Ex Parte Flygare et al

Patent Trials and Appeals Board

Jul 5, 2019

13650277 - (D) (P.T.A.B. Jul. 5, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/650,277 10/12/2012
55694 7590 07/09/2019
DRINKER BIDDLE & REATH (DC)
1500 K STREET, N.W.
SUITE 1100
WASHINGTON, DC 20005-1209
FIRST NAMED INVENTOR
John A. Flygare
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.
215050-0002-00-US-538466 7476
EXAMINER
KOSTURKO, GEORGE W
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
07/09/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
DBRIPDocket@dbr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOHN A. FLYGARE, JANET L. GUNZER-TOSTE,
THOMAS PILLOW, PHILIP WILSON HOW ARD,
and LUKE MASTERSON
Appeal2017-008476
Application 13/650,277
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 appeal 1,2 under 35 U.S.C. § 134 involving claims to a
conjugate comprising a pyrrolobenzodiazepine (PBD) dimer compound
connected via a linker to a cell binding agent. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse
and enter a new ground of rejection.
1 Appellants identify the Real Party in Interest as Genentech, Inc. and
Medimmune Limited (see App. Br. 2).
2 We have considered and refer to the Specification of Oct. 12, 2012
("Spec."); Final Office Action of May 17, 2016 ("Final Action"); Appeal
Brief of Nov. 7, 2016 ("App. Br."); Examiner's Answer of Mar. 23, 2017
("Ans."); and Reply Brief of May 23, 2017 ("Reply Br.").
Appeal2017-008476
Application 13/650,277
Statement of the Case
Background
"[D]imeric PBD compounds bearing C2 aryl substituents ... have
been shown to be highly useful cytotoxic agents." (Spec. 2: 12-17). The
prior art "describes the preparation of dimer PBD compounds having linker
groups for connection to a cell binding agent, such as an antibody" (Id. at
3: 10-11 ). "The use of antibody-drug conjugates (ADC) ... for the local
delivery of cytotoxic or cytostatic agents ... targets delivery of the drug
moiety to tumors" (Id. at 3: 17-19). "The present inventors have developed a
novel approach to forming PBD conjugates with cell binding agents" (Id. at
4:9-10).
The Claims
Claims 1, 2, 4, 5, 8-13, 18-20, 22, 23, 25-32, 42, and 44--48 are on
appeal. Claims 1 and 44 are the independent claims, and claim 1 is
representative and reads as follows:
1. A conjugate of formula (A):
2
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Application 13/650,277
the dotted lines indicate the optional presence of a double bond
between (a) Cl and C2 or C2 and C3 and (b) Cl' and C2' or C2'
and C3'·
'
R2 is independently selected from H, OH, =O, =CH2, CN,
R, OR, ==CH-RD, =C(RD)2, O-S02-R, C02R and COR, and
optionally further selected from halo or dihalo;
where RD is independently selected from R, C02R, COR,
CHO, C02H, 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', N02, Me3Sn and halo;
Y is selected from a single bond, and a group of formulae
Al or A2:
(}\1)
where N shows where the group binds to the N 10 of the
PBD moiety;
Ru and R L2 are independently selected from H and
methyl, or together with the carbon atom to which they are
bound form a cyclopropylene group;
CBA represents a cell binding agent, wherein the cell
binding agent is an antibody or an active fragment thereof;
Q is independently selected from 0, Sand NH;
R 11 is either H, or R or, where Q is 0, SQ3M, where Mis
a metal cation;
R_and R' are each independently selected from
optionally substituted C1-12 alkyl, C3-20 heterocyclyl and Cs-20
aryl groups, and optionally in relation to the group NRR', Rand
R' together with the nitrogen atom to which they are attached
form an optionally substituted 4-, 5-, 6- or 7- membered
heterocyclic ring;
3
(i\2)
Appeal2017-008476
Application 13/650,277
wherein R12 R16 R19 and R17 are as defined for R2 R6 R9
' ' ' ' and R7 respectively;
wherein R" is a C3-12 alkylene group, which chain may be
interrupted by one or more heteroatoms selected from 0, S,
N(H), and NMe and/or aromatic rings, which rings are
optionally substituted;
X and X' are independently selected from 0, Sand N(H);
and
wherein S of the conjugate of formula (A) is linked by a
disulfide bond to a free S on the cell binding agent.
The Rejection3
The Examiner rejected claims 1, 2, 4, 5, 8-13, 18-20, 22, 23, 25-32,
42, and 44--48 under 35 U.S.C. § I03(a) as obvious over Eigenbrot, 4 Gauzy, 5
Vlahov, 6 and Berry7 (Final Act. 3-10).
The Examiner finds that Eigenbrot teaches "linking of cysteine
modified monoclonal antibodies to cytotoxic frameworks in order to
generate potent antibody-drug conjugates" including "linking site-specific
engineered antibodies with cysteine residues (ThioMabs) with DNA
intercalating cytotoxic drugs in order to inhibit tumor growth" (Final Act. 3).
3 The provisional obviousness double patenting rejection over US
13/641,198 is moot in view of the abandonment of that application on Dec.
15, 2017.
4 Eigenbrot et al., US 7,521,541 B2, issued Apr. 21, 2009.
5 Gauzy et al., WO 2007/085930 Al, published Aug. 2, 2007.
6 Vlahov et al., Design and regioselective synthesis of a new generation
of targeted chemotherapeutics. Part 1: EC] 45, a Jolie acid conjugate of
desacetylvinblastine monohydrazide, 16 BIOORGANIC & MEDICINAL CHEM.
LETTERS 5093---6 (2006).
7 Berry et al., Synthesis and Biological Evaluation of an NJ 0-Psec
Substituted Pyrrolo[2,l-c] [l ,4]benzodiazepine Prodrug, 12 BIOORGANIC &
MEDICINAL CHEM. LETTERS 1413---6 (2002).
4
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Application 13/650,277
The Examiner finds Gauzy teaches "pyrrolobenzodiazepine
framework of Formula (A) as a potent DNA intercalating cytotoxic scaffold
to coordinate to antibodies for the treatment of cancer" (Final Act. 3). The
Examiner finds "Gauzy and coworkers further envisage linking the cytotoxic
PBD scaffold to the cell binding agent via an acid labile, thioether prodrug
moieties" (Final Act. 4).
The Examiner acknowledges that the "combination of Eigenbrot and
Gauzy do not specifically teach the acid-labile, disulfide linker connecting
the cysteine-modified antibody to the cytotoxic pyrrolobenzodiazepine core"
Final Act. 4).
The Examiner finds that Vlahov teaches the claimed linker as
providing a "disulfide bridge between the peptide and prodrug-cytotoxic
core ... including its desirable acid-lability and reducible disulfide bond,
which efficiently promotes the decoupling of the cytotoxic payload from the
conjugated peptide within the endosomes of cancer cells" (Final Act. 4--5).
The Examiner finds that Berry teaches "N-10 protected PBD' s ( as
shown in Formula (A)) are devoid of their pivotal cytotoxicity as they are
incapable of intercalating with DNA (page 1413). Berry teaches that upon
hydrolysis or enzymatic removal of the carbamate N-10 prod rug moiety, the
free N-10 C 11 imine forms, exerting advantageous cytotoxicity towards an
array of neoplasms" (Final Act. 5).
The Examiner finds it obvious "to couple the potent cysteine modified
trastuzumab to the art-recognized cytotoxic intercalating
pyrrolobenzodiazepine scaffold via the acid labile, reducible disulfide bond
at the NlO position of the pyrrolobenzodiazepine core in view of the
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Application 13/650,277
combine teachings of Vlahov and Berry to arrive at the instantly claimed
compounds" (Final Act. 5).
The issue with respect to this rejection is: Does a preponderance of the
evidence of record support the Examiner's conclusion that the prior art
suggests the claimed compounds?
Findings of Fact
1. Eigenbrot teaches that its invention relates to "antibodies
engineered with reactive cysteine residues and more specifically to
antibodies with therapeutic or diagnostic applications. The cysteine
engineered antibodies may be conjugated with chemotherapeutic drug"
(Eigenbrot 1: 13-17). Antibodies include trastuzumab (see Eigenbrot 5:36).
2. Eigenbrot teaches "drug moiety (D) of the antibody-drug
conjugates (ADC) includes any compound, moiety or group which has a
cytotoxic or cytostatic effect. Drug moieties include: (i) chemotherapeutic
agents, which may function as ... DNA intercalators" (Eigenbrot 63 :20-25).
3. Gauzy teaches
derivatives that retain high cytotoxicity and that can be
effectively linked to cell binding agents. It has previously been
shown that the linkage of highly cytotoxic drugs to antibodies
using a cleavable link, such as a disulfide bond, ensures the
release of fully active drugs inside the cell, and such conjugates
are cytotoxic in an antigen specific manner.
(Gauzy 5).
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4. Gauzy teaches compounds of formula (I) shown below
(Gauzy 6).
5. Gauzy teaches selections for the various substituents that mirror
those required by claim 1, where:
R2 and R12 in claim 1 may be halogens, CN, OR and
other groups and the identically placed RI, R2, RI', and R2' in
Gauzy's formula I may be halogens, CN, OR and other groups
(Gauzy 6);
U, and U' can be absent and W can be Hin Gauzy's
formula I ( Gauzy 6);
R17 and R7 in claim I may be Hor OR and the identically
placed Y and Y' in Gauzy's formula I may be Hor OR (Gauzy
7);
R6, R9, R16, and R19 in claim 1 may be H like the
identically placed positions in Gauzy's formula I (Gauzy 6);
X and X' in claim 1 may be O like the identically placed
X and X' in Gauzy's formula I may be O (Gauzy 7);
R" in claim 1 may be a C3-12 alkylene group substituted
with O like the identically placed An and A'n' groups in
Gauzy's formula I may be alkenyl (Gauzy 7, 9) and the central
T group may be an O (Gauzy 7);
Y linked to the COOCCS in claim 1 ( where Ru and R L2
are H) is like the identically placed W' in Gauzy is a linker
(Gauzy 6).
6. Vlahov teaches "Receptor-specific targeting, as one
approach, can potentially herald a new era in selective drug delivery
to pathologic cells" (Vlahov 5093, col. 1 ).
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7. Vlahov teaches, in scheme 3, a linker as shown below:
Of~
·"" ' ~
()
H ~ ~
The linker comprises an NCOOCCS group (see Vlahov 5095).
8. Berry teaches "NI 0-protected PBD prodrugs suitable for use in
ADEPT- and GDEPT-type therapies. These contained NI0-[4-
(nitrobenzyl)carbamate] protecting groups which could be enzymatically
removed in the presence of nitroreductase and co-factor NADH to produce
the parent cytotoxic PBD molecules" (Berry 1413, col. 2).
Principles of Law
Under the lead compound analysis rubric, we must first "determine[]
whether a chemist of ordinary skill would have selected the asserted prior art
compounds as lead compounds, or starting points, for further development
efforts." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir.
2012). "The second inquiry in the analysis is whether the prior art would
have supplied one of ordinary skill in the art with a reason or motivation to
modify a lead compound to make the claimed compound with a reasonable
expectation of success." Id. at 1292.
Analysis
We agree with Appellants' contention that "a person of ordinary skill
in the art would not have relied on Berry to modify Gauzy by attaching an
antibody to a single N-10 position of a P BD dimer. The protecting groups
8
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Application 13/650,277
of Berry are substantially different from a much larger antibody or an active
fragment thereof' (App. Br. 11-12). We agree with Appellants that the
"purpose of a protecting group above also differs from that of an antibody.
Berry relates more to characterization of specific protecting groups that can
be attached to the N-10 position to modulate cytotoxicity" (App. Br. 12).
Finally, we agree that
even if a person of ordinary skill in the art were to apply the
teachings of the Berry reference to the Gauzy structure, the
clear suggestion would be to modify the PBD monomer at both
sides, in order to provide the protection relied upon by the
Examiner. There is no reason why a person of ordinary skill
would make an asymmetric modification at only one N-10
position.
(App. Br. 12).
In the Final Action, the Examiner relies upon Kamal to demonstrate
asymmetric attachment (see Final Act. 9), but Kamal is not cited in the
statement of rejection. In the Examiner's Answer, the Examiner does not
address Appellants' point that there is no reason, based on Berry or Vlahov,
to asymmetrically attach the linker to PBD dimer as required for the
conjugate of claim 1. A prima facie case for obviousness requires "a reason
that would have prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention does." KSR
Int'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007).
Conclusion of Law
A preponderance of the evidence of record supports the Examiner's
conclusion that the prior art suggests the claimed compounds.
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Application 13/650,277
New Ground of Rejection
Under the provisions of 3 7 C.F .R. § 41. 50(b ), we enter the following
new ground of rejection8 based substantially on the Examiner's analysis in
the related application 13/641,198 that we affirmed in Appeal 2017-001647.
Claim 1 is rejected under 35 U.S.C. § I03(a) as obvious over Hartley,9
Chari, 10 Vlahov, and Kamal. 11
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the conclusion that Hartley, Chari, Vlahov,
and Kamal render obvious an asymmetric pyrrolobenzodiazepine dimer of
claim 1?
Findings of Fact
9. 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
8 We limit our consideration to the claim 1. We leave it up to the Examiner
to consider the remaining claims in light of the cited prior art and other prior
art. The PTAB serves as a board of review, not a de novo examination
tribunal. See 35 U.S.C. 6(b).
9 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").
1° Chari et al., US 2009/0274713 Al, publ. Nov. 5, 2009 ("Chari").
11 Kamal et al., Pyrrolo[2,l-c] [l,4]benzodiazepine-~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 13/650,277
Institute (NCI) anticancer drug screen with 50% net growth inhibition"
(Hartley, abstract).
10. Figure 1 of Hartley is reproduced, in part, below:
"Fig. 1. Structures of the ... PBD dimer[] ... SJG-136" (Hartley 6694, col. 1).
11. 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).
12. 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 ,r 2).
13. Chari teaches "the drug can be any of many small molecule
drugs, including, but not limited to ... pyrrolobenzodiazepine dimers"
(Chari ,r 105).
14. 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 ,r 255).
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Application 13/650,277
15. 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 ,r 129).
16. 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 ,r 268).
17. 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 ,r 256).
18. Kamal teaches the "pyrrolo[2,1-c][l,4]benzodiazepines (PBDs)
are a class of small molecules which bind to NH2 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).
19. 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 3 7 69,
col. 2).
20. Vlahov teaches, in scheme 3, a linker as shown below:
7
The linker comprises an NCOOCCS group (see Vlahov 5095).
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Application 13/650,277
21. Scheme 2 of Kamal is reproduced below:
I ~ .,,CH(SEt)2 RO~NH~ _
:\·1e0 h :<8
0
:b: R=A.
5h:R"'B
,i)-,~'(Yo-(.CH:~
C\~OMe
0
A
0-.N
M,.:OOC O ~· .
AcO~C\ 0 ~ 1.
AcO~ \\ II
OAc (?
c=o
I
RO .NH -_ ry''".., ,,,CH!SEtt
Meo~No
0
12a: R '" A
12b: R :ss B
iii c:: 13b: R ~ B, R 1 ~ OAc, R~ ~ Mc,
14h: H = B. R.1 = OH, R2 = Mt
ivC. 15h: R = ft R 1 = OH, R2 = H
The key step of coupling the PBD intermediates Sa-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 he carboxylic ester afforded the desired PBD ~-glucuronide prodrugs
15a-b
(Kamal 3770, col. 2 and 3771).
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22. Figure 2 of Kamal, showing Compound 15a, is reproduced, in
part, below:
"Figure 2. Pyrro[2,1-c][l,4]benzodiazepine ~ -glucuronide prodrugs: 15a
prodrug of imine-amide mixed dimer" (Kamal 3770).
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
Analysis
Hartley's PBD dimer named SJG-136 is reasonably considered a
"lead clinical candidate" (FF 11 ). Chari teaches targeting cancer compounds
including PBD dimers (FF 13-14) by conjugation to antibodies for "greater
potency" and "greater aqueous solubility" (FF 12) and in order to treat
cancer (FF 16). Thus, Chari provided the ordinary artisan reason to
conjugate antibodies to PBD dimers such as SJG-136.
Chari teaches that the ordinary artisan would have been able to
conjugate "the cytotoxic agents described herein", including PBD dimers
(FF 13-14), "in such a manner that the resulting compound still retains the
specificity and/or activity of the starting compound" (FF 17). In the
previous appeal, Appellants noted that based on the patents cited by Chari
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Application 13/650,277
regarding PBD dimers, "there may be a suggestion to modify both NI 0
positions based on the configuration of protecting groups used in the
synthesis ofSJG-136" (Appeal 2017-001647; App. Br. 10).
Vlahov teaches linkage using a linker consistent with claim 1 (FF 20),
and Kamal teaches the chemistry of asymmetric attachment of a conjugate to
a PBD dimer to the NIO position (FF 21-22), demonstrating that the NIO
position is a site that would "give one skilled in the relevant chemical art the
motivation to make close relatives (homo logs, analogs, isomers, etc.) of the
prior art" SJG-136 compound. In re Dillon, 919 F.2d 688, 696 (Fed. Cir.
1990).
We find that the combination of Hartley, Chari, Vlahov, and Kamal
both suggests and provides a reasonable expectation of success in
conjugating an antibody to the NIO position of SJG-136 using a linker
consistent with claim 1. "Obviousness does not require absolute
predictability of success ... all that is required is a reasonable expectation of
success." In re Kubin, 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 NIO position of a PBD dimer with Hartley's teaching of SJG-136 as a
lead compound (FF 9-22), we find that in the absence of any evidence to the
contrary, the prior art is presumed enabled. In re Antor Media Corp., 689
F.3d 1282, 1289 (Fed. Cir. 2012).
In order to expedite prosecution, we consider the Flygare Declaration,
dated Jan. 15, 2015 and the Second§ 1.132 Declaration of Dr. Philip Wilson
Howard, dated Apr. 7, 2017 and filed in the related 13/641,198 application.
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The Flygare Declaration asserts that a particular form of the
compound, limited to a particular chemical formula, a particular linker, and
a particular antibody, were "efficacious in an in vivo Fo5 efficacy model of
breast cancer" (Flygare Deel. ,r 11 ). However, even if we credit that this
particular composition with the precise structure shown in Exhibit C as
compound 22 and linked to an anti-CD33 antibody was unexpectedly
superior, this evidence is not commensurate with the much broader recitation
in claim 1 of an immense genus of compounds that may use any antibody or
active fragment as a cell binding agent. Unexpected results must be
"commensurate in scope with the degree of protection sought by the claimed
subject matter." In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
The Howard Declaration asserts that it was known "to symmetrically
modify PBD dimers for attachment to antibodies" but that "synthesis of an
asymmetric modified dimer derived from SJG-136 ... would necessarily
have been unpredictable because the way SJG-136 is synthesized maintains
the symmetry of the compounds throughout" (Howard Deel. ,r 6).
We find this argument unpersuasive for the same reasons given by the
Examiner in the Final Action of the related 13/641,198 case dated May 4,
2017. As the Examiner points out "the prior art teaches multiple methods
for synthesizing PBD dimers ... but Declarant addresses only the single
reference Gregson" 12 (Final Act. 13/641,198 5/4/2017 at 23). The Examiner
notes that other methods of synthesizing asymmetric PBD dimers were
known, because US 7,429,658 and US 7,049,311 disclose such asymmetric
12 Gregson et al., Synthesis of a novel C2/C2 '-exo unsaturated
pyrrolobenzodiazepine cross-linking agent with remarkable DNA binding
affinity and cytotoxicity, CHEM. COMMUN. 797-8 (1999).
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PBD dimers (see Final Act. 13/641,198 5/4/2017 at 23-24). Moreover,
Gregson never states that asymmetric synthesis would not function, but
rather simply teaches protection of the NlO/NlO' positions followed by
deprotection to obtain the PBD dimer (see Gregson 798, col. 1 ).
In contrast, other prior art demonstrates asymmetric synthesis of
similar compounds. While we appreciate that Kamal is an imine-amide
mixed dimer, Kamal demonstrates synthesis of an asymmetric compound
with an antibody linked at a single monomer of the dimer at the NlO
position (FF 22). Similarly, Eigenbrot, cited in the instant application,
recognizes that U and U' linked to the PBD dimer at the NlO positions may
be "the same or different" and one of the two may simply be an H, resulting
in an asymmetric PBD dimer (see Eigenbrot 6).
We are also not persuaded by Declarant's statement that "[t]here is no
reasonable way to start with the singly protected compound of Kamal 15a
and arrive at a symmetric PBD dimer which has been asymmetrically
modified/protected on one side, leaving an imine bond intact on the other
side" (Howard Deel. ,r 13). The ordinary artisan of ordinary skill would
look to references teaching methods of generating asymmetric dimers. The
citation of a single reference, Gregson, that does not address asymmetric
dimers is not sufficient to demonstrate that such synthesis would have been
unpredictable in view of the teachings of Kamal and Eigenbrot.
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SUMMARY
In summary, we reverse the rejection of claims 1, 2, 4, 5, 8-13, 18-20,
22, 23, 25-32, 42, and 44--48 under 35 U.S.C. § 103(a) as obvious over
Eigenbrot, Gauzy, Vlahov, and Berry.
We enter a new ground of rejection of claim 1 over Hartley, Chari,
Vlahov, and Kamal pursuant to 37 C.F.R. § 4I.50(b). Section 4I.50(b)
provides "[a] new ground of rejection pursuant to this paragraph shall not be
considered final for judicial review." Section 41.50(b) also provides:
When the Board enters such a non-final decision, the
appellant, within two months from the date of the decision,
must exercise one of the following two options with respect to
the new ground of rejection to avoid termination of the appeal
as to the rejected claims:
( 1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating
to the claims so rejected, or both, and have the matter
reconsidered by the examiner, in which event the prosecution
will be remanded to the examiner. The new ground of rejection
is binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the
opinion of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
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Application 13/650,277
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure§ 1214.01.
REVERSED; 37 C.F.R. § 4I.50(b)
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