Ex Parte Akhtari et al

Patent Trial and Appeal Board

Dec 29, 2016

13784343 (P.T.A.B. Dec. 29, 2016)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/784,343 03/04/2013 MASSOUD AKHTARI UCLA-029CON 4689
93726 7590 01/03/2017
EPA - Bozicevic Field & Francis LLP
Bozicevic, Field & Francis
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
YOUNG, MICAH PAUL
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
01/03/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MASSOUD AKHTARI and JEROME ENGEL1
Appeal 2015-007729
Application 13/784,343
Technology Center 1600
Before RICHARD J. SMITH, TAWEN CHANG, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to
compositions comprising a functionalized magnetic nanoparticle (MNP),
which have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We AFFIRM.
STATEMENT OF THE CASE
According to the Specification, “[ejach [imaging] technique currently
in use [to diagnose, stage, and monitor various diseases, such as neurological
1 Appellants identify the Real Party in Interest as The Regents of the
University of California. (Appeal Br. 3.)
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Application 13/784,343
disorders and tumors,] has certain drawbacks.” (Spec. 12.) Further
according to the Specification, “[t]he present disclosure provides
compositions comprising 2-deoxyglucose-fimctionalized magnetic
nanoparticles (2-DG-functionalized MNPs, or 2DG-MNPs)” that are “useful
in diagnostic (e.g., imaging) methods” and “can also be used in treatment
methods.” {Id. at 136.)
Claims 1, 3, 7—22, 24—26, and 28—32 are on appeal. Claim 1 is
illustrative and reproduced below:
1. A pharmaceutical composition comprising:
a) a functionalized magnetic nanoparticle (MNP) comprising at
least one functional moiety, wherein the at least one functional moiety
comprises 2-deoxyglucose, and wherein the functionalized MNP
exhibits differential affinity and/or metabolic uptake into a
mammalian tissue;
wherein the magnetic nanoparticle comprises a magnetic core
particle and a biocompatible substrate, and wherein the 2DG is linked
to the biocompatible substrate;
wherein the 2DG is linked to the biocompatible substrate via
the 1-OH oxygen, the 3-OH oxygen, the 4-OH oxygen of 2DG, or via
a carbon atom of 2DG; and
b) a pharmaceutically acceptable carrier.
(Appeal Br. i (Claims App’x).)
The Examiner rejects claims 1, 3, 7—22, 24—26, and 28—32 under 35
U.S.C. § 103(a) as being unpatentable over Akhtari2 and Tidmarsh.3 (Ans.
3.)
2 Akhtari et al., WO/102377 A2, published Sept. 28, 2006.
3 Tidmarsh et al., US 2006/0142207 Al, published Jun. 29, 2006.
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I.
Issue
The Examiner finds that Akhtari teaches “a pharmaceutical
composition comprising a functionalized magnetic nanoparticle comprising
at least one functional moiety comprising a glucose derivative.” (Ans. 3.)
The Examiner finds that Akhtari’s MNPs comprise a magnetic core and a
biocompatible substrate and that the glucose derivative such as
fludeoxyglucose is linked to the biocompatible substrate. (Id. ) The
Examiner finds that Akhtari teaches that its functionalized MNP exhibits
differential affinity or uptake with respect to certain types of mammalian
tissue. (Id.) The Examiner finds that Akhtari discloses that the MNPs may
comprise “further functional moieties including therapeutic agents” and that
the nanoparticles may be useful in predicting, detecting, and treating certain
diseases. (Id. at 3—4.)
The Examiner finds that Akhtari is silent with respect to the specific
linkage of the glucose derivative to the biocompatible substrate. (Id. at 4.)
However, the Examiner finds that “[t]he binding of the glucose derivative
compounds to a substrate via hydroxyl groups is well known in the art as
seen in [Tidmarsh].” (Id.) In particular, the Examiner finds that Tidmarsh
discloses a method of treating disease comprising “the administration of a
composition comprising glucose derivatives such as 2-deoxyglucose (2DG)
bound to a biocompatible substrate,” where “[t]he 2DG is bound to [the]
biocompatible substrate . . . via the 1-OH, 3-OH or 4-OH oxygen.” (Id.)
The Examiner concludes that it would have been obvious to combine the
teachings of Akhtari and Tidmarsh with a reasonable expectation of success
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since both references disclose treating disease with formulations containing
glucose derivative-bound component. {Id.)
Appellants contend that the cited art fails to teach or suggest (1) a
functionalized MNP comprising a functional moiety comprising 2DG or (2)
linking the 2DG to the biocompatible substrate via the 1-OH oxygen, the 3-
OH oxygen, the 4-OH oxygen, or a carbon atom of 2DG. (Appeal Br. 5—
12.) Appellants further contend that Tidmarsh in fact teaches away from
using the 1-OH oxygen, the 3-OH oxygen, the 4-OH oxygen, or a carbon
atom of 2DG as attachment sites. {Id. at 5, 12—13.)
The issue with respect to this rejection is whether the combination of
Akhtari and Tidmarsh teaches or suggests a functionalized MNP comprising
a functional moiety comprising 2DG, where the 2DG is linked to the
biocompatible substrate of the MNP via its 1-OH oxygen, 3-OH oxygen, 4-
OH oxygen, or a carbon atom.
Findings of Fact
1. Akhtari teaches pharmaceutical compositions comprising (a)
pharmaceutically acceptable carrier(s) and (b) “functionalized magnetic
nanoparticles comprising a functional group, which . . . exhibit differential
binding to a tissue.” (Akhtari Abstract, 171; see also id. at || 6, 23.)
Akhtari teaches that suitable functional groups include, e.g., “moieties that
bind differentially to a brain tumor.” (Id. at | 67.)
2. Akhtari teaches that the nanoparticles “can consist of a core
made of one substance and one or more shells made of another
substance(s).” (Id. at 125.) Akhtari further teaches that “[t]he core material
is generally [a magnetic resonance imaging (MRI)-]visible agent” and “is
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typically coated.” (Id. at 126.) Aktari teaches that “[s]uitable coatings
include . . . dextran, albumin, starch, silicon, and the like.” (Id.)
3. Akhtari teaches embodiments of its invention in which “a
functional moiety . . . binds with higher or lower affinity to epileptic tissues
in the brain.” (Id. at | 64.) Akhtari teaches that “examples of such
functional moieties include . . . glucose or a glucose derivative such as
fludeoxyglucose, where the glucose is differentially taken up by epileptic
tissues, compared to normal, non-epileptic tissues.” (Id.)
4. Akhtari teaches imaging diseased tissue using its functionalized
MNP and further teaches a magnetic resonance imaging (MRI)-visible drug
delivery system using functionalized MNP that further comprises therapeutic
agents for targeted delivery to a specific tissue. (Id. at Abstract, || 22, 47,
61.)
5. Tidmarsh teaches “methods and compositions ... for the
treatment of cancer that take advantage of the increased uptake of glucose-
anti-neoplastic agent conjugates in cancer cells relative to normal cells.”
(Tidmarsh Abstract.)
6. Tidmarsh teaches that “some structures are preferred for the
conjugates used in [its] methods”:
For example, the 2 position of D-glucose, 2-deoxyglucose, and 2-
glucosamine is a preferred site of attachment for the linker in the
conjugates of the invention. Other sites of attachment are not
preferred. For example, the hydroxy group at the 6 position of D-
glucose, deoxyglucose, and glucosamine is phosphorylated upon entry
into a cell, and the presence of the phosphate group inhibits diffusion
of the resulting compound from the cell. With conjugates carrying an
anti-neoplastic agent at this position, phosphorylation cannot occur.
Accordingly, conjugates of 2-deoxyglucose are preferred wherein the
antineoplastic agent is attached at a position other than the 6-position.
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In one embodiment, the anti-neoplastic agent is attached at the 2-
position. Alternative conjugates can be prepared wherein the anti­
neoplastic agent is attached to the 3-position or 4-position, although
such conjugates may not be rapidly phosphorylated, if at all. A
conjugate that can be rapidly phosphorylated after incorporation in the
cells, with the consequence that the conjugate remains in the cell, is a
preferred conjugate of the invention. Accumulation of the conjugate
in the cells provides greater certainty that the cell will be killed by the
conjugate.
Accordingly, in one group of preferred embodiments, the
glucose-anti-neoplastic agent conjugate has the formula:
wherein L is a bond or linking group; Z is an anti-neoplastic agent;
each X is independently selected from the group consisting of O and
NH; R1, R3 and R4 are each members independently selected from the
group consisting of H, (C1-C12 )alkyl, (Ci-Ci2)acyl and a solubility or
partitioning effector component. . . . The solubility or partitioning
effector component can be essentially any component that increases
the solubility of the resultant conjugate in aqueous solution, relative to
the conjugate having a hydrogen atom at the same position. Suitable
solubility or partitioning effector components include oligoethylene
glycol, oligopropylene glycol, polyhydroxylated carbon chains
(typically one to thirty carbons in length) and the like.
.... In [a] group of most preferred embodiments, the glucose-
antineoplastic agent conjugate has the formula la in which each
X is O, and two of R1, R3 and R4 are H, with the remaining member of
R1, R3 and R4being a solubility or partitioning effector component.
(Id. at 11117-119.)
7. The Specification states that the MNP of the invention
/
comprises
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a magnetic core particle and a biocompatible substrate. The one or
more functional groups is linked to the biocompatible substrate, either
directly or via a linker. The combination of the biocompatible
substrate and the one or more functional groups is referred to herein as
the "coating."
Suitable biocompatible substrates include, but are not limited
to, polysaccharides and oligosaccharides, and derivatives thereof,
including, e.g., dextran, . . . ; a polymer, including e.g., a polyethylene
glycol. . . ; a phospholipid; a compound such as silica, aluminum
silica, a silicone, etc.; and proteins and derivatives thereof, including,
e.g., albumin, synthetic proteins, etc.
(Spec. 1138-39.)
Analysis
We agree with the Examiner that the combination of Akhtari and
Tidmarsh teaches or suggests a functionalized MNP comprising a functional
moiety comprising 2DG, where the 2DG is linked to the biocompatible
substrate of the MNP via its 1-OH oxygen, 3-OH oxygen, 4-OH oxygen, or
a carbon atom. Akhtari teaches functionalized magnetic nanoparticles
comprising a core of MRI-visible agent (i.e., a magnetic core) and a coating
of, e.g., dextran, which the Specification discloses as a biocompatible
substrate. (FF2, FF7.) Akhtari further teaches an MNP comprising as a
functional moiety a glucose derivative such as fludeoxyglucose, where the
glucose is differentially taken up by epileptic tissues as compared to normal
tissues. (FF3.)
While Akhtari does not explicitly teach the claimed linkage
mechanism between the glucose derivative and the biocompatible substrate,
this limitation is suggested by Tidmarsh, which discloses that anti-neoplastic
agents conjugated to glucose derivatives such as 2-deoxyglucose are
differentially taken up by cancer cells relative to normal cells, and further
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discloses that, while the 2 position of the 2-deoxyglucose is the preferred site
of attachment for the linker and anti-neoplastic agent, “[alternative
conjugates can be prepared wherein the anti-neoplastic agent is attached to
the 3-position or 4-position.” (FF6.) Likewise, Tidmarsh teaches one of the
most preferred embodiments where the anti-neoplastic agent is linked to the
2-deoxyglucose at the 2 position of the 2-deoxyglucose while a solubility or
partitioning effector such as oligoethylene glycol is attached via the 1-OH
oxygen, the 3-OH oxygen, or the 4-OH oxygen of the 2-deoxyglucose. (Id. )
It would have been obvious for a skilled artisan to link 2-
deoxyglucose to the biocompatible substrate of Akhtari’s MNP via the
linkage suggested by Tidmarsh, given Akhtari’s disclosure that suitable
functional groups for its MNPs include glucose derivatives and moieties that
bind differentially to a brain tumor and Tidmarsh’s disclosure that its anti­
neoplastic drug/2-deoxyglucose conjugate is differentially taken up by
cancer cells relative to normal cells. (FF1, FF5.)
Appellants first contend that Akhtari does not specifically disclose 2-
deoxyglucose as a functional moiety for its MNP. (Appeal Br. 6—8.) In
particular, Appellants argue that Akhtari only discloses glucose and
fludeoxyglucose, which Appellants argue differ from 2-deoxyglucose in that
glucose and fludeoxyglucose have an —OH and —F attached to the 2-carbon,
respectively, whereas 2-deoxyglucose has an —H at the same position. (Id. at
8.)
We are not convinced. As an initial matter, we note that the
Specification defines 2DG to include “2DG derivatives and 2DG variants”
and further states that “2DG derivatives and variants include, but are not
limited to, all therapeutic or functional molecules that contain one or more
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2DG molecule(s) its derivatives or variants as part of their basic chemical
structure.” (Spec. 1 68.) Appellants have not explained why, based on this
definition, the broadest reasonable interpretation of “2DG” as used in the
claims would not encompass fludeoxyglucose. (See also Spec. Figs. 7, 8, Tflf
13—14 (depicting conjugation of 2DG-MNP at the 6-carbon and 2-carbon
site where “2DG” appears to have —Br and —NH2 attached at the 6-carbon
and 2-carbon positions); Tidmarsh 131 (“[Ujnless otherwise indicated, ‘2-
DG’ simply refers to a glucose-like moiety lacking a hydroxyl or oxygen or
ester linkage at the 2 position.”).)
Even if 2DG does not encompass fludeoxyglucose, moreover, we
agree with the Examiner that Akhtari’s disclosures of differential uptake of
glucose and glucose derivatives such as fludeoxyglucose by certain tissues
render the use of 2DG obvious. (Ans. 5.) In particular, these disclosures
would suggest to a skilled artisan that it is the basic glucose structure that
fludeoxyglucose shares with 2DG, rather than the fluorine at the 2 position,
that renders fludeoxyglucose suitable as a functional moiety for Akhtari’s
MNPs.
Finally, we note that Appellants’ argument is further flawed because
Tidmarsh discloses 2DG. (FF6.) “Non-obviousness cannot be established
by attacking references individually where the rejection is based upon the
teachings of a combination of references. . . . [The reference] must be read,
not in isolation, but for what it fairly teaches in combination with the prior
art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Appellants also argue that Akhtari does not disclose the positions and
the atoms of the glucose or glucose derivative to which the MNP is attached.
(Appeal Br. 7—8.) This is unpersuasive because the rejection relies on
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Tidmarsh to disclose this limitation. In re Merck, 800 F.2d at 1097. For
similar reasons, we are not convinced by Appellants’ argument that
Tidmarsh does not teach or suggest a biocompatible substrate/MNP (Appeal
Br. 9, 11—12); as discussed above, these limitations were disclosed by
Akhtari.
Appellants argue that Tidmarsh does not suggest and in fact teaches
away from the claimed linkage between 2DG and the biocompatible
substrate of the MNP. (Id. at 11—14.) Appellants first argue that
conjugation sites on 2DG that Tidmarsh discloses as advantageous for its
invention may not be suitable for conjugation to an MNP, as “the
consideration and criteria for functionality of a 2DG-anti-neoplastic agent
conjugate are not necessarily the same as the considerations and criteria for
functionality of a 2DG-MNP conjugate.” (Id. at 12, 13.) We are not
persuaded. Tidmarsh teaches that certain attachment sites on 2DG are
preferable in order to allow the 2DG conjugate to remain in the cell after
incorporation, so as to provide greater certainty that the conjugate exerts its
therapeutic effect (i.e., kill cancer cells). (FF6.) Since Akhtari also teaches
using functionalized MNPs that further comprise therapeutic agents for
targeted delivery to a specific tissue (FF4), we find that a skilled artisan
would have reason to use the 2DG attachment sites suggested by Tidmarsh
for attaching glucose derivatives to the MNPs described in Akhtari, with a
reasonable expectation of success. Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007) (explaining that “expectation of success need
only be reasonable, not absolute”).
Appellants further argue that Tidmarsh teaches away from the claimed
linkage sites because it teaches that “the 2 position ‘is a preferred site of
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attachment for the linker in the conjugates of the invention’ and that ‘[ojther
sites of attachment are not preferred.’” (Appeal Br. 12 (citation omitted).)
This argument is not convincing. As an initial matter and as Appellants
point out, “Tidmarsh exemplifies linkage at. . . the 2 carbon [position].”
(Id.; FF6.) Thus, the claims read on Tidmarsh’s preferred 2DG attachment
site. (Appeal Br. i (“wherein the 2DG is linked . . . via the 1-OH oxygen, the
3-OH oxygen, the 4-OH oxygen of 2DG, or via a carbon of 2DG”)
(emphasis added).)
To the extent Appellants’ teaching away argument is directed towards
attachment via the 1-OH oxygen, the 3-OH oxygen, and the 4-OH oxygen of
2DG, the argument is still not persuasive. “A statement that a particular
combination is not a preferred embodiment does not teach away absent clear
discouragement of that combination.” Syntex (U.S.A.) LLC v. Apotex, Inc.,
407 F.3d 1371, 1380 (Fed. Cir. 2005) (citations omitted). Here, Tidmarsh
specifically states that alternative conjugates can be prepared where the anti­
neoplastic agent is attached to the 3-position or the 4-position and further
teach preferred embodiments where solubility or partitioning effectors such
as oligoethylene glycol are attached to the 1-OH, 3-OH, or 4-OH oxygen of
2DG. (FF6.)
Accordingly, we affirm the Examiner’s rejection of claim 1. Claims
3, 7—22, 24—26, and 28—32, which were not separately argued, fall with
claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 1, 3, 7—22, 24—26, and 28—32.
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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
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