romaguera, 5 and Piccaluga. 6
II. Claims 1, 2, 11, and 30-32 for obviousness-type double
patenting over: (i) claims 1-30 of the '765 patent;7 (ii) claims
3 The Examiner, "in order to simplify the issues for appeal," withdrew some
of the§ 103 and double patenting rejections. Ans. 14--15. We do not
address those withdrawn rejections in this decision.
4 Weers et al., WO 2006/099875 Al, published Sept. 28, 2006.
5 Jorge E. Romaguera et al., High Rate of Durable Remissions After
Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With
Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus High-Dose
Methotrexate and Cytarabine, 23:28 JOURNAL OF ONCOLOGY 7013-7024
(2005).
6 Pier Paolo Piccaluga et al., First experience with gemtuzumab ozogamicin
plus cytarabine as continuous infusion for elderly acute myeloid leukaemia
patients, 28 LEUKEMIA RESEARCH 987-990 (2004).
7 Park et al., US 8,153,765 B2, issued Apr. 10, 2012 ("the '765 patent").
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Application 13/130,867
Claim 1
Issue
1-12 of the '406 patent; 8 and (iii) claims 1-8 of the '301
patent. 9 The double patenting rejections rely on the claims of
the above-noted patents in further view of Weers, Romaguera,
and Piccaluga. Ans. 11-12. 10
I - OBVIOUSNESS
According to the Examiner, Weers, Park, Romaguera, and Piccaluga
render obvious the anti-CD38 antibody and cytarabine combination recited
in claim 1. Ans. 3-11.
Appellants respond that no adequate motivation to combine the prior
art references has been provided. App. Br. 8-9; see also id. at 11-12.
Appellants further argue that the claimed combination displays unexpected
synergism and, thus, that claim 1 is nonobvious. Id. at 14--23.
The issue on appeal is whether the preponderance of the evidence on
this record supports the Examiner's conclusion that claim 1 would have been
obvious over the cited prior art. We discuss further below.
Findings of Fact (FF)
The Examiner's findings of fact, statement of the rejection, and
supporting reasoning are provided at pages 3-11 and 16-25 of the
8 Lejeune et al., US 9,259,406 B2, issued Feb. 16, 2016 ("the '406 patent").
9 Lejeune et al., US 8,633,301 B2, issued Jan. 21, 2014 ("the '301 patent").
10 The Examiner provisionally rejected the appealed claims for double
patenting over claims in U.S. Application No. 13/131,389. Ans. 12. Based
on Patent Office records, that application went abandoned on November 30,
2016 and the provisional rejection is, accordingly, moot.
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Examiner's Answer. See also Adv. Act. (dated Feb. 25, 2016); Adv. Act.
( dated May 18, 2016). The following findings are provided for emphasis
and convenient reference.
FF 1. Weers relates to "[i]solated human monoclonal antibodies
which bind to human CD38, and related antibody-based compositions."
Weers, Abstract. Weers teaches that such antibodies are useful for treating,
for example, multiple myeloma, which is a B cell malignancy and disease
that attacks bones and bone marrow, resulting in tumors throughout the
skeletal system. Id. at 1 :3-9. According to Weers, about 1 % of all cancers
and more than 10% of all hematologic malignancies can be attributed to
multiple myeloma. Id. at 1: 10-11.
FF 2. Weers describes "CD38 binding peptides ('CD38BPs')" useful
for the treatment "of disorders involving cells expressing CD38, such as
multiple myeloma." Id. at 20: 17-19. Weers teaches the CD38BP may be an
antibody, including a humanized or chimeric antibody. Id. at 26:21-24.
FF 3. Weers describes methods for treating or preventing a disorder
involving cells expressing CD38 by administering a therapeutically effective
amount of the CD38BP. Id. at 168:3-7. According to Weers, "[t]he
CD3 8BP composition may be administered alone or along with another
therapeutic agent, such as described elsewhere [in Weers] which acts in
conjunction with or synergistically with the CD3 8BP composition to treat or
prevent the diseases." Id. at 168:4--7. Weers also teaches that its
compositions may be "administered in combination therapy, i.e., combined
with other therapeutic agents ... [ and that] [ s ]uch administration may be
simultaneous, separate or sequential." Id. at 175: 19-22.
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FF 4. Weers teaches "a method for treating multiple myeloma, which
comprises administration of a therapeutically effective amount of a CD3 8BP
... and at least one chemotherapeutic agent to a subject in need thereof." Id.
at 176:7-10. Weers teaches that "such a chemotherapeutic agent may be
selected from an antimetabolite, such as methotrexate, ... cytarabine,
fludarabine, ... and similar agents." Id. at 176:14--17 (emphasis added).
FF 5. Park relates to antibodies, including humanized antibodies,
which bind to CD3 8 and are capable of killing CD3 8+ cells by apoptosis,
antibody-dependent cell-mediated cytotoxicity (ADCC), and/or
complement-dependent cytotoxicity (CDC). Park, Abstract. Park teaches
that such antibodies may be used to treat tumors that express CD3 8 protein,
such as in multiple myeloma. Id.; see also id. at 64:10-15 (disclosing that
CD3 8 is expressed in a variety of other malignant hematological disorders,
including B-cell acute lymphocytic leukemia, mantle-cell lymphoma, and
chronic or acute myeloid leukemia).
FF 6. Park teaches that a therapeutic composition may comprise an
anti-CD38 antibody and a second therapeutic agent. According to Park,
"[t]his second therapeutic agent can be also chosen from the group of
chemotherapeutic or immunomodulatory agents." Id. at 6: 12-30.
FF 7. Park tested the in vivo activities of the anti-CD38 antibody
hu38SB19. See, e.g., id. at 84--86 (Example 9). In a multiple myeloma
tumor model, Park reports that "hu3 8SB 19 and mu3 8SB 19 antibodies or a
chimeric IgG 1 control antibody were given to mice intravenously at a dose
of 40 mg/kg, twice per week, in three successive weeks." Id. at 85:13-18.
According to Park, none of the tumors in the control groups (IgG 1 or PBS
controls) regressed, yet "treatment with hu3 8SB 19 or mu3 8SB 19 led to
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Application 13/130,867
tmnor regression in 8 of 10 or 6 of 10 animals, respectively." Id. at 85: 18-
23; see also id. at 84:29-30 ("The treatment with either mu38SB19 or
hu3 8SB 19 significantly extended the survival of mice compared to that of
PBS-treated mice .... ").
FF 8. Romaguera relates to a study on survival rates of subjects with
mantle-cell lymphoma (MCL) receiving combination therapy with rituximab
and a chemotherapy regimen including hyper-CV AD, 11 methotrexate, and
cytarabine. Romaguera, Abstract. As explained in Romaguera, "[t]he
monoclonal anti-CD20 antibody rituximab has shown activity in untreated
patients with MCL." Id. at 7014, left col. Romaguera also explains that
therapy with hyper-CV AD, methotrexate, and cytarabine has proven
effective in patients with aggressive MCL variants. Id. Regarding
combination therapy, Romaguera reports that "the results of this trial show
that rituximab plus hyper-CV AD alternating with rituximab plus
methotrexate-cytarabine is an effective regimen for induction of complete
remissions in patients with newly diagnosed aggressive MCL and produces
prolonged remissions in patients 65 years of age or younger." Id. at 7022.
FF 9. Piccaluga relates to a study on administration of gemtuzumab
ozogamicin (a humanized anti-CD33 antibody conjugated to calicheamicin)
in combination with cytarabine for the treatment of acute myeloid leukemia.
Piccaluga, Abstract. Piccaluga discloses that, following administration of
the above combination, "[ f]ive out of nine patients achieved a CR [ complete
11 Hyper-CV AD includes fractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone. Romaguera, 7014, left col.
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Application 13/130,867
remission]. In particular, 3/5 untreated and 2/4 relapsed/refractory patients
obtained a CR." Id. at 987.
FF 10. Table 1 from Appellants' Specification is below.
Tahk !: Combfrrntirm of lm38SB l9 and P~Jrno Ara-C again~! 8dvaneed huma.n T-ccll acute lymph1)b!a~tic btkemia DND-41
implanted in SCID [cmak mice.
,Lgent mute
Dn~c in mirfkg/inj (total dme)
hu38SBi9 IV Palmo Arn{ SC
40.0 (160.0)
40.0 (160.0l
40.0 {)60.0)
40 . .0 (160.0)
40.0 (160.0)
96.3 (385.2i
58.0 (232.0)
36.[)(144.f)l
22J (89.21
96.3 /385.2l
58.0 (232.0)
36.0 ( t44.D.i
22.3 {89.21
Schedule . % BWC M
. " Drug deab ct· ... 1 , ~ na rrnav1
18. 2L 24- 27
IK 21. 24- 27
18. 2L 24- 27
0/6
N6
0/6
0/6
-2.l (19)
-26{1i3])
-6.1 (3))
-4.6 (30,
0/6 -Cl.5132)
5/6
0/6
016
0/6
-21.6 (34)
,(ij (30)
-3.2 !31!
-1.7 {!9/
T-C
indavs -(750 mg)
6J
60.5
48.6
22.l
90.9
30.8
0.5 0/6
5.4 1" J/tJ
4.3 0/6
2.0 0/6
5/6
8.l 3.16
1.
L. l 0/6
CnmmenJ\
HOT -lntctive
! TOX.l(
! HNTD - highly ,1c1ivc
I
Highly acri ve
Active
1 Tnx;., t .•• l
! HNTD -Hiirhh, ,ictive
t \.' ..
t H' '' . i -1~ru.y acm-e
• s •
~ auive
Tumor doublinE time= J.4 days. Median tum)r ~izc al start of therapy= 124-136 mg. Time for median control tumor tD rc,lch 750 mg
= 26.9 davs. BWC = htdy weight cfomgc, T-C = rumor growth defav. HOT= hfohN dose tested. HNTD = highest nontoKic dose.
TFS = iu;,m. free surviH~rs, I\;= in!rn:cnou~, SC= su~ul,meous. Formulation;: hu38SB J 9 = phosphate hufl~r dine without Ca".,.
and Ml. oH 7.4. Palmo Ara·C = 3 % ethanoL l % polvwrhate 8(), 96 % water. ..... ': . . ' ,•
Spec. 12; 12 App. Br. 15. Table 1 relates to a tumor model for a human T-cell
acute lymphoblastic leukemia cell line implanted in mice, and shows results
( e.g., log cell kill, tumor-free survival (TFS), etc.) for mice receiving the
anti-CD38 antibody hu38SB19 or Palmo Ara-C (a cytarabine derivative), or
a combination ofhu38SB19 and Palmo Ara-C. Spec. 10:5-11:31, 12. An
antibody formulation was administered intravenously ( 40 mg/kg) and a
formulation of Palmo Ara-C was administered subcutaneously to mice at
12 Table 1, reproduced here, reflects the amendments to the Specification
submitted on January 22, 2016.
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Application 13/130,867
specific dosage levels (e.g., 58.0 mg/kg, 22.3 mg/kg, etc.), and those
administrations were given at 18, 21, 24, and 27 days after implantation. Id.
at 10: 13-21; id. at 12 (Table 1 ). Certain mice received only the antibody
formulation (total dose of 160 mg/kg (40 x 4)), certain mice received only
the Palmo Ara-C formulation (e.g., total dose 233 mg/kg (58.0 x 4)), and
certain mice received both the antibody and Palmo Ara-C formulations. For
example, as shown in the bottom row of Table 1, six mice received a total
dose of 160 mg/kg of the antibody formulation along with a total dose of
89.2 mg/kg (22.3 x 4) of the Palmo Ara-C formulation. Id. at 12 (Table 1).
Principles of Law
"[T]he burden of showing unexpected results rests on he who asserts
them. Thus it is not enough to show that results are obtained which differ
from those obtained in the prior art: that difference must be shown to be an
unexpected difference." In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
Moreover, "[i]t is well settled that unexpected results must be established by
factual evidence. Mere argument or conclusory statements in the
specification does not suffice." In re De Blauwe, 736 F.2d 699, 705 (Fed.
Cir. 1984).
"[W]e attribute no magic status to synergism per se since it may be
expected or unexpected." In re Huellmantel, 324 F.2d 998, 1003 (CCPA
1963); see also In re Kollman, 595 F.2d 48, 55 n.6 (CCPA 1979)
("Synergism, in and of itself, is not conclusive of unobviousness in that
synergism might be expected.").
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Application 13/130,867
Analysis
The Examiner finds that Weers teaches "a composition comprising an
antibody that binds CD3 8 and cytarabine and that the antibodies can have
ADCC, CDC and/or cause apoptosis and be humanized for treating multiple
myeloma." Ans. 3. The Examiner finds that Weers "specifically teach[ es]
at page 17 6 that 'In one embodiment, the present invention provides a
method for treating multiple myeloma, which method comprises
administration of a therapeutically effective amount of a CD3 8BP ... and at
least one chemotherapeutic agent." Id. And, the Examiner highlights,
Weers identifies cytarabine as one such chemotherapeutic agent. Id.
As for an anti-CD38 antibody having the specific complementarity
determining regions (CDRs) and sequences as claimed, the Examiner turns
to Park. Id. According to the Examiner, Park teaches "an antibody that
specifically binds to CD3 8 that comprises the amino acid sequences of SEQ
ID Nos: 62, 64, 66 that are 100% identical to the instant SEQ ID Nos: 62,
64, 66." Id. Also, the Examiner finds, "instant SEQ ID Nos: 62, 64, 66
comprise the CDRs of SEQ ID Nos: 13, 81, 15-18 such that the prior art also
contains these sequences." Id. The Examiner finds that Park teaches "the
hu3 8 SB 19 antibody which is effective in treating mouse models of
lymphoma and multiple myeloma," and also teaches that the described "anti-
CD38 antibodies can be combined with chemotherapeutic agents." Id. at 3-
4; see also id. at 17 ("Notably, as evidenced by Park ... in 2 lymphoma
mouse models and 2 multiple myeloma models the hu3 8SB 19 antibody
extended the survival of mice, prevented tumor growth, and/or led to tumor
regression.").
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Application 13/130,867
The Examiner cites to Romaguera and Piccaluga as evidencing
combinations of antibodies or ADCs (antibody-drug conjugates) with known
chemotherapeutic agents, including cytarabine. Id. at 4. According to the
Examiner, such combinations are commonly known in the art for use in
treating hematological cancers. Id.; see also id. at 17.
The Examiner concludes it would have been obvious to produce a
combination of the anti-CD38 humanized antibody of Park (hu38SB19) and
cytarabine as claimed. Id. The Examiner reasons that the skilled artisan
would have been motivated to make this combination, inter alia, "to test the
effectiveness of the combination in treating leukemia, multiple myeloma or
lymphoma cancers ... in order to determine if such a combination might be
effectively used to treat the disease in humans in a clinical setting." Id.
Also, the Examiner reasons, given the known effectiveness of Park's
antibody in killing cancer cells, it would have been obvious to use that
antibody in combination with other known anti-cancer agents. Id. at 4--5.
According to the Examiner, the skilled person would have been motivated to
make a pharmaceutical combination of known antibodies (hu38SB19) and
chemotherapeutic agents ( e.g., cytarabine) that were taught for use in
treating multiple myeloma and other hematological cancers. Id. at 14; see
also id. at 13-14 ("One would have been motivated to do so with a
reasonable expectation of success because [Weers] teaches that a
chemotherapeutic agent including cytarabine can be administered with an
anti-CD3 8 antibody and antibody and cytarabine combinations were known
in the art."), 17 ("a combination of the hu3 8 SB 19 antibody with cytarabine
merely combines prior art elements according to known methods to yield
predictable results.").
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Appellants argue "that there is still no motivation to combine the
teachings of Weers et al. and Park et al. in light of the teachings of
Romaguera et al. and Piccaluga et al." App. Br. 12; see also id. at 8-9.
According to Appellants, Weers "does not teach that the combination of
cytarabine with an anti-CD38 antibody would be a particularly suitable or
effective agent" and, instead, Weers simply recited "cytarabine in a
boilerplate list of hundreds of potential conjugates and compositions with no
teaching that cytarabine was preferred." Id. at 9. As for Park, Appellants
contend it "makes no mention of cytarabine" or combinations with
cytarabine specifically. Id. According to the Appellants, "the Examiner is
using an improper obvious to try rationale." Id. at 9, 12.
Appellants' arguments are unpersuasive. Obviousness does not
require that a particular combination be identified in the art as the
"preferred" or best option. 13 In any event, here Park exemplifies an
especially effective anti-CD38 antibody (hu38SB19) for the treatment of,
inter alia, multiple myeloma - providing the skilled artisan a clear and
specific reason for using that antibody as an alternative to the anti-CD38
antibodies identified in Weers, which are also described as useful for
treating multiple myeloma. FF 1-2, 7; Ans. 17, 19. Although Park does not
expressly disclose combinations ofhu38SB19 with cytarabine, Park teaches
13 Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir.
1989) ("[I]n a section 103 inquiry, the fact that a specific [embodiment] is
taught to be preferred is not controlling, since all disclosures of the prior art,
including unpreferred embodiments, must be considered.") (internal
quotation marks omitted); see also In re Mouttet, 686 F.3d 1322, 1334 (Fed.
Cir. 2012) ("[J]ust because better alternatives exist in the prior art does not
mean that an inferior combination is inapt for obviousness purposes.").
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generally that its antibodies may be combined with chemotherapeutic agents.
FF 6. Also, Weers explicitly identifies cytarabine and suggests its use in
combinations with anti-CD38 antibodies for treating multiple myeloma and
other cancers. FF 4. The Examiner's rejection does not rest merely on
"obvious to try" reasoning when the art itself teaches or suggests the
combination claimed. Merck, 874 F.2d at 807 ("[D]isclos[ing] a multitude
of effective combinations does not render any particular formulation less
obvious. This is especially true because the claimed composition is used for
the identical purpose taught by the prior art."). And the Examiner's findings
and conclusion are buttressed further by Romaguera and Piccaluga, which
show that cytarabine is a well-known chemotherapeutic agent, commonly
used in combination therapy with antibody and/or antibody drug conjugates
for the treatment of hematological cancers, providing an even further
evidentiary basis for the skilled artisan's motivation to have used cytarabine
in combination with Park's antibody. FF 8-9.
Appellants next argue that unexpected synergism with the claimed
combination rebuts any primafacie case of obviousness. App. Br. 14. More
specifically, citing the Specification's Table 1 (see FF 10), Appellants argue
that the "results demonstrate that an anti-CD38 antibody (hu38SB19) and
cytarabine act synergistically to decrease tumor growth, giving much better
results in combination than would be expected from the results obtained with
either agent alone." Id. at 16. For example, Appellants cite results
comparing (i) intravenous administration of 40.0 mg/kg (160.0 mg/kg total
after four doses) of the hu38SB19 antibody alone, (ii) subcutaneous
administration of 36.0 mg/kg (144 mg/kg total after four doses) of a
formulation of a cytarabine derivative (Palmo-Ara-C) alone, and (iii)
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combination therapy with both formulations. App. Br. 14--16. In this
example, the number of tumor-free survivors (TFS) following administration
of the hu38SB19 formulation alone was 0/6 and the log10 cell kill was
determined to be 0.5 (inactive). 14 Id. at 14--15. With administration of36.0
mg/kg (144 mg/kg total) of the Palmo-Ara-C formulation, TFS was 0/6 and
log10 cell kill was 4.3 (highly active). App. Br. 14--15. But with
combination therapy at those dosages, TFS was 3/6 and log10 cell kill
increased to 8.1 (highly active). Id.; see Spec. 11:4--5 (defining
"Therapeutic Synergism" as follows: "a combination has therapeutic
synergism if it is more active than the best single agent of the study (by at
least 1 log cell kill)").
We have considered Appellants' arguments related to alleged
unexpected synergism along with the Specification's test results. App. Br.
14--23; Reply Br. 8-12. But when those arguments and results are balanced
against the remainder of the record, the preponderance of the evidence
remains in the Examiner's favor, supporting the Examiner's conclusion that
claim 1 would have been obvious. We explain further below.
The Examiner finds that Appellants' test results are not commensurate
with the broad scope of the combination claimed. We agree. For example,
the Examiner points out that Appellants' own testing shows that certain
combinations display synergism, but others do not. Ans. 19, 23. Indeed, as
noted by the Examiner, "based on the [Specification's] definition it does not
14 As explained in the Specification, "TFS" corresponds to complete
regression below the limit of tumor palpation for the entire duration of the
study(> 100 days after the last treatment), and log cell kill is measure of
antitumor efficacy. Spec. 10:25-11:3.
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appear the combination with Ara-C at the lowest or highest dose [ when
combined with the antibody formulation] displays therapeutic synergism."
Ans. 19; see also Adv. Act. (Feb. 25, 2016) ("It was further noted that the
claims were not commensurate because they cover all combinations yet it
appears that specific doses are required based on table 1."). As Table 1
makes clear, the combination of 40 mg/kg (160 mg/kg total) of the antibody
formulation with 22.3 mg/kg (89.2 mg/kg total) of Palmo Ara-C- a
combination encompassed by claim 1 - provided no improvement in
tumor-free survival and only a marginal increase in log10 cell kill that falls
below the threshold of therapeutic synergism set in the Specification. FF 1 O;
Spec. 11:4--5. Some of the combinations using higher overall doses of the
cytarabine derivative do display synergism as noted above. But claim 1 is
wholly silent on dosages of either the antibody or cytarabine that are
required. And Appellants' assertion that "the skilled artisan would conclude
that the synergistic effect is ... independent of the particular total doses
indicated in Table 1" is contradicted by the data itself. App. Br. 19; Reply
Br. 12. As already explained, some embodiments falling within the scope of
claim 1 do not provide synergism, much less unexpected synergism. 15
15 "It is well established that the objective evidence of nonobviousness must
be commensurate in scope with the claims." In re Lindner, 457 F.2d 506,
508 (CCPA 1972). Claim 1 recites a "combination," not a method of
treatment, much less a treatment for particular cancers. See Adv. Act. (May
18, 2016) ("[W]hile the results may be applicable to method claims they
were not sufficient for the pending product claims."). Further to this point,
the results in the Specification purporting to show synergism are for one
type of cancer (T-cell acute lymphoblastic leukemia), the treatment involved
specific routes of administration (IV for the antibody formulation and
subcutaneously for the cytarabine formulation), and a particular dosing
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The Examiner also points out that attorney argument is generally
insufficient to show that results observed are surprising or unexpected. See,
e.g., Ans. 20. According to the Examiner, "nowhere in the specification or
other evidence of record does it state or suggest that therapeutic synergism is
surprising or unexpected as argued by Appellant's counsel." Id. at 19--20
( emphasis by Examiner). 16 Appellants submitted no affidavit or other
persuasive evidence to demonstrate that the skilled artisan would have
considered the results in the Specification to be unexpected. Id. To the
contrary, Appellants respond that they have "stated through counsel that the
results are unexpected." Reply Br. 9. But such statements from counsel fall
short in rebutting the rejection here, particularly where the evidence of
obviousness is reasonably strong. De Blauwe, 736 F.2d at 705; Lindner, 457
F.2d at 508. 17 Synergism, standing alone, does not demonstrate
nonobviousness, and Appellant bears the burden of making a sufficient
schedule ( one administration on each of days 18, 21, 24, and 27). Spec. 10-
12; compare Park, 85 (providing effective treatment of multiple myeloma by
administering 40 mg/kg intravenously, twice per week over three weeks (for
a total of six doses), with administration starting four days after inoculation).
16 We note that, for one of the results shown in Table 1, the Specification
characterizes the result (TFS of 5 of the 6 mice) as "[ r ]emarkabl[ e ]." Spec.
11:24--25. We agree with the Examiner, however, that the evidence on this
record is wanting to establish unexpected or surprising results for the broad
combination claimed.
17 Pfizer Inc. v. Apotex Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) ("[E]ven
if Pfizer showed ... unexpectedly superior results, this secondary
consideration does not overcome the strong showing of obviousness in this
case. Although secondary considerations must be taken into account, they
do not necessarily control the obviousness conclusion.").
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evidentiary showing that any synergism is, in fact, unexpected.
Huellmantel, 324 F.2d at 1003; Klosak, 455 F.2d at 1080.
Appellants argue that other prior art references support a finding that
the alleged synergism was unexpected. App. Br. 16-19, 20-21. More
specifically, pointing to references that the Examiner cited to show that
synergy with cytarabine combinations would have been expected,
Appellants argue these references show the opposite - that such synergism
is unpredictable and unexpected. Id. For example, with respect to the
Johnson 18 reference, Appellants contend synergy was observed with a
combination of cytarabine and a radiolabeled anti-CD20 antibody but not
when combined with a naked antibody. Id. at 17; see also Remarks (April
25, 2016) 11, 13. Regarding the Roth 19 reference, Appellants acknowledge
that synergy was shown for cytarabine in combination with a CD95 ligand in
malignant glioma cells, but Appellants contend Roth suggests this synergism
is attributable to specific mechanistic activities of the target cells. App. Br.
18; see also Remarks (April 25, 2016) 12-13. To the extent synergy is
shown with cytarabine combinations in these other references, Appellants
argue "the synergy observed ... is limited to the specific compounds
studied," and that none of the references studied a combination of cytarabine
and an anti-CD38 antibody. Id. at 17-18.
18 Timothy A. Johnson et al., Synergistic cytotoxicity of Iodine-l 3 l-Anti-
CD20 Monoclonal Antibodies and Chemotherapy for Treatment of B-Cell
Lymphomas, 85 INT. J. CANCER 104--112 (2000).
19 Wilfried Roth et al., Immunochemotherapy of malignant glioma:
synergistic activity of CD95 ligand and chemotherapeutics, 44 CANCER
lMMUNOL. lMMUNOTHER. 55---63 (1997).
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On the record before us, we are unpersuaded these other references
demonstrate that synergism with the claimed combination would have been
unexpected. On the one hand, the references show that combinations of
cytarabine with several different agents (e.g., CD95 ligands, anti-FAS IgM
antibodies, radiolabeled-anti-CD20 antibodies) provide synergy. See App.
Br. 17-18 (table summarizing references). Consistent with the Examiner's
position, this provides some evidentiary support for the notion that synergy
with cytarabine combinations like claimed would have been reasonably
expected. See, e.g., Ans. 21-22. 20 On the other hand, as Appellants argue,
the references also demonstrate that synergism was not universally observed
with all cytarabine combinations. Id.; see also Remarks (April 25, 2016) 9-
13. As to these other references, we find the argument and evidence is in
equipoise. But when we consider the entire record here, the preponderance
of the evidence still tilts in favor of the conclusion of obviousness for all the
reasons explained above.
Claims 2, 11, and 30-32
Appellants address dependent claims 2, 11, and 30-32 under separate
headings, yet Appellants' argument again relies on alleged unexpected
20 The Examiner also cites to disclosure in Weers as generally indicating that
the identified therapeutic agents ( which includes cytarabine) can act
synergistically with anti-CD38 antibodies. Ans. 22; FF 3. Hence, the
Examiner finds, "as the prior art recognized that synergy could occur, it is
unclear on what basis the synergy might be considered 'unexpected'
especially in the absence of other evidence." Ans. 22. The Examiner also
finds that, if synergistic effects cannot be generalized ( as Appellants argue),
this would further illustrate why the results in the Specification are not
commensurate with the claims "because the claims are not limited to a
specific combination that has synergistic effect." Ans. 23.
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synergism with the claimed combination. App. Br. 23-25. For reasons
discussed above, based on the record before us, we are unpersuaded
Appellants have provided evidence of unexpected synergism that outweighs
the evidence of obviousness. Ans. 24--25. We otherwise adopt as our own
the Examiner's findings of fact, reasoning, and conclusion of obviousness
with respect to these dependent claims. Ans. 3-11, 16-25.
Conclusion of Law
The preponderance of the evidence on this record supports the
Examiner's conclusion that claims 1, 2, 11, and 30-32 would have been
obvious over Weers, Park, Romaguera, and Piccaluga.
II-DOUBLE PATENTING
The Examiner rejected the pending claims for obviousness-type
double patenting over the claims of the '765 patent, the claims of the '406
patent, and the claims of the '301 patent. Ans. 12. The Examiner finds that
the patented claims recite anti-CD38 antibodies with the CDRs/sequences
encompassed by pending claim 1, and that the patented claims further
disclose combinations of those antibodies with other therapeutic or
chemotherapeutic agents (e.g., vincristine). Id. at 12-13; see, e.g., the '765
patent ( claim 22), the '406 patent ( claim 1 ), the '301 patent ( claim 1 ).
Because the patented claims do not identify cytarabine, the Examiner makes
the rejections in further view of Weers, Romaguera, and Piccaluga, which
( as discussed above) teach the use of combinations with the known
chemotherapeutic agent cytarabine for treating multiple myeloma and other
hematological cancers. Id. at 12-13; FF 4, 8-9. The Examiner provides
substantially the same rationale for using cytarabine in combination with an
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anti-CD38 antibody to kill cancer cells to that discussed above related to the
§ 103 rejection. Ans. 13-14.
Appellants argue the obviousness-type double patenting rejections as
a group. App. Br. 25. Appellants contend that none of the patented claims
are directed to a pharmaceutical combination comprising cytarabine and,
like argued above, Appellants contend the combination of the antibodies and
cytarabine as recited in pending claim 1 provides "unexpected properties."
App. Br. 25-26; Reply Br. 12-14.
Whether the patented claims recite cytarabine is not dispositive. The
teaching of combinations with cytarabine is provided in the secondary
references (e.g., Weers (FF 4)), and Appellants' argument, thus, fails to
grapple with the rejections as framed and what the art as a whole teaches.
Although we agree with Appellants that evidence of unexpected
properties should, when such evidence is presented, be considered in an
obviousness-type double patenting inquiry, 21 the evidence here is
insufficient to rebut the Examiner's prima facie case. First, the alleged
unexpected synergism suffers from the same shortcomings discussed above,
including that the results in the Specification are not commensurate in scope
with the broad combination recited in pending claim 1. Second, as the
Examiner points out, "the instant combination has not been established to
display unexpected results as compared to the results obtained with
combinations of the claims in the recited patents," such as the anti-CD38
antibody/melphalan combination (in claim 1 of the '406 patent) or the anti-
21 See Eli Lilly and Co. v. Teva Parenteral Medicines, Inc., 689 F.3d 1368,
1381 (Fed. Cir. 2012) (holding a "[t]he district court's categorical
repudiation of Lilly's evidence [on unexpected results] was ... erroneous.").
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CD38 antibody/vincristine combination (as recited in claim 1 of the '301
patent). Ans. 26. Without such comparisons, Appellants fail to show
unexpected synergism with the anti-CD38 antibody/cytarabine combination
versus the combination of anti-CD38 antibodies and other chemotherapeutic
agents as in the patented claims.
Appellants' contentions regarding the double-patenting rejections of
the dependent claims, which again rely on alleged unexpected properties,
fall for substantially the same reasons. App. Br. 26-27.
SUMMARY
We affirm the rejections for obviousness and obviousness-type double
patenting on appeal.
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
21