Ex Parte Brahmbhatt et al

Patent Trial and Appeal Board

May 31, 2017

13711848 (P.T.A.B. May. 31, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/711,848 12/12/2012 Himanshu BRAHMBHATT 060348-0309 6857
22428 7590 06/02/2017
Foley & Lardner LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
SAMALA, JAGADISHWAR RAO
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
06/02/2017 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):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HIMANSHU BRAHMBHATT and JENNIFER MACDIARMID
Appeal 2015-004149
Application 13/711,84s1
Technology Center 1600
Before RACHEL H. TOWNSEND, DEVON ZASTROW NEWMAN, and
DAVID COTTA, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for treating a brain tumor in a subject, which have been rejected as
anticipated and obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
“[Bjrain cancer treatment. . . represents one of the biggest challenges
in oncology.” (Spec. 17.) “Systemic therapy ... is limited[] by virtue of
the so-called blood brain barrier (BBB).” (Spec. 15.) “This barrier resides
within the brain’s capillary endothelium.” {Id. 1 6.) “[Bjrain uptake is
1 Appellants identify the Real Party in Interest as EnGeneIC Molecular
Delivery Pty. Ltd. (Appeal Br. 2.)
Appeal 2015-004149
Application 13/711,848
further restricted by a relative paucity of fenestrae and pinocytotic vesicles
within the brain capillary endothelial cells.” (Id. 149.) Furthermore, there
are “numerous drug transport proteins, which move drugs out of the brain”
even if they can get to the BBB. (Id. Tffl 49—50.)
“Biopharmaceuticals, which are large molecule drugs, do not cross the
BBB.” (Id. 148.) “[I]t has been shown that molecules would need to be as
small as <400 Daltons ... to be able to cross the pores found in the BBB.”
(Spec. 144.) Even then, it is believed that the small molecule needs to be
lipid soluble to cross the BBB by lipid mediation. (Id. 148.)
Some brain tumors have disrupted BBB. (See Spec. 147.) Particles
of 50 to 150 nm “are not thought to be able to extravasate through the BBB
via disruptions in the barrier.” (Id.) Some nanoparticles, smaller than 12
nm, following intravenous administration, are able to “extravasate into brain
tumor because of the disrupted BBB of brain tumor vessels,” but they are
also able to extravasate “to a lesser extent into normal brain tissue.” (Id.
f 46.) Other nanoparticles are transcytosed across the blood vessel
endothelial cells by first binding to low-density lipoprotein receptors,
“which are known to be over-expressed in endothelial blood capillary
vessels associated with the BBB,” and then being “internalized by the blood
vessel endothelial cells” and subsequently transcytosed. (Spec. 40-41,
43.) These receptors, however, are also “ubiquitously located in endothelial
cells throughout the circulatory system.” (Spec. 43.)
Appellants’ invention is directed to a method of treating a brain tumor
that has blood vessels with fenestrations in their walls through systemic
administration of a therapeutically effective amount of a composition
comprised of a plurality of intact, bacterially derived minicells, where each
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Application 13/711,848
minicell of the plurality encompasses an anti-neoplastic agent. (Id. 110.)
These minicells are about 400 nm. (Id. 151.)
Claims 1, 7—10, and 15—23 are on appeal.2 Claim 1 is representative
and reads as follows:
1. A method for treating a brain tumor in a subject,
comprising administering systemically a therapeutically
effective amount of a composition comprised of a plurality of
intact, bacterially derived minicells, wherein each minicell of
said plurality encompasses an anti-neoplastic agent; and
wherein the brain tumor has blood vessels with fenestrations in
their walls through which the minicells can extravasate
passively.
(Appeal Br. 14.)
The following grounds of rejection by the Examiner are before us on
review:
Claims 1, 7, 8, 10, 15—19, and 21—23 under 35 U.S.C. § 102(b) as
anticipated over Brahmbhatt.3
Claims 1, 7—10, and 15—23 under 35 U.S.C. § 103(a) as unpatentable
over Brahmbhatt and MacDiarmid.4
2 Claims 2—6 and 11—14 are also pending, but stand withdrawn from
consideration. (Appeal Br. 14—15.)
3 Brahmbhatt et al., WO 2005/079854 Al, published Sept. 1, 2005.
4 MacDiarmid et al., Bacterially-Derived Nanocells for Tumor-Targeted
Delivery of Chemotherapeutics and Cell Cycle Inhibitors, 6:17 Cell Cycle
2099-105 (2007).
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Application 13/711,848
DISCUSSION
Claim 1 is Not Anticipated by Brahmbhatt
The Examiner finds that Brahmbhatt teaches a method for treating a
brain cancer by systemically administering a therapeutic amount of
bacterially derived minicells containing Doxorubicin, which meets the
requirements of claim 1. (Non-Final Action 4;5 Final Action 3^4 (“the same
patient is being administered the same active agent... by the same mode of
administration ... in the same amount in both the instant claims and the
prior art reference.”).) According to the Examiner, a brain cancer reads on a
brain tumor (Non-Final Action 4), and “the brain tumor inherently has blood
vessels with fenestrations in their walls as disclosed by Applicants (see
Applicants’ specification, [0051]).” (Final Action 3.) The Examiner further
contends that “although the reference is silent about the ‘through which the
minicells can extravasate passively’[. . .], it does not appear that the claim
language or limitation[] result[s] in a manipulative difference in the method
steps when compared to the prior art disclosure.” {Id.) According to the
Examiner, that limitation is merely an unknown but inherent function of the
prior art process, and the claimed method merely recites a new benefit of an
old process, which “cannot render the process again patentable.” {Id.)
We disagree with the Examiner’s factual findings that Brahmbhatt
teaches a method of treating a brain tumor as claimed. While it is true that
“anticipation does not require actual performance of suggestions in a
5 Non-Final Action having a mailing date of January, 13, 2014. In the Final
Action, the Examiner states that the rejection of claims 1, 7—8, 10, 15—19,
and 21—23 is “maintained for reasons of record in the previous office action
filed on 1/13/2014.” (Final Action 3.)
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Application 13/711,848
disclosure . . . Impax Labs., Inc. v. Aventis Pharms. Inc., 468 F.3d 1366,
1382 (Fed. Cir. 2006), it is, nevertheless, required that the “prior art
reference discloses within the four comers of the document not only all of
the limitations claimed but also all of the limitations arranged or combined
in the same way as recited in the claim.” Net MoneyIN, Inc. v. VeriSign,
Inc., 545 F.3d 1359, 1371 (Fed. Cir. 2008).
Brahmbhatt states that “a wide variety of solid tumors — cancer,
papillomas, and warts — should be treatable” by including in bacterially
derived intact minicells, a “therapeutic nucleic acid molecule” having “a
sequence that corresponds to or is derived from a gene that is associated with
tumor suppression.” (Brahmbhatt 27.) Brain cancer is listed along with a
number of other cancers as representative of cancers that should be so
treatable. {Id.). Brahmbhatt does not, however, describe of treating brain
cancer by administering minicells. Rather Brahmbhatt generally provides
that a composition of bacterially derived intact minicells “can be
administered via various routes and to various sites in a mammalian body to
achieve the therapeutic effect(s) desired, either locally or systemically” and
that “[t]he mode and site of administration is dependent on the location of
the target cells.” {Id. at 22.)
Brahmbhatt generally notes that the bacterially derived intact
minicells can include a medicament for use in cancer chemotherapy. {Id. at
24.) Brahmbhatt then provides examples demonstrating (i) that cancer
chemotherapeutic drugs can be packaged into intact minicells, (Brahmbhatt
Ex. 1 and 2); (ii) that significant amounts of drugs can be transferred into the
cytoplasm of intact minicells without causing instability of the minicells and
without drug leakage, {id. at Ex. 3 and 4); (iii) that bispecific ligands can be
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attached to surface structures of drug-packaged minicells and that such
minicells can bind in vitro to mammalian brain cancer cells as well as
mammalian breast cancer cells and deliver drug within those cells by
endocytosis (id. at Ex. 5 and 6); (iv) that drug-packaged minicells with
bispecific ligands attached to the surface can deliver the drug to mammalian
breast cancer cells in a nude mouse xenograft model when the minicells are
delivered intravenously, and that the drug can stabilize and or cause
regression of the breast cancer tumor without causing significantly unwanted
toxicity (id. at Ex. 7, 8, and 10.); and (v) that drug-packaged minicells with
bispecific ligands attached to the surface can deliver the drug to mammalian
ovarian cancer cells in a nude mouse xenograft model and can stabilize the
ovarian cancer tumor (id. at Ex. 9).
One of the limitations of claim 1 is to administer a therapeutically
effective amount of minicells in the brain tumor treatment. Because
Brahmbhatt does not disclose a particular method for treating brain cancer in
a subject with minicells that include an antineoplastic compound, it does not
teach what a therapeutically effective amount of minicells for treating a
brain tumor with an antineoplastic compound is.
In addition, Brahmbhatt does not teach systemic administration of
minicells that include an anti-neoplastic agent to a brain tumor that has
blood vessels with fenestrations in their walls. The only method specifically
referencing delivery of minicells with antineoplastic agent to brain cells in
Brahmbhatt is the in vitro example set forth in Example 5. That example is
an in vitro method of delivering Doxorubicin to non-phagocytic human U87-
MG astrocytoma cells via ligand-targeted minicells. (Brahmbhatt 37—38.)
The human U87-MG astrocytoma cells are known to overexpress the EGF
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receptor on the cell surface. (Id. at 37.) The cells were grown in tissue
culture plates. (Id. at 38.) Minicells, which were labeled with an anti-EGFR
monoclonal antibody, were added to the culture plates to incubate with the
human brain cancer cells. (Id.) From the experiment, it was believed that
anti-EGFR monoclonal antibody “enabled the Doxorubicin-packaged
minicells to strongly adhere to the surface of the astrocytoma cells.” (Id. at
38—39.) Nothing in this description, or any other description in Brahmbhatt,
discloses delivering minicells to a brain tumor with blood vessels having
fenestrations in their walls, much less by systemic administration. Page 22
of Brahmbhatt, relied on by the Examiner, indicates that “[a] composition of
the present invention can be administered via various routes and to various
sites in a mammalian body[] to achieve the therapeutic effect(s) desired,
either locally or systemically.” This general description is not tantamount to
a teaching that systemic administration is used to treat a specific cancer,
much less a brain tumor.
Furthermore, even though Brahmbhatt generally suggests a method
for treating a brain tumor, nothing in Brahmbhatt teaches that all brain
tumors have blood vessels with fenestrations in their walls through which
the minicells can extravasate passively. The Examiner contends that having
such fenestrations is an inherent feature of a brain tumor, citing Appellants’
Specification at paragraph 51. (Final Action 3.) However, Appellants’
Specification refers only to growing tumor, not all brain tumors. (Spec.
51.) And there is no other evidence provided by the Examiner to establish
that every brain tumor necessarily and inevitably has blood vessels with
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fenestrations in their walls through which minicells can pass,6 such that
Brahmbhatt’s general teaching of a method for treating a brain tumor
inherently teaches the requirement of claim 1 that the minicells can
extravasate passively through such fenestrations to treat the brain tumor.
In light of the foregoing, we agree with Appellants that Brahmbhatt
does not teach treating the patient population required by claim 1 (Reply Br.
7) or a method of treating that patient population with a therapeutically
effective amount of a composition comprised of a plurality of intact,
bacterially derived minicells, wherein each minicell of said plurality
encompasses an anti-neoplastic agent (Appeal Br. 11). Thus, we do not
sustain the Examiner’s rejection of claim 1 as being anticipated by
Brahmbhatt.
6 Appellants provided evidence that they contend suggests that the
Specification at paragraph 51 cannot be interpreted to mean all brain tumors
have leaky vessels. (See Appeal Br. 8—9.) The evidence is an article by
Gambarota and Leenders, “Characterization of Tumor Vasculature in Mouse
Brain by USPIO Contract-Enhanced MRI,” in Methods in Molecular
Biology 111, In Vivo NMR Imaging (Springer Science+Business Media,
2011) in which it is stated in the abstract: “In certain tumor types, especially
diffuse glioma in the brain, incorporated tumor vessels are not necessarily
leaky.” The reference further explains that “[tjumors have developed a
number of ways to ensure a proper blood supply” and while a key feature of
angiogenesis, which is one of the ways to ensure proper blood supply, is
“increased permeability of the newly formed vessels,” another way to ensure
proper blood supply is “incorporation of pre-existent vessels.” (Gambarota
at 477—78.) This evidence further demonstrates that the Examiner’s reliance
on Appellant’s paragraph 51 is insufficient support for the Examiner’s
assertion that all brain tumors have leaky vasculature.
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Application 13/711,848
The Examiner Failed to Make Out A Prima Facie Case of Obviousness of
Claim 1
The Examiner’s obviousness rejection only relies upon MacDiarmid
for teaching a chemotherapy drug having a lethal dose 50 that is lower than
the effective dose 50, required by claim 9. (Non-Final Action 6—8, Final 6
(“On this record, it is reasonable to conclude that the same patient is being
administered the same active agent such as bacterially derived minicells (see
BRAHMBHATT@ page 5, line 8; and Applicants’ claim 1) containing
Doxorubicin (see BRAHMBHATT @ page 36, line 5; and Applicants’
specification, [0130]) by the same mode of administration such as
administering systemically (see BRAHMBHATT@ page 22, lines 9-11; and
Applicants’ specification, [0010]) in the same amount in both the instant
claims and the prior art reference.”).) Because MacDiarmid is not relied
upon to cure the deficiencies noted above, we conclude that the Examiner
did not make out a proper prima facie case of obviousness in rejecting
claims 1, 7—10, and 15—23 under 35 U.S.C. § 103(a).
SUMMARY
We reverse the rejection of claims 1, 7, 8, 10, 15—19, and 21—23 under
35 U.S.C. § 102(b) as being anticipated by Brahmbhatt.
We reverse the rejection of claims 1, 7—10, and 15—23 under
35 U.S.C. § 103(a) as being unpatentable over Brahmbhatt and MacDiarmid.
REVERSED
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