Ex Parte Howard et al

Patent Trial and Appeal Board

Feb 7, 2017

13641198 (P.T.A.B. Feb. 7, 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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/641,198 10/15/2012 Philip Wilson Howard 215050-0001-00-US-538465 2037
55694 7590 02/09/2017
DRINKER BIDDLE & REATH (DC)
1500 K STREET, N.W.
SUITE 1100
WASHINGTON, DC 20005-1209
EXAMINER
BEANE, RANDALL L
ART UNIT PAPER NUMBER
1675
NOTIFICATION DATE DELIVERY MODE
02/09/2017 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):
DB RIPDocket @ dbr. com
penelope. mongelluzzo @ dbr. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PHILIP WILSON HOWARD, LUKE MASTERSON,
ARNAUD TIBERGHIEN, JOHN A. FLYGARE,
JANET L. GUNZER, PAUL POLAKIS, ANDREW POLSON,
HELGA E. RAAB, and SUSAN D. SPENCER
Appeal 2017-001647
Application 13/641,198
Technology Center 1600
Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
DAVID COTTA, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a
pharmaceutical composition comprising dimeric pyrrolobenzodiazepines.
The Examiner rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“Some pyrrolobenzodiazepines (PBDs) have the ability to recognise
and bond to specific sequences of DNA; the preferred sequence is PuGPu.
1 Appellants identify the Real Party in Interest as Medimmune Limited (see
App. Br. 2).
Appeal 2017-001647
Application 13/641,198
The first PBD antitumour antibiotic, anthramycin, was discovered in 1965”
(Spec. 1:9—11). “[DJimeric PBD compounds bearing C2 aryl substituents . .
. have been shown to be highly useful cytotoxic agents” (Spec. 2:9—14).
The Claims
Claims 1, 3—26, 28, 29, 32, 42, 44, 48—50, 53, and 54 are on appeal.
Independent claim 1 is representative and reads as follows:
1. A pharmaceutical composition comprising a conjugate of
Formula (AC):
AC
and salts and solvates thereof, wherein:
the dotted lines indicate the optional presence of a double bond
between Cl and C2 or C2 and C3;
X is selected from O, S and NH;
R” is a C3-12 alkylene group, which chain may be interrupted by
one of more heteroatoms selected from O, S, NH, and NMe, and/or
aromatics rings selected from benzene and pyridine, which are
optionally substituted by NH2;
R2 is independently selected from H, OH, =0, =CH2, CN, R,
OR, =CH-RD, =C(Rd)2, O-SO2-R, CO2R and COR, and optionally
further selected from halo or dihalo;
where RD is independently selected from R, CO2R, COR, CHO,
CO2H, and halo;
R6 and R9 are independently selected from H, R, OH, OR, SH,
SR, NH2, NHR, NRR’, N02, Me3Sn and halo;
R7 is independently selected from H, R, OH, OR, SH, SR, NH2,
NHR, NRR’, NO2, Me3Sn and halo;
2
Appeal 2017-001647
Application 13/641,198
R10 is a linker connected to a cell binding agent selected from
(i) an antibody, (ii) a fragment of an antibody that contains at least one
binding site, and (iii) a cyclic polypeptide;
Q is independently selected from O, S and NH;
R11 is either H, or R or, where Q is O, SO3M, where M is a
metal cation;
R and R’ are each independently selected from optionally
substituted C1-12 alkyl, C3 20 heterocyclyl and C5-20 aryl groups, and
optionally in relation to the group NRR’, R and R’ together with the
nitrogen atom to which they are attached form an optionally
substituted 4-, 5-, 6- or 7-membered heterocyclic ring; and
wherein R2 , R6”, R7 *, R9”, and X” are independently selected
from the same groups as R2, R6, R7, R9, and X, respectively.
The Issues
A. The Examiner rejected claims 1, 21—26, 28, 29, 32, 42, 48, 49, 53, and
54 under 35 U.S.C. § 103(a) as obvious over Hartley,2 Chari,3 Thurston,4 and
Kamal5 (Ans. 3—7).
B. The Examiner rejected claims 3—19, 42, 44, and 48—50 under 35
U.S.C. § 103(a) as obvious over Hartley, Chari, Thurston, Kamal, and
Ducry6 (Ans. 16—21).
2 Hartley et al., SJG-136 (NSC 694501), A Novel Rationally Designed DNA
Minor Groove Interstrand Cross-Linking Agent with Potent and Broad
Spectrum Antitumor Activity. Part 1: Cellular Pharmacology, In vitro and
Initial In vivo Antitumor Activity, 64 Cancer Res. 6693—99 (2004)
(“Hartley”).
3 Chari et al., US 2009/0274713 Al, publ. Nov. 5, 2009 (“Chari”).
4 Thurston et al., US 7,049,311 Bl, issued May 23, 2006 (“Thurston”)
5 Kamal et al., Pyrrolo[2,l-c][l,4]benzodiazepine-(3-glucuronide Prodrugs
with a Potential for Selective Therapy of Solid Tumors by PMT and ADEPT
Strategies, 18 Bioorganic Medicinal Chem. Lett. 3769-73 (2008)
(“Kamal”).
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Application 13/641,198
C. The Examiner provisionally rejected claims 1,3,4, 19—26, 28, 29, 32,
42, 44, 48, 49, 53, and 54 on the ground of nonstatutory double patenting as
being unpatentable over claims 1—13, 18—22, 24, 28—32, and 44-48 of
copending Application No. 13/650,277 (Ans. 23—24).
D. The Examiner rejected claims 1, 3—25, 28, 42, 44, 48, 49, 53, and 54
on the ground of nonstatutory double patenting as being unpatentable over
claims 2—11 of copending Application No. 14/051,743 (Ans. 25—26).
A. 35 U.S.C. § 103(a) over Hartley, Chari, Thurston andKamal
The Examiner finds “Hartley discloses the pyrrolobenzodiazepine
dimer (‘PBD dimer’) of SJG-136 (NSC 694501) as a ‘lead candidate’ for
cancer therapeutics” but “Hartley does not teach that SJG-136 may be
attached to an antibody at the N10 position of SJG-136 via a linker” (Ans.
4).
The Examiner finds Chari provides “motivation for forming
immunoconjugates between PBD dimers and antibodies using cleavable
linkers” but “Chari does not explicitly teach that an antibody could be linked
to a PBD dimer at the N10 position” (Ans. 4—5).
The Examiner finds Kamal teaches “the N10 position is amenable to
chemical modification and has previously been used in asymmetrically-
modified PBDs” including “antibody-directed enzyme prodrug therapies”
and that “PBD prodrugs may be synthesized wherein a single monomer is
6 Ducry et al., Antibody-Drug Conjugates: Linking Cytotoxic Payloads to
Monoclonal Antibodies, 21 Bioconjugate Chemistry 513 (2010) (“Ducry”).
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Appeal 2017-001647
Application 13/641,198
modified at the N10 position using a self-immolating linker attached to an
enzyme-cleavable linker” (Ans. 5—6).
The Examiner finds it obvious
to specifically select the lead compound SJG-136, and modify
SJG-136 with an antibody as explicitly suggested by Chari, to
desirably form a PBD-antibody conjugate. Furthermore, an
artisan would be guided to make such modifications at the N10
position, which had previously been shown to be amenable to
modification by self-immolating enzyme-cleavable linkers.
(Ans. 6).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Hartley, Chari, and Kamal render
obvious an asymmetric pyrrolobenzodiazepine dimer of claim 1?
Findings of Fact
1. Hartley teaches “SJG-136 (NSC 694501) is a rationally
designed pyrrolobenzodiazepine dimer that binds in the minor groove of
DNA. It spans 6 bp with a preference for binding to purine-GATC-
pyrimidine sequences. The agent has potent activity in the National Cancer
Institute (NCI) anticancer drug screen with 50% net growth inhibition”
(Hartley, abstract).
2. Figure 1 of Hartley is reproduced, in part, below:
T I
'X,
N. ^ w A » ft
v X-
^ a
v '-v'vs*' "V \ 14
'Xkw
Vi
o yr* 4J#
)r
O
%
V....xv
5
Appeal 2017-001647
Application 13/641,198
“Fig. 1. Structures of the . . . PBD dimer[] . . . SJG-136” (Hartley 6694, col.
1).
3. Hartley teaches “the rationally designed pyrrolobenzodiazepine
dimer, SJG-136, is the lead clinical candidate in a novel class of compounds
that produce unique sequence selective guanine-guanine cross-links”
(Hartley 6698, col. 2).
4. Chari teaches:
methods of making cell-binding agent-drug conjugates
comprising modification of cell-binding agents with these
cross-linkers, followed by reaction with drugs, or modification
of the drugs with these crosslinkers, followed by reaction with
cell-binding agents. The improved method of making
conjugates provides the ability to link a higher number of drug
molecules per cell-binding agent resulting in greater potency
and providing greater aqueous solubility to the conjugates.
(Chari 12).
5. Chari teaches “the drug can be any of many small molecule
drugs, including, but not limited to . . . pyrrolobenzodiazepine dimers”
(Chari 1105).
6. Chari teaches “cytotoxic agents according to the present
invention include pyrrolobenzodiazepine dimers that are known in the art
(U.S. Pat. Nos. 7,049,311; 7,067,511; 6,951,853; 7,189,710; 6,884,799;
6,660,856 [)]” (Chari 1255).
7. Chari teaches “the cell-binding agent is an antibody ... it binds
to an antigen that is a polypeptide and may be a transmembrane molecule
(e.g. receptor) or a ligand such as a growth factor” (Chari 1129).
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Application 13/641,198
8. Chari teaches “immunoconjugates could also be used for the
manufacture of a medicament useful for treating or lessening the severity of
disorders, such as, characterized by abnormal growth of cells (e.g., cancer)”
(Chari 1268).
9. Chari teaches that “[o]ne skilled in the art of cytotoxic agents
will readily understand that each of the cytotoxic agents described herein can
be modified in such a manner that the resulting compound still retains the
specificity and/or activity of the starting compound” (Chari 1256).
10. Kamal teaches the “pyrrolo[2,l-c][l,4]benzodiazepines (PBDs)
are a class of small molecules which bind to Nth of the guanine in the minor
groove of DNA, leading to cytotoxicity. This class of molecules have shown
a potential to be developed as anticancer agents” (Kamal 3769, col. 2;
citations omitted).
11. Kamal teaches the “lack of selectivity towards cancer tissues is
one of the major drawbacks that is associated with anticancer agents,
including the PBDs that are in the process of development” (Kamal 3769,
col. 2).
12. Figure 2 of Kamal, showing Compound 15a, is reproduced, in
part, below:
OH
o
o„ H .OH
o o
7
Appeal 2017-001647
Application 13/641,198
“Figure 2. Pyrro[2,l-c][l,4]benzodiazepine P -glucuronide prodrugs: 15a
prodrag of imine-amide mixed dimer” (Kamal 3770).
13. Scheme 2 of Kamal is reproduced below:
5b; R - B 12b; R - B
0,N
f\-CH-
B
iHj 13b: R - B. R1 - OAc. R“ « Me
14b: R = B. R1 = OH, R- = Me
15b; R = B. R l = OH, R2=H
The key step of coupling the PBD intermediates 5a—b with the
glucuronide promoiety 11 using triphosgene and dibutyltin
dilaurate to yield the carbamates 12a-b, which upon
deprotection of the diethylthioacetal group provided the
carbinolamine intermediates 13a—b. The carbinolamines 13a—b
were deacetylated using NaOMe in methanol at 0—5 °C to
provide the intermediates 14a—b, followed by the hydrolysis of
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Appeal 2017-001647
Application 13/641,198
the carboxylic ester afforded the desired PBD p-glucuronide
prodrags 15a-b
(Kamal 3770, col. 2 and 3771).
Principles of Law
Proof of obviousness based on structural similarity requires
clear and convincing evidence that a medicinal chemist of
ordinary skill would have been motivated to select and then to
modify a prior art compound (e.g., a lead compound) to arrive
at a claimed compound with a reasonable expectation that the
new compound would have similar or improved properties
compared with the old.
Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir.
2010).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 3—7; FF 1—13) and agree that the
claims are obvious over Hartley, Chari, and Kamal. We address Appellants’
arguments below.
Appellants contend “the combination of Kamal with Hartley, Chari
and the ’311 patent [Thurston] is not sufficient to suggest asymmetric
modification of SJG-136 at one of the two N10 positions. Appellants’
position is supported by evidence in the form of a Rule 1.132 Declaration by
Dr. Howard” (App. Br. 8). Appellants contend:
Dr. Howard states that Chari mentions PBD dimers only in
passing and provides no teaching as to how PBD dimers may be
incorporated in conjugates. At paragraph 7 of the Declaration,
Dr. Howard states that Kamal does not teach how to conjugate
a PBD dimer, let alone how to conjugate a PBD dimer with two
imine bonds to an antibody or similar [agent].
9
Appeal 2017-001647
Application 13/641,198
(App. Br. 8). Appellants contend that “Chari does not disclose conjugating
an antibody or other agent to one of two N10-C11 imine bonds, in an
asymmetric manner consistent with present claim 1” (App. Br. 9).
We do not find the arguments or the Howard Declaration7 persuasive.
There is no dispute that Hartley’s PBD dimer named SJG-136 is a “lead
clinical candidate” (FF 3). Chari teaches targeting cancer compounds
including PBD dimers (FF 5—6) by conjugation to antibodies for “greater
potency” and “greater aqueous solubility” (FF 4) and in order to treat cancer
(FF 8). Thus, Chari provided the ordinary artisan reason to conjugate
antibodies to PBD dimers such as SJG-136.
While Appellants and the Howard Declaration correctly note that
Chari does not suggest a particular position on SJG-136 for conjugation,
Chari does teach that the ordinary artisan would have been able to conjugate
“the cytotoxic agents described herein”, including PBD dimers (FF 5—6), “in
such a manner that the resulting compound still retains the specificity and/or
activity of the starting compound” (FF 9). Indeed, Appellants acknowledge
that based on the patents cited by Chari regarding PBD dimers, “there may
be a suggestion to modify both N10 positions based on the configuration of
protecting groups used in the synthesis of SJG-136” (App. Br. 10).
Moreover, the Examiner relies upon Kamal to demonstrate the
chemistry of asymmetric attachment of a conjugate to a PBD dimer to the
N10 position, demonstrating that the N10 position is a site that would “give
one skilled in the relevant chemical art the motivation to make close
7 Declaration of Dr. Philip Wilson Howard, dated Sept. 9, 2015.
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Application 13/641,198
relatives (homologs, analogs, isomers, etc.) of the prior art” SJG-136
compound. In re Dillon, 919 F.2d 688, 696 (Fed. Cir. 1990) (see FF 12—13).
The Howard Declaration does not identify any evidence of uncertainty
or unpredictability in binding an antibody to PBD dimers as suggested by
Chari, nor any unpredictability in forming an asymmetric attachment at the
N10 position as shown by Kamal, but rather simply states that “Kamal does
not teach how to a conjugate a PBD dimer, let alone how to conjugate a
PBD dimer with two imine bonds to an antibody or similar” (Howard Dec.
17). That statement does not, however, rise to the level of evidence
demonstrating the absence of a reasonable expectation of success.
Accordingly, we find that the combination of Hartley, Chari, and Kamal
provides a reasonable expectation of success in conjugating an antibody to
the N10 position of SJG-136. “Obviousness does not require absolute
predictability of success ... all that is required is a reasonable expectation of
success” In reKubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citation
omitted). In addition, given the detailed description in Chari regarding
conjugation of antibodies and Kamal’s specific disclosure of a conjugate to
the N10 position of a PBD dimer (FF 4—13), we agree with the Examiner
that “in the absence of any evidence to the contrary, the prior art is presumed
enabled” (Ans. 13).
Appellants contend that “Kamal does not fairly suggest modifying a
symmetric PBD dimer, such as SJG-136, in an asymmetric manner. The
starting compound for modification in Kamal is already asymmetric and thus
very different from SJG-136 or the other symmetric PBD dimers shown
above” (App. Br. 12).
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Application 13/641,198
We do not find this argument persuasive because the reasoning
ignores the specific disclosure of Kamal showing an asymmetric PBD dimer
(FF 12). We also agree with the Examiner that Chari provides “motivation
to modify a PBD using a single cell-binding agent, such as an antibody, to
arrive at a PBD dimer” (Ans. 13) and that:
an artisan faced with a decision of “where” to attach the cell­
binding agent to a PBD, such as SJG-136, would look to the
prior art and identify which positions within a PBD dimer were
art-recognized as amenable to asymmetric modifications using
a linker, such as, a self-immolating moiety. Accordingly,
Kamal established that the prior art provided reasonable
guidance to select and modify PBDs at the N10 position from
among the eight available positions for modification.
(Ans. 14).
Appellants contend that:
None of Hartley, Chari, and the ’311 patent [Thurston] suggest
modifying SJG-136 so as to preserve one of the N10 imine
bonds while modifying the other imine bond to form a
conjugate. Kamal, in combination with the other cited
references, also does not suggest preserving an imine bond at
the N10 position of a conjugate, a limitation found in the
presently claimed conjugates.
(App. Br. 13—14). Appellants further contend the prior art does “not suggest
the advantages of the presently claimed conjugates that retain an imine bond
at one N10 position, while also having an antibody or other cell-binding
agent that can be released in the lysosome of a cell to yield a compound with
an imine bond at each of the two N10 positions” (App. Br. 14).
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Application 13/641,198
We do not find these arguments persuasive because they suggest that
the prior art must anticipate in order to render the claims obvious. “Non­
obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
references.”/!? re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). It is
this combination of teachings that suggests the SJG-136 conjugate of the
claim, including the teaching of an asymmetric PBD dimer of Kamal, not the
teachings of each reference considered alone.
We also agree with the Examiner’s point that “‘crucial’ nature of this
bond [the C10-N11 imine bond] for activity is contradicted by the prior art,
which identifies that PBD dimers lacking a single C10-N11 imine bond in
one PBD ring were fully enabled for binding DNA” (Ans. 15).
Moreover, Appellants do not identify any evidence in the Howard
Declaration or Specification that demonstrates any unexpected result for the
claimed compound based on the presence of the imine bond at one of the
N10 positions. That is, Appellants do not compare a conjugated SJG-136
with the compound 15a of Kamal or with any other compound and
demonstrate that the asymmetric SJG-136 conjugate demonstrates any
secondary consideration.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Hartley, Chari, and Kamal render obvious an asymmetric
pyrrolobenzodiazepine dimer of claim 1.
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Application 13/641,198
B. 35 U.S.C. § 103(a) over Hartley, Chari, Thurston, Kamal, andDucry
Appellants do not separately argue this obviousness rejection, instead
relying upon their arguments to overcome the rejection over Hartley, Chari,
and Kamal. The Examiner provides sound fact-based reasoning for
combining Hartley, Chari, and Kamal with Ducry (see Ans. 16—21). Having
affirmed the obviousness rejection of claim 1 over Hartley, Chari, and
Kamal for the reasons given above, we also find that the further obvious
combination with Ducry renders claims 3—19, 42, 44, and 48—50 for the
reasons given by the Examiner.
C. and D. Double Patenting
We summarily affirm the obviousness-type double patenting
rejections that were not contested by Appellants (see Reply Br. 10). See
Manual of Patent Examining Procedure § 1205.02 (“If a ground of rejection
stated by the examiner is not addressed in the appellant’s brief, that ground
of rejection will be summarily sustained by the Board.”)
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Hartley, Chari, Thurston and Kamal. Claims 21—
26, 28, 29, 32, 42, 48, 49, 53, and 54 fall with claim 1.
We affirm the rejection of claims 3—19, 42, 44, and 48—50 under
35 U.S.C. § 103(a) as obvious over Hartley, Chari, Thurston, Kamal, and
Ducry.
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Application 13/641,198
We affirm the provisional rejection of claims 1,3,4, 19—26, 28, 29,
32, 42, 44, 48, 49, 53, and 54 on the ground of nonstatutory double patenting
as being unpatentable over claims 1—13, 18—22, 24, 28—32, and 44^48 of
copending Application No. 13/650,277.
We affirm the provisional rejection of claims 1, 3—25, 28, 42, 44, 48,
49, 53, and 54 on the ground of nonstatutory double patenting as being
unpatentable over claims 2—11 of copending Application No. 14/051,743.
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
15