Ex Parte Rajopadhye et al

Board of Patent Appeals and Interferences

May 21, 2007

09281474 (B.P.A.I. May. 21, 2007)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MILAND RAJOPADHYE, D. SCOTT EDWARDS,
THOMAS D. HARRIS, STUART J. HAMINWAY,
SHUANG LIU, and PRAHLAD R. SINGH
__________

Appeal 2007-0856
Application 09/281,474
Technology Center 1600
__________

Decided: May 21, 2007
__________

Before TONI R. SCHEINER, ERIC GRIMES, and LORA M. GREEN,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
compound comprising a targeting moiety and a chelator. The Examiner has
rejected the claims for obviousness and obviousness-type double patenting.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm the obviousness
rejection and reverse the obviousness-type double patenting rejection.
Appeal 2007-0856
Application 09/281,474

BACKGROUND
“Angiogenesis is the process by which new blood vessels are formed”
(Specification 3). Angiogenesis is “an important component of a variety of
physiological processes including ovulation, embryonic development,
wound repair, and collateral vascular generation in the myocardium. It is
also central to a number of pathological conditions such as tumor growth
and metastasis, diabetic retinopathy, and macular degeneration.” (Id.)
“Integrins are a diverse family of heterodimeric cell surface receptors
by which endothelial cells attach to the extracellular matrix, each other and
other cells” (id. at 4).
The integrin αvβ3 is minimally expressed on normal blood
vessels, but, is significantly upregulated on vascular cells
within a variety of human tumors. The role of the αvβ3
receptors is to mediate the interaction of the endothelial cells
and the extracellular matrix and facilitate the migration of the
cells in the direction of the angiogenic signal, the tumor cell
population.
(Id.)
The Specification describes compounds “comprised of a peptide or
peptidomimetic targeting moiety that binds to a receptor that is upregulated
during angiogenesis, . . . an optional linking group, . . . and a metal chelator”
(id. at 8). The receptor may be αvβ3 (id. at 9-10).
“A ‘chelator’ . . . is the moiety or group on a reagent that binds to a
metal ion through the formation of chemical bonds with one or more donor
atoms” (id. at 57). “The metal chelator . . . is selected to form stable
complexes with the metal ion chosen for the particular application.
Chelators . . . for diagnostic radiopharmaceuticals are selected to form stable
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complexes with the radioisotopes that have imageable gamma ray or
positron emissions.” (Id. at 75.) Chelators can also be selected to form
therapeutic radiopharmaceuticals (id. at 80).
“The term ‘peptide’ . . . means “a linear compound that consists of
two or more amino acids . . . that are linked by means of a peptide bond. . . .
The term ‘peptide’ also includes compounds containing both peptide and
non-peptide components, such as pseudopeptide or peptidomimetic residues
or other non-amino acid components.” (Id. at 59.) “A . . . ‘peptidomimetic’
is a compound which mimics the structure of an amino acid residue or a
peptide, for example, by using linking groups other than amide linkages
between the peptide mimetic and an amino acid residue (pseudopeptide
bonds) and/or by using non-amino acid substituents and/or a modified amino
acid residue” (id.). “The term ‘amino acid’ . . . means an organic compound
containing both a basic amino group and an acidic carboxyl group” (id. at
58).
DISCUSSION
1. CLAIMS
Claims 1-10, 12-35, 48-50, 52, and 53 are pending and on appeal. We
will focus on independent claims 1, 52, and 53, which are representative.
The dependent claims subject to each rejection have not been separately
argued and will therefore stand or fall with the claim on which they depend.
37 C.F.R. § 41.37(c)(1)(vii).
Claim 1 is reproduced in the Claims Appendix of Appellants’ Brief,
and is directed to a compound comprising a peptide or peptidomimetic αvβ3
receptor targeting moiety bound to a chelator. Claim 1 further recites that
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the compound has a linking group of a specified formula between the
targeting moiety and chelator. The Examiner correctly points out that the
linking group recited in claim 1 can simply be, for example, O, S, C(=O), or
an amino acid, where g, g’, k, h’, g’’, h’’, and g’’’ are all zero, as they can be
(Answer 11).1
Claims 52 and 53 read as follows:
52. A compound comprising a peptide or peptidomimetic αvβ3 receptor
targeting moiety bound to a chelator.
53. A compound, comprising a peptide or peptidomimetic αvβ3 receptor
targeting moiety bound to a chelator, wherein said chelator is a
diaminedithiol, monoamine-monoamidedithiol, triamide-monothiol,
monoamine-diamide-monothiol, diaminedioxime, hydrazine, or cyclic
polyaminocarboxylate, or acyclic polyaminocarboxylate.
2. REFERENCES
The Examiner relies on the following references:
Palladino US 5,780,426 Jul. 14, 1998
Sharma US 6,331,285 B1 Dec. 18, 2001
Harris US 6,511,648 B2 Jan. 28, 2003
Cheesman US 6,558,649 B1 May 6, 2003
3. OBVIOUSNESS
Claims 1, 2, 12-15, 17, 19-21, 25, 27, 28, 31-35, 48-50, 52, and 53
stand rejected under 35 U.S.C. § 103 as obvious over Palladino in view of
Sharma. The Examiner relies on Palladino for disclosing “peptides that may
be used to treat diseases involving αvβ3 receptors,” including cancer and

1 In fact, when s, s’, s’’, t, and t’ are also 0, it is unclear whether claim 1
requires a linking group at all.
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angiogenic-based diseases (Answer 5). The Examiner argues that Palladino
describes “non-RGD (RGD is the peptide sequence Arg-Gly-Asp) peptides
that bind to the αvβ3 integrin receptor” (id.). The Examiner also argues that
Palladino discloses that the “peptides may be labeled and discloses that a
metal binding domain[] may be utilized. . . . [T]he phrase ‘metal binding
domains’ is equivalent to ‘chelators’ in the art.” (Id. at 9-10.) In addition,
the Examiner argues that Palladino “disclose[s] that the labels are optionally
attached by spacer arms of various lengths to reduce potential stearic [sic,
steric] hindrance. . . . [T]he phrase ‘spacer’ is interchangeable with . . .
‘linking group’ in the art.” (Id. at 10.)
The Examiner relies on Sharma for disclosing “peptide
metalloconstructs that are useful for biological, therapeutic, diagnostic
imaging, or radiotherapeutic purposes” (id. at 6). The Examiner argues that
Sharma “is directed to peptides that . . . may be cyclic RGD mimics . . . ,
which are complexed with a metal ion binding backbone (chelator) and
complexed with a metal” (id. at 10). The Examiner also argues that Sharma
discloses that the peptide (i.e., the biological-function domain) is “distinct”
from the metal binding backbone (id. at 7).
In addition, the Examiner argues that Sharma discloses “[v]arious
chelators/ligands containing nitrogen, oxygen, and sulfur based coordination
atoms . . . used to generate a tetradentate peptide construct. The tetradentate
structure may be N4, N3S, N2S2, NS3, N2SO, or any similar combination
yielding tetradentate coordination utilizing nitrogen, sulfur, and oxygen
atoms.” (Id.) In particular, the Examiner argues that N3S is the “same as
[claim 53’s] triami[d]e-monothiol or monoamine-diamide-monothiol
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Application 09/281,474

combination” and that N2S2 is the “same as [claim 53’s] diaminedithiol or
monoamine-monoamidedithiol combination” (id. at 11). The Examiner also
argues that Sharma discloses “a peptide chain linked to a N3S containing
chelator by a C(=O) spacer group” (id.).
The Examiner concludes that “one of ordinary skill in the art would be
motivated to combine the teachings of Palladino et al and Sharma et al since
both references are directed to peptides that may be labeled and contain a
linking group” (id. at 10). “[W]hile Appellant[s] assert[] that the complexes
of Sharma et al are conformationally constrained, the pending claims do not
exclude conformationally constrained conjugates” (id.).
We conclude that the Examiner has set forth a prima facie case that
claims 1, 52, and 53 would have been obvious. With regard to claim 52,
Palladino describes a non-RGD peptide that binds to the αvβ3 integrin
receptor and the use of this peptide for treating or detecting diseases
involving this receptor (Palladino, col. 7, ll. 13-28). To diagnose disease,
Palladino describes “determining the level of binding of the peptide to the
αvβ3 integrin receptor. . . . To determine the level of binding, the peptide is
labelled with a detectable label” (id. at col. 19, l. 61, to col. 20, l. 19). As a
label, Palladino describes “polypeptide epitopes recognized by a secondary
reporter,” for example, “metal binding domains” (id. at col. 6, ll. 37-54).
Based on the teachings of Palladino, we conclude that it would have been
obvious to combine a metal binding domain, which constitutes a chelator as
this term is used in the Specification, with the non-RGD peptide.
With regard to claim 53, Sharma describes a metallo-construct
including “a metal ion-binding backbone for complexing with a metal ion,
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and a biological-function domain” that is “conformationally constrained
upon complexing the metal ion-binding backbone with the metal ion”
(Sharma, col. 10, ll. 8-15). The biological-function domain “may constitute
a ligand capable of forming a member of a ligand and receptor pair” (id. at
col. 10, ll. 45-48). The metal ion acts as a label (id. at col. 1, ll. 22-23). In
particular, Sharma describes “a molecule which, upon complexing with a
metal ion, includes a biological-function domain which is specific for one or
more of the RGD-binding integrin family of receptors for use in diagnostics
and therapeutic modalities” (id. at col. 20, ll. 17-21).
In addition, Sharma describes a metal ion-binding backbone including
a plurality of amino acids having nitrogen, sulfur, or oxygen atoms available
to complex the metal ion (id. at col. 10, ll. 28-35). The preferred backbone
is “based on the requisite number of particular coordinating groups required
by the coordination sphere of a given complexing metal ion” (id. at col. 27,
ll. 12-15). “Coordinating groups in the peptide chain include nitrogen atoms
of amine, [or] amide . . . ; [and] sulfur atoms of thiols” (id. at col. 27, ll. 21-
23). Specifically, Sharma describes a tetradentate peptide construct of, e.g.,
N3S or N2S2 (id. at col. 27, ll. 30-42). Based on the teachings of Sharma, we
agree with the Examiner that it would have been obvious to include a
diaminedithiol, a monoamine-monoamidedithiol, a triamide-monothiol, or a
monoamine-diamide-monothiol as the metal binding domain of Palladino.
With regard to claim 1, Palladino discloses that the labels may be
“attached by spacer arms of various lengths to reduce potential stearic [sic,
steric] hindrance” (Palladino, col. 6, ll. 54-55). In addition, Sharma depicts
a metallopeptide having a C(=O) between the metal ion-binding backbone
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and the biological-function domain (Sharma, col. 39, ll. 50-61). As
discussed above, claim 1 encompasses a compound with a spacer consisting
of C(=O). Thus, we agree with the Examiner that it would have been
obvious to include a linking group within the formula recited in claim 1
between the non-RGD peptide and the metal binding domain of Palladino to
reduce potential steric hindrance.
Appellants argue that Palladino “lacks a chelator, or in the alternative,
lacks the limitation of the ‘targeting moiety bound to a chelator’” (Br. 5).
In particular, Palladino refers to “immunological labeling techniques as
opposed to chelators” (id.).
We are not persuaded by this argument. Although Palladino also
describes labeling techniques that do not involve chelators, we agree with
the Examiner that Palladino describes a targeting moiety bound to a chelator
for the reasons discussed above.
Appellants also argue that Sharma “relates to conformationally fixed
peptides and metallo-constructs that have a metal ion binding backbone. . . .
A metal is attached to O, N, or S, atoms present in the backbone or side
chains of the peptide. Thus, Sharma also fails to teach a ‘targeting moiety
bound to’ a chelator.’” (Br. 6.) “In fact, in col. 39, the Sharma reference
states ‘[i]n these constructs a metal binding site is introduced between two
pre-selected ends of a linear peptide that contains the biological function
domain.’ . . . If the peptide targeting moiety is the chelator, it’s not ‘bound
to’ the chelator.” (Id.) “Therefore, even when combined, the references fail
to teach all limitations of the claims” (id.)
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In addition, Appellants argue that the references do not provide
motivation to combine them. Palladino “has a non-RGD targeting moiety
that does not appear to be conformationally fixed. In contrast, the Sharma
reference has a conformationally fixed RGD containing peptide.” (Br. 7.)
If one skilled in the art removed the ‘conformationally fixed’
portion of the Sharma reference, the metal binding ability
would be lost, thus, there is no motivation. On the other hand,
the Examiner has cited no evidence that the Palladino
reference’s non-RGD targeting moiety could be
conformationally fixed and retain activity. If it causes the
targeting moiety to lose activity, the modification would be
unsatisfactory for its intended purpose.
(Id.)
We are not persuaded by these arguments. First, these arguments do
not apply to claim 52 because claim 52 would have been obvious in view of
Palladino alone, as discussed above.
With regard to claims 1 and 53, we disagree with Appellants’
argument that Sharma does not describe a targeting moiety bound to a
chelator. As pointed out by the Examiner, Sharma discloses that the
biological-function domain may be “distinct from the metal binding
backbone,” that is, the two domains “can be differentiated in the molecule”
(Sharma, col. 30, l. 19, to col. 31, l. 1). Thus, Sharma describes a compound
in which the biological-function domain, which can be a targeting moiety, is
bound to the metal binding backbone (i.e., chelator).
We also disagree with Appellants’ argument that there would have
been no motivation to combine Palladino with Sharma. The relevant
question is “whether there was an apparent reason to combine the known
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elements in the fashion claimed by the patent at issue.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. __, __, 82 USPQ2d 1385, 1396 (2007).
Here, we agree with the Examiner that it would have been obvious to
one of ordinary skill in the art to include the metal-ion binding backbones
described in Sharma as the metal binding domain of Palladino. Although
Sharma describes including these metal-ion binding backbones in a structure
that conformationally fixes the biological-function domain, Appellants have
provided no evidence that including these metal-ion binding backbones to
label the non-RGD peptide of Palladino would cause the non-RGD peptide
to lose activity. In addition, we agree with the Examiner that one of
ordinary skill in the art would have included a linking group, such as the
C(=O) depicted in Sharma, between the non-RGD peptide and the metal
binding domain of Palladino in order to reduce potential steric hindrance.
With regard to claim 1, Appellants argue that Palladino “states that
‘[i]n some embodiments, labels are attached by spacer arms of various
lengths to reduce potential stearic hindrance.’ . . . However, the labels are
not chelators, and thus the limitation of ‘a linking group between the
targeting moiety and chelator’ cannot be met.” (Br. 8.) Appellants also
argue that the Examiner “failed to analyze how one skilled in the art, armed
with the Palladino reference’s single disclosure of ‘spacer arms’ (found
solely at col. 6, lines 54-55) would arrive at Appellants[’] claimed formula”
(id.).
We are not persuaded by these arguments. First, we find that
Palladino describes labels that are chelators for the reasons discussed above.
Second, although Palladino does not describe the structure of its spacer
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arms, we conclude that spacer arms within the linking group formula of
claim 1 would have been obvious for the reasons discussed above.
We conclude that the Examiner has set forth a prima facie case that
claims 1, 52, and 53 would have been obvious over Palladino in view of
Sharma, which Appellants have not rebutted. We therefore affirm the
rejection of claims 1, 52, and 53 under 35 U.S.C. § 103. Claims 2, 12-15,
17, 19-21, 25, 27, 28, 31-35, and 48-50 depend from and therefore fall with
claim 1.
4. OBVIOUSNESS-TYPE DOUBLE PATENTING
Claims 1-10, 12-35, 48-50, 52, and 53 stand rejected under the
judicially-created doctrine of obviousness type double patenting over the
claims of Harris and Cheesman. The Examiner argues that the present
claims are not patentably distinct from the claims of Harris and Cheesman
because both the present claims and the patented claims “are directed to a
targeting moiety, chelator, peptide/non-peptide, optionally a metal, and
optionally, a linker” (Answer 3 and 4). Although the claims of Harris and
Cheesman recite that the targeting moiety is a non-peptide, the Examiner
argues that
the term ‘non-peptide’ means preferably less than three amide
bonds in the backbone core of the targeting moiety or
preferably less than three amino acids or amino acid mimetics
in the targeting moiety (see . . . [Cheesman], column 28,
lines 14-17; . . . and [Harris], column 67, lines 6-9). In the
instant invention, . . . the term ‘peptide’ is defined as a linear
compound that consists of two or more amino acids that are
linked by means of a peptide bond. In addition, Appellant[s]
disclose[] that the term ‘peptide’ also includes compounds
containing both peptide and non-peptide components such as
pseudopeptide or peptidomimetic residues or other non-amino
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acid components. Thus, Appellant[s’] use of the term ‘peptide’
encompasses both peptide and non-peptide targeting moieties.
(Id. at 9.)
Appellants argue that Harris “relates to a compound, comprising a
targeting moiety and a chelator, wherein the targeting moiety is a quinolone
nonpeptide. In contrast, the Appellants[’] claims recite that the targeting
moiety is a ‘peptide or peptidomimetic.’” (Br. 10.) Similarly, Appellants
argue that Cheesman “relates to a compound, comprising a targeting moiety
and a chelator, wherein the targeting moiety is a benzodiazepine nonpeptide.
In contrast, the Appellants[’] claims recite that the targeting moiety is a
‘peptide or peptidomimetic.’” (Br. 11.)
We conclude that the Examiner has not set forth a prima facie case
that the claims of Harris and Cheesman are patentably indistinct from the
instant claims. As noted by Appellants, claim 1 of Harris and Cheesman
recite a targeting moiety that is a quinolone nonpeptide and a
benzodiazepine nonpeptide, respectively. Identifying the targeting moiety as
a quinolone nonpeptide or a benzodiazepine nonpeptide indicates that a
quinolone or a benzodiazepine that is not part of a peptide can be used to
target the receptor. Granted, Harris and Cheesman define the term
“nonpeptide” as meaning “preferably less than three amide bonds in the
backbone core of the targeting moiety or preferably less than three amino
acids or amino acid mimetics in the targeting moiety” (Harris, col. 67, ll. 6-
10; Cheesman, col. 28, ll. 14-17). However, we do not agree with the
Examiner that the recitation of a quinolone nonpeptide or a benzodiazepine
nonpeptide targeting moiety suggests a targeting moiety that is a peptide,
even if the peptide can include non-peptide components.
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Thus, we do not agree that the Examiner has set forth a prima facie
case that the patented compounds, comprising a quinolone nonpeptide or a
benzodiazepine nonpeptide, are not patentably distinct from the instantly
claimed compounds, comprising a peptide or peptidomimetic targeting
moiety. We therefore reverse the obviousness-type double patenting
rejection of claims 1-10, 12-35, 48-50, 52, and 53.
OTHER ISSUE
As discussed in footnote 1, there is arguably some ambiguity as to
whether claim 1 necessarily requires a linking group. If prosecution of this
case is continued, this ambiguity should be resolved.
SUMMARY
We affirm the rejection of claims 1, 2, 12-15, 17, 19-21, 25, 27, 28,
31-35, 48-50, 52, and 53 under 35 U.S.C. § 103. However, we reverse the
rejection of claims 1-10, 12-35, 48-50, 52, and 53 for obviousness-type
double patenting. Thus, claims 3-10, 16, 18, 22-24, 26, 29, and 30 are not
currently subject to a rejection.

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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-IN-PART

lbg

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