Takara Bio USA, Inc.

Patent Trials and Appeals Board

May 26, 2020

2019005227 (P.T.A.B. May. 26, 2020)

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.
15/415,754 01/25/2017 Michael Haugwitz CLON-125DIV 4313
93726 7590 05/26/2020
EPA - BOZICEVIC FIELD & FRANCIS LLP
BOZICEVIC, FIELD & FRANCIS
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
PROUTY, REBECCA E
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
05/26/2020 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 MICHAEL HAUGWITZ,
THOMAS PATRICK QUINN, ANDREW ALAN FARMER,
and MONTSERRAT MORELL FERNÁNDEZ
__________

Appeal 2019-005227
Application 15/415,754
Technology Center 1600
__________

Before FRANCISCO C. PRATS, TAWEN CHANG, and
DAVID COTTA, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to finally reject claims 35, 37–47, and 63–66. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as Takara Bio
USA, Inc. Appeal Br. 3.
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STATEMENT OF THE CASE
The following rejections are before us for review:
(1) Claims 35, 37–39, 43–47, 63, and 66, under 35 U.S.C. § 103(a) as
being unpatentable over Gho,2 Thaa,3 and Clontech4 (Ans. 3–6);
(2) Claims 40–42, under 35 U.S.C. § 103(a) as being unpatentable
over Gho, Thaa, Clontech, and Mangeot5 (Ans. 6–7); and
(3) Claims 64 and 65, under 35 U.S.C. § 103(a) as being unpatentable
over Gho, Thaa, Clontech, and Warming6 (Ans. 7–8).
Claim 35, the sole independent claim on appeal, is illustrative and
reads as follows:
35. A micro-vesicle comprising:
a membrane-associated chimeric protein comprising a
first dimerization domain; and
a target chimeric protein that is not membrane-associated
comprising a second dimerization domain,
wherein the first and second dimerization domains are
specifically bound to each other in a dimerized complex or the
first and second dimerization domains are bound to each other
by a single dimerization mediator.

Appeal Br. 29.

2 WO 2011/002239 A2 (published Jan. 6, 2011). US 2012/0177574 A1
(published July 12, 2012) is the undisputed English equivalent of Gho cited
by the Examiner, which we also cite herein.
3 Bastian Thaa et al., Viruses as vesicular carriers of the viral genome: A
functional module perspective, 1803 BIOCHIM. BIOPHYS. ACTA 507–519
(2010).
4 Clontech, Switch on Protein-Protein Interactions, pp. 1–5 (2013) (date
provided by Information Disclosure Statement filed Jan. 25, 2017).
5 WO 2011/058052 A1 (published May 19, 2011).
6 WO 2013/188522 A2 (published Dec. 19, 2013).
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DISCUSSION
The Examiner’s Prima Facie Case
In rejecting claims 35, 37–39, 43–47, 63, and 66, the Examiner cited
Gho as describing microvesicles that include therapeutic or diagnostic
substances contained within the vesicle itself or embedded in the vesicle’s
membrane. Ans. 3. The Examiner cited Gho as disclosing that the vesicles
may be naturally shed from nucleated cells that recombinantly express the
diagnostic/therapeutic substances, and the substances may be proteins such
as growth factors, cytokines, or antibodies. Id. at 3–4.
The Examiner noted in particular Gho’s teaching that “the cells from
which the microvesicles are derived can be transformed to express plasma
membrane proteins which have been fused to heterologous domains [0146]
[0157]” as well as Gho’s teaching that “it is known that the activity of
proteins or peptides displayed on plasma membranes is higher when they are
expressed within cells as a result of higher local concentration [0162].” Ans.
4.
The Examiner found that Gho differs from the rejected claims in that
Gho “do[es] not explicitly teach that when the therapeutic substance is a
protein, that the therapeutic protein be engineered to comprise a domain
which will bind directly or indirectly to a domain of a membrane associated
protein.” Ans. 4.
The Examiner cited Thaa as teaching that “enveloped viruses and
cellular vesicles share obvious morphological and functional properties
(abstract) and discuss[ing] the many similarities in the production and
effects of enveloped viruses and cellular vesicles.” Ans. 4. The Examiner
noted in particular Thaa’s teaching that “to create a functional transport
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vesicle or virus, the cargo and components of the vesicle must be
specifically transported to the budding site and that viral assembly is the
means of doing so for viruses (page 510).” Id.
The Examiner cited Thaa as disclosing that several of the proteins
present in influenza virus vesicles were bound to each other, in a manner
encompassed by the rejected claims:
Thaa et al. teach influenza virus particles comprise a
transmembrane protein (HA) which binds to a target protein
(NP) through a dimerization mediator (M) (see Fig. 3).
Alternatively, one could characterize both the NP and M
proteins as target proteins and thus Thaa et al. teach a complex
comprising two target proteins that each comprise a
dimerization domain. Thaa et al. teach that the HA protein is
required for viral budding (page 513) and is also a viral
membrane fusion protein (page 516).
Ans. 4–5.
The Examiner cited Clontech as describing a system in which two
proteins could be configured to bind together through a dimerization
mediator in a manner encompassed by the rejected claims:
Clontech Switch On Protein Interactions teach a system
wherein two proteins can be engineered to inducibly dimerize
by fusing each with a dimerization domain (Dmr) wherein the
domains dimerize directly (DmrD domains) or in the presence
of a small organic molecule (DmrB domains in the presence of
the B-B homodimerizer or DmrA and DmrC domains in the
presence of the A/C heterodimerizer).
Ans. 5.
Based on the cited references’ combined teachings, the Examiner
reasoned that a skilled artisan would have considered it obvious to prepare a
microvesicle encompassed by the rejected claims:

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[A]s Gho et al. teach the therapeutic or diagnostic substance can
be a protein present within the microvesicles or embedded in
the membrane of the vesicles, and Thaa et al. teach that the
influenza viral NP protein is incorporated in the viral envelope
by binding to the viral M protein which is bound to the
cytoplasmic portion of the transmembrane HA protein and
teach that enveloped viruses and cellular vesicles share obvious
morphological and functional properties, it would have been
obvious to target a therapeutic protein of Gho et al. to the cell
membrane of the cell from which the microvesicles are
prepared by an analogous process wherein the therapeutic
protein is fused to a domain which binds to a domain
engineered into to a transmembrane protein that localizes in the
microvesicles. One of ordinary skill in the art would have
found it obvious to use the Clontech system to engineer [the]
Clontech Dmr binding domain into the therapeutic protein and a
transmembrane protein that localizes in the microvesicles.
Ans. 5–6.
Analysis
In proceedings before the Patent and Trademark Office,
the Examiner bears the burden of establishing a prima facie
case of obviousness based upon the prior art. “[The Examiner]
can satisfy this burden only by showing some objective
teaching in the prior art or that knowledge generally available to
one of ordinary skill in the art would lead that individual to
combine the relevant teachings of the references.”

In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992) (citations omitted,
bracketed material in original).
In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), although the
Supreme Court emphasized “an expansive and flexible approach” when
evaluating claims for obviousness, id. at 415, the Court nonetheless also
reaffirmed the importance of determining “whether there was an apparent
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reason to combine the known elements in the fashion claimed by the patent
at issue.” Id. at 418 (emphasis added).
Ultimately, therefore, as our reviewing court has stated, “[i]n
determining whether obviousness is established by combining the teachings
of the prior art, the test is what the combined teachings of the references
would have suggested to those of ordinary skill in the art.” In re GPAC Inc.,
57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations omitted).
In the present case, having carefully considered the evidence and
arguments presented by Appellant and the Examiner, Appellant persuades us
that the Examiner has not shown that the vesicles of Appellant’s claim 35
would have been obvious in view of Gho, Thaa, and Clontech. In particular,
we are not persuaded that the Examiner has explained with sufficient
specificity why the teachings in Thaa and Clontech would have prompted a
skilled artisan to configure Gho’s vesicles to include two chimeric proteins
having the arrangement required by Appellant’s claim 35.
As seen above, claim 35 recites a “micro-vesicle” that contains two
chimeric proteins, one protein being membrane-associated, and the other
“target” protein not being membrane-associated. Appeal Br. 29. Claim 35
recites that the two proteins are specifically bound to each other by
dimerization domains present on each of the proteins, with the specific
binding being either direct binding in the form of a “dimerized complex”
between the dimerization domains, or through a dimerization mediator that
binds to the two dimerization domains. See id.
As the Examiner found, Gho discloses microvesicles that may be
derived from cells, the microvesicles capable of delivering therapeutic or
diagnostic substances to target tissues or cells. See Gho, abstract; id. ¶ 158.
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In particular, as the Examiner found, Gho discloses that membrane-
bound proteins, such as antibodies on the surface of the vesicles, can be used
to target the vesicles to specific cells, such as cancer cells, and deliver a drug
such as doxorubicin to the cancerous cells. Gho ¶¶ 146–150. Gho further
explains that the therapeutic/diagnostic substances to be delivered may be
present inside the vesicles, or on the vesicles’ surfaces. Id. ¶ 151.
As the Examiner found, Gho explains that one or more binding and/or
therapeutic/diagnostic proteins may be recombinantly expressed in cells, and
in the vesicles subsequently formed, by causing the cells to naturally shed
the vesicles containing the recombinantly produced proteins. See Gho ¶¶
157–158. In particular, Gho explains:
It is known that the activity of proteins or peptides displayed on
plasma membranes is higher than when they are expressed
within cells as a result of the higher local concentration.
Proteins or peptides on plasma membranes may act as ligands
to trigger signaling or as antagonists to inhibit the function of
various ligands.
Id. ¶ 162.
Turning to the second reference cited by the Examiner, Thaa is a
review article that discusses the common features involved in the formation
of enveloped viruses and cellular transport vesicles. See Thaa 507
(“Enveloped viruses and cellular transport vesicles share obvious
morphological and functional properties. Both are composed of a closed
membrane, which is lined with coat proteins and encases cargo.
Transmembrane proteins inserted into the membrane define the target
membrane area with which the vesicle or virus is destined to fuse.”
(Abstract)). Thaa includes a discussion of the various proteins, including
membrane-bound proteins, involved in the budding of influenza virus
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vesicles from cells, as well as the fusion of the viral vesicles to target cells.
See id. at 510–511, 513, 516.
Turning to the third reference cited by the Examiner, Clontech
discloses a commercialized system that induces two proteins of interest to be
bound together in cells, thereby activating a desired cellular pathway. See
Clontech 2. As recited in Appellant’s claim 35, Clontech discloses that each
of the two proteins that are desired to be brought together in cells are
modified with dimerizing domains, designated DmrA and DmrC. See id.
Once expressed in cells, the modified (chimeric) proteins are induced to bind
together by a small molecule (the A/C Heterodimerizer) that binds to the
dimerizing domains of the two modified proteins. See id.
Clontech discloses in particular that a membrane-bound protein and a
non-membrane-bound protein in a cell can be induced to bind together,
resulting in activation of a signal transduction pathway. See Clontech 3
(figure in upper right corner showing A/C Heterodimerizer-mediated
binding of DmrA and Dmr C modified proteins). Indeed, we note that
Appellant’s examples use the Clontech technology. See Spec. 34–36.
Thus, to summarize, as the Examiner found, Gho describes
microvesicles that can deliver therapeutic proteins in a targeted fashion
using membrane-bound proteins, Thaa discloses that influenza viral vesicle
budding and cell fusion involves specific interactions between viral proteins
including membrane-bound proteins, and Clontech discloses that a
dimerization mediator may be used in intact cells to induce a chimeric
membrane-bound protein to bind with another chimeric protein, in turn
activating a desired cellular pathway.
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We are not persuaded that the Examiner has explained with sufficient
specificity which particular elements of Gho, Thaa, and Clontech a skilled
art would have combined to arrive at the vesicles recited in Appellant’s
claim 35, and how those prior art elements correspond to the features recited
in claim 35. The Examiner appears to posit that a skilled artisan would have
been motivated to express, in Gho’s cells, the proteins involved in influenza
virus budding and viral vesicle fusion described in Thaa, thereby promoting
Gho’s cells to form vesicles that are predisposed to fuse with target cells.
See Ans. 5–6 (determining that it would have been obvious to target Gho’s
therapeutic protein “to the cell membrane of the cell from which the
microvesicles are prepared by an analogous process wherein the therapeutic
protein is fused to a domain which binds to a domain engineered into to a
transmembrane protein that localizes in the microvesicles”). The Examiner
does not explain sufficiently clearly, however, which elements of the posited
Gho/Thaa combination correspond to which specific features of the vesicles
of Appellant’s claim 35, or whether Clontech is also required to arrive at all
of the features of claim 35.
Moreover, the Examiner points to no specific teachings in any of the
references suggesting that it would be desirable, suitable, or even useful, to
recombinantly express the viral proteins described in Thaa when preparing a
vesicle containing therapeutic/diagnostic substances, as described in Gho.
We acknowledge Thaa’s teaching that formation of viral vesicles and
cellular transport vesicles are similar processes. Thaa 507 (Abstract); see
also Ans. 6 (suggesting the obviousness of using “an analogous process” to
form Gho’s vesicles); Ans. 12 (asserting that a skilled artisan had motivation
“to use the means of specifically transporting and incorporating the cargo of
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enveloped viruses (i.e., the vRNP) into the virus for the analogous process of
specifically transporting and incorporating the cargo of a transport vesicle as
disclosed by Gho et al. into the transport vesicle”).
However, absent some specific teaching in the prior art, or
identification of knowledge available to a skilled artisan suggesting the use
of Thaa’s influenza virus proteins in drug-delivering vesicles like those
described in Gho, we are not persuaded that the similarity between viral
vesicle formation and cellular transport vesicle formation would have been
sufficient to prompt a skilled artisan to express Thaa’s influenza virus
proteins in Gho’s cells, as a way ultimately to form Gho’s microvesicles.
And again, absent some identification of which specific elements from Gho
and Thaa correspond to which specific features recited in Appellant’s claim
35, we are not persuaded that the Examiner has explained adequately why
claim 35 would have been prima facie obvious in view of the cited
references.
We are not persuaded, moreover, that the Examiner has explained
sufficiently why a skilled artisan would have configured the proteins of
Gho’s microvesicles to have the dimerizing features described in Clontech.
In setting forth the prima facie case, the Examiner states as to Clontech that
“[o]ne of ordinary skill in the art would have found it obvious to use the
Clontech system to engineer Clontech Dmr binding domain into the
therapeutic protein and a transmembrane protein that localizes in the
microvesicles.” Ans. 6. In setting forth the prima facie case, however, the
Examiner does not explain clearly why a skilled artisan would have
configured Gho’s therapeutic and transmembrane proteins to have
Clontech’s dimerizing domains.
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In responding to Appellant’s arguments, the Examiner expands on the
rationale for applying Clontech’s dimerizing domains to Gho’s proteins:
Thaa et al. makes clear that the “selection and enrichment of a
desired cargo” is provided by the presence of a binding site
specific for a desired cargo within the transmembrane protein(s)
of the virus. Thus to provide such a system to the shedding
microvesicles a skilled artisan would understand that one would
need to provide a binding site specific for a desired cargo to a
transmembrane protein of the shedding microvesicle. As
Clontech specifically discloses a system for providing a rapid
and specific binding interaction of two proteins of interest a
skilled artisan would have been motivated to select this system
to engineer the transmembrane protein and desired cargo
protein of Gho et al. to provide a specific binding interaction of
the two that would select and enrich the cargo protein in the
microvesicle of Gho et al. . . .
Ans. 14–15.
Thus, as we understand it, the Examiner’s position is that, because
Thaa teaches that influenza viral vesicle formation involves binding of
certain cargo proteins to transmembrane proteins, a skilled artisan would
have modified Gho such that Gho’s therapeutic/diagnostic protein would
bind to a vesicle-inducing viral transmembrane protein, and the skilled
artisan would have used Clontech’s dimerizing domains to accomplish that
binding. We are not persuaded.
In particular, as discussed above, we are not persuaded that the
Examiner has as identified specific teachings in any of the references
suggesting that it would be desirable, suitable, or even useful, to
recombinantly express the viral proteins described in Thaa when preparing a
vesicle containing therapeutic/diagnostic substances, as described in Gho.
We are not persuaded, therefore, that the Examiner has explained
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sufficiently why Thaa would have motivated a skilled artisan to use
Clontech’s dimerizing domains to cause binding between a transmembrane
vesicle-inducing protein, and a therapeutic/diagnostic protein in Gho’s
vesicles.
In sum, for the reasons discussed, having carefully considered all of
the arguments and evidence advanced by both the Examiner and Appellant,
we find that the Examiner has not shown by a preponderance of the evidence
that the vesicles of Appellant’s claim 35 would have been obvious in view of
Gho, Thaa, and Clontech. We therefore reverse the Examiner’s rejection of
claim 35, and its dependent claims 37–39, 43–47, 63, and 66, over Gho,
Thaa, and Clontech.
In rejecting claims 40–42, all of which depend directly or ultimately
from claim 35, the Examiner cited Gho, Thaa, and Clontech for the
teachings discussed above, and cited Mangeot as evidence that the additional
features recited in claims 40–42 would have been obvious features of the
vesicles suggested by Gho, Thaa, and Clontech. See Ans. 6–7. Because the
Examiner did not identify any teachings in Mangeot that remedy the
deficiencies discussed above of Gho, Thaa, and Clontech in relation to claim
35, we also reverse the Examiner’s rejection of claims 40–42 over Gho,
Thaa, Clontech, and Mangeot.
In rejecting claims 64 and 65, both of which depend ultimately from
claim 35, the Examiner cited Gho, Thaa, and Clontech for the teachings
discussed above, and cited Warming as evidence that the additional features
recited in claims 64 and 65 would have been obvious features of the vesicles
suggested by Gho, Thaa, and Clontech. See Ans. 7–8. Because the
Examiner did not identify any teachings in Warming that remedy the
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deficiencies discussed above of Gho, Thaa, and Clontech in relation to claim
35, we also reverse the Examiner’s rejection of claims 64 and 65 over Gho,
Thaa, Clontech, and Warming.
CONCLUSION
In summary:
Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed
35, 37–39, 43–47,
63, 66
103(a) Gho, Thaa,
Clontech
35, 37–39, 43–
47, 63, 66
40–42 103(a) Gho, Thaa,
Clontech, Mangeot
40–42
64, 65 103(a) Gho, Thaa,
Clontech, Warming
64, 65
Overall Outcome 35, 37–47, 63–
66

REVERSED