Ex Parte Aadal et al

Patent Trial and Appeal Board

Apr 17, 2017

13387094 (P.T.A.B. Apr. 17, 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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/387,094 01/25/2012 Peter Aadal 09663.0106FPW O 1052
23552 7590 04/19/2017
MERCHANT & GOULD P.C.
P.O. BOX 2903
MINNEAPOLIS, MN 55402-0903
EXAMINER
EPPS -SMITH, JANET L
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
04/19/2017 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):
US PT023552@ merchantgould .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PETER AADAL,
GUNNAR ANDERS SON, and OLGA ANDERS SON
Appeal 2016-002719
Application 13/387,094
Technology Center 1600
Before JEFFREY N. FREDMAN, ROBERT A. POLLOCK, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to a method
for determining whether a nanoparticle is transported across the blood-brain
barrier. The Examiner rejected the claims as obvious. We have jurisdiction
under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“The present invention is directed to insect models that are aimed to
reflect vertebrate blood-brain barrier (BBB) penetration of nanoparticles.
1 Appellants identify the Real Party in Interest as N2MO A/S (see App. Br.
2).
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Application 13/387,094
Investigation of BBB penetration of nanoparticles is extremely important
since there is an increasing use of nanoparticles and the profile for many of
these are yet to be understood” (Spec. 1:7—10). “On the one hand successful
CNS drugs have to cross the BBB. On the other hand BBB penetration of
nanoparticles may also cause unwanted side effects” (Spec. 1:12—13).
The Claims
Claims 1, 3—7, and 9-12 are on appeal. Claim 1, the sole independent
claim, is representative and reads as follows:
1. A method for determining whether a nanoparticle is
transported across the blood brain barrier (BBB), said method
comprises the steps of:
administering the nanoparticle to an insect having a BBB,
wherein the insect is selected from the group consisting of the
orders Blattoidea and Acridoidea;
incubating the insect;
dissecting the brain from the insect; and
measuring the concentration of the nanoparticle in the
brain.
The issue
The Examiner rejected claims 1, 3—7, and 9—12 under 35 U.S.C.
§ 103(a) as obvious over Thomas,2 Poss,3 Labhesetwar,4 Stork,5 and Mayer6
(Ans. 2—7).
2 Thomas, M., Insect Blood-Brain Barrier: A Radioisotope Study of the
Kinetics of Exchange of a Liposoluble Molecule (n-Butanol), 64 J. Exp. Biol.
119-130 (1976) (“Thomas”).
3 Poss et al., US 2005/0214221 Al, published Sept. 29, 2005 (“Poss”).
4 Labhasetwar et al., US 7,332,159 B2, issued Feb. 19, 2008
(“Labhasetwar”).
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The Examiner finds:
Thomas (1976) teaches the known use of the Blattoidea BBB
for studying the kinetics of exchange of molecules across the
insect BBB, and further teaches that this system can be used as
a model system to study the vertebrate BBB. Poss et al.
provides clear suggestion and motivation for using an insect
BBB to study the movement of nanoparticles across the blood
brain barrier. Labhasetwar et al. (US7332159B2) describes
modifications of the nanoparticle formulation to enhance
transport of nanoparticles across the blood brain barrier. (See
col. 5, last |). Moreover, Stork et al. teaches that the insect
BBB, e.g. the Drosophila BBB, is homologous to the
mammalian BBB. Stork et al. also teaches that the insect
BBB is useful in identifying agents which are capable of
crossing the BBB, see Figure 2 and page 594. Furthermore,
Mayer et al. states that “[o]n a cellular level, the vertebrate and
insect BBSs share many common features.”
(Ans. 6). The Examiner concludes the ordinary artisan “seeking to assess
the movement of nanoparticles across the vertebrate BBB . . . would have
had a reasonable expectation that the use of insect BBB models from the
Blattoidea family, and Drosophila, would provide an accurate prediction
regarding the movement of nanoparticles across the vertebrate BBB” (Ans.
7).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that the prior art renders the
claims obvious?
5 Stork et al., Organization and Function of the Blood-Brain Barrier in
Drosophila, 28 J. Neuroscience 587—597 (2008) (“Stork”).
6 Mayer et al., Evolutionary Conservation of Vertebrate Blood-Brain Barrier
Chemoprotective Mechanisms in Drosophila, 29 J. Neuroscience 3538—3550
(2009) (“Mayer”).
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Findings of Fact
1. Labhasetwar teaches “injection of. . . [a] nanoparticle
formulation via the carotid artery or jugular vein. Using this protocol, it has
now been shown that the nanoparticles can cross the blood brain barrier”
(Labhasetwar 3:47—50).
2. Labhasetwar teaches administering a “suspension of
nanoparticles . . . either via the intracarotid, intrajugular vein, or intravenous
route” to rats, incubating the rats for “[o]ne hour after nanoparticle
administration . . . and the brains collected for quantitative analysis of
nanoparticle uptake” (Labhasetwar 8:53—61).
3. Labhasetwar teaches “the dye concentration in the sample was
determined using high performance liquid chromatography (HPLC). A
standard plot using nanoparticles was prepared using identical conditions to
determine the amount of nanoparticles localized in the brain” (Labhasetwar
9:2-6).
4. Poss teaches a method that
includes the steps of: (a) administering to a subject an optical
imaging probe of the present invention; (b) allowing time for
the optical imaging probe to reach the target tissue and,
preferably, but not necessary, for molecules in the target tissue
to metabolize the probe; (c) illuminating the target tissue with
light of a wavelength absorbable by the optical imaging probe;
and (d) detecting the optical signal emitted by the optical
imaging probe.
(Poss 132).
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5. Poss teaches the test “subject may be a mammal, including a
human. The subject may also be non-mammalian, (i.e., C. elegans,
drosophila, etc.)” (Poss 133).
6. Poss teaches the “probes of the present invention may be also
be constructed using .. . iron oxide nanoparticles” (Poss 193).
7. Poss teaches “preferred brain imaging agents of the present
invention also have blood brain barrier permeability” (Poss 1 58).
8. Stork teaches
different glial cells [in Drosophila] . . . comprise the functional
blood-brain barrier. The integrity of this barrier can be
measured after injection of labeled dextran molecules into the
hemolymph . . . the use of differently sized dextran allows
addressing a possible size selectivity of the barrier. To
determine the kinetics of dextran uptake we used a Zeiss 5 Live
LSM .... This allowed us to directly follow and quantify the
dextran uptake in living embryos.
(Stork 590, col. 1-2).
9. Stork teaches:
In Drosophila two Claudin-like proteins have been described to
be required for formation of normal epithelial barrier formation
.... Here, we show that both Sinuous and Megatrachea are also
needed for the establishment of normal blood-brain barrier
formation. Similarly, it was shown previously that mammalian
claudin5 is a major component of tight junctions of brain
endothelial cells. claudin5 mutant mice show no structural or
ultrastructural deficits, but have an impaired blood-brain
barrier.
(Stork 594, col. 1-2).
10. Mayer teaches “on a cellular level, the vertebrate and insect
BBBs share many common features. . . . The Dm proteins that make up the
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pleated septate junctions [in Drosophila] are nearly identical to the
vertebrate proteins that compose the tight junctions” (Mayer 3538, col. 2).
11. Mayer teaches:
BBB-specific genes and processes found in model organisms,
particularly Drosophila, could lead to novel insights into the
organization and cellular separation of the multiple protective
BBB physiologies. These considerations, we believe, make our
model system remarkably useful in terms of understanding how
ancient and resilient organisms, such as the fruit fly, protect
their CNS. Last, this approach may promote the identification
of common, conserved regulatory pathways that contribute to
chemical protection biology and BBB physiology across
species.
(Mayer 3549, col. 2).
12. Thomas teaches, in studies on cockroaches, “that the insect
central nervous system is highly permeant to the alcohols, as expected from
their comparatively high liposolubility. They are also broadly in agreement
with those obtained on the mammalian central nervous system, which also
possesses a blood-brain barrier” (Thomas 9).
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.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Wrigley found a “strong case of obviousness based on the prior art
references of record. [The claim] recites a combination of elements that
were all known in the prior art, and all that was required to obtain that
combination was to substitute one well-known . . . agent for another.” Wm.
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WrigleyJr. Co. v. Cadbury Adams USALLC, 683 F.3d 1356, 1364 (Fed.
Cir. 2012).
Analysis
We adopt the Examiner’s findings regarding the scope and content of
the prior art (Ans. 2—7; FF 1—12) and agree that the claimed method would
have been obvious over the teachings of Thomas, Poss, Labhasetwar, Stork,
and Mayer.
Appellants contend “[n]one of the cited references teach or suggest
using insects from the orders Acridoidea (e.g., locusts) or Blattodea (e.g.,
cockroaches) for determining whether a nanoparticle is transported
across the blood brain barrier (BBB)” (App. Br. 9) (emphasis original).
We find this argument unpersuasive because the Examiner’s rejection
is based on obviousness, not anticipation. Labhasetwar teaches a process of
determining whether, and how much, nanoparticle is transported across the
blood-brain barrier that differs from claim 1 solely in studying rats rather
than insects (FF 1—3). Similarly, Poss teaches a process for determining
whether an imaging probe reaches a desired target tissue in a subject (FF 4)
where the subjects include insects like Drosophila (FF 5), the imaging probe
may be nanoparticles (FF 6), and the imaging agent may require passing the
blood-brain barrier (FF 7). Stork teaches a process for determining whether
a compound passes the blood-brain barrier in Drosophila that involves
administering the compound to the insect, incubating the insect, and
visualizing the compound in the insect’s brain (FF 8—9). Mayer teaches that
“vertebrate and insect BBBS share many common features” (FF 10) and
suggests the use of insect model systems for “identification of common,
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conserved regulatory pathways that contribute to chemical protection
biology and BBB physiology across species” (FF 11). Thomas teaches
results on cockroach blood-brain barriers that were “in agreement with those
obtained on the mammalian central nervous system” (FF 12).
Therefore, we agree with the Examiner that the ordinary artisan,
informed by Labhasetwar and Poss of processes for analyzing nanoparticle
delivery to the blood-brain barrier, informed by Stork and Mayer of
commonalities between insect and mammalian blood-brain barriers and by
Mayer’s teaching of insects as a model system (FF 11), would have
reasonably selected known insect equivalents for testing of blood-brain
barrier accessibility to nanoparticles, including the cockroach system
demonstrated by Thomas as a known equivalent insect system that shares
features with the mammalian system (FF 12) because “all that was required
to obtain that combination was to substitute one well-known . . . agent for
another.” Wrigley, 683 F.3d at 1364.
Appellants separately argue each of the references, contending that
“Thomas fails to teach the limitations of the intact BBB as alleged by the
Office”; that there “is no disclosure in Poss, implicit or explicit, that
describes the use of Drosophila as a model for determining blood brain
barrier (BBB) penetration of nanoparticles in mammals”; that “Labhasetwar,
similar to Poss, does not disclose or suggest that Drosophila, much less any
insects from the orders recited in claim 1 are useful as an intermediate model
for determining BBB penetration of nanoparticles in mammals”; that “Stork
does not disclose or suggest anything about the BBB permeability of
nanoparticles in Drosophila”; and that “Mayer simply describes similarities
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between the molecular architecture of Drosophila BBB with that of human
BBB” (App. Br. 9-10).
We do not find these arguments persuasive because they fail to
address the combination of teachings, rather than the teachings of any single
reference alone. “Non-obviousness cannot be established by attacking
references individually where the rejection is based upon the teachings of a
combination of references.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed.
Cir. 1986). A reference “must be read, not in isolation, but for what it fairly
teaches in combination with the prior art as a whole.” Id.
Appellants contend, regarding claims 5, 9, and 10, that “the Office
Action fails to point to any teaching in the cited references wherein
measuring the concentration of the nanoparticle is performed by
homogenizing the dissected brains and analyzing the concentration of the
nanoparticle in the homogenate by liquid chromatography” (App. Br. 10).
Appellants further contend “the Office must provide a reason why one of
ordinary skill in the art would perform the method steps in claims 5 and 9—
10, along with the limitations recited in the claims they depend therefrom”
(Id.).
We do not find this argument persuasive because Labhasetwar teaches
the amount of a component in dissected brain samples (FF 2) “was
determined using high performance liquid chromatography (HPLC). A
standard plot using nanoparticles was prepared using identical conditions to
determine the amount of nanoparticles localized in the brain” (FF 3). As the
Examiner reasons, “[although . . . [Labhasetwar’s] method was employed
using a rat model of the BBB, it is clear that this method of quantifying the
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level of nanoparticle uptake into the brain is not novel and can be applied in
other systems with an intact BBB, including insect models of the vertebrate
BBB” (Ans. 10). That is, Labhasetwar’s method of measuring nanoparticles
in rat brains (FF 3) may reasonably be applied to other known model
systems for the blood-brain barrier including cockroaches (FF 12). Thus,
application of the method in the claimed insect models is obvious.
Appellants contend “[a]t the very most, Thomas teaches tissue
extracts from a neural cord, not a BBB. For at least these reasons, Thomas
teaches away from the claimed invention” (App. Br. 12). Appellants
contend that “[sjimilar to Thomas, Poss also teaches away from the
Applicants’ claimed invention. Poss fails to teach or suggest incubating an
optical imaging probe on an intact insect. What’s more, Poss does not teach
or suggest the use of an intact BBB” (App. Br. 12).
We find the teaching away arguments unpersuasive. A teaching away
requires a reference to actually criticize, discredit, or otherwise discourage
the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
(“The prior art’s mere disclosure of more than one alternative does not
constitute a teaching away from any of these alternatives because such
disclosure does not criticize, discredit, or otherwise discourage the solution
claimed”). Appellants do not identify, and we do not find, any teaching in
any of the cited prior art which teaches criticizes, discredits, or discourages
the use of cockroach blood-brain barriers as a model system in the
nanoparticle screening process of Labhasetwar (FF 1—3). Indeed, in
contrast, Poss teaches insects may be screened in such a system (FF 4—5),
Mayer teaches insects can serve as model systems for analysis of the blood-
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brain barrier (FF 11) and Thomas teaches that cockroach and mammalian
blood-brain barriers share common features (FF 12). Disclosed examples
and preferred embodiments do not constitute a teaching away from a broader
disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 446 n.3
(CCPA 1971).
Appellants contend:
Merely because one type of insect (Drosophila) tissue can be
used to model aspects of the BBB does not make obvious doing
the same in another type of insect. Moreover, the use of
Drosophila tissue would not lead one of ordinary skill in the art
to another type of insect, in addition to incubation of a
nanoparticle on an intact insect. One of ordinary skill in the art
would not have a reasonable expectation of success in modeling
the BBB in Acridoidea or Blattodea based on the teachings of
the cited references, which teach using Drosophila tissue for
this purpose.
(App. Br. 14).
We are not persuaded. We agree with the Examiner that there would
have been a reasonable expectation of success because
it was known at the time of the instant invention that the BBB
of insects is similar to that observed in mammalian/vertebrate
systems. See Mayer et al., which teaches that: “[HJowever, on
a cellular level, the vertebrate and insect BBBs share many
common features.” See page 3538, 2nd paragraph.
Furthermore, Stork et al. (see page 591, last paragraph) taught
the use of an insect model to assay for the movement of
nanoparticles across the BBB. Stork et al. also teaches that
regulation and differentiation of the insect nervous system
appears to be conserved, see page 587.
(Ans. 11). Indeed, all of the evidence of record (FF 5, 9-11), as opposed to
attorney argument, suggests that cockroach and Drosophila blood-brain
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barriers are similar to those of mammals such as rats, and that there are
“common, conserved regulatory pathways that contribute to chemical
protection biology and BBB physiology across species” (FF 11). See In re
Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a
brief cannot take the place of evidence.”).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
prior art renders the claims obvious.
SUMMARY
In summary, we affirm the rejection of claims 1,5,9, and 10 under
35 U.S.C. § 103(a) as obvious over Thomas, Poss, Labhesetwar, Stork, and
Mayer. Claims 3, 4, 6, 7, 11, and 12 that were not separately argued fall
with claim 1.
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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