Seppo Yla-Herttuala et al.

Patent Trials and Appeals Board

Jan 31, 2020

15221265 - (D) (P.T.A.B. Jan. 31, 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.
15/221,265 07/27/2016 Seppo YLA-HERTTUALA Trizell - GB07/02695.8 5263
22925 7590 01/31/2020
Pharmaceutical Patent Attorneys, LLC
801 Brickell Avenue
9th Floor #9101
Miami, FL 33131-4924
EXAMINER
NGUYEN, QUANG
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
01/31/2020 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):
administration@LicensingLaw.net
docket@LicensingLaw.net
mark.pohl@licensinglaw.net
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SEPPO YLA-HERTTUALA, KARI J. AIRENNE, and
HANNA P. LESCH1
Appeal 2019-001329
Application 15/221,265
Technology Center 1600

Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims related to
lentiviral vectors, which have been rejected on several grounds. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
“According to the present invention, a method of generating a
lentivirus vector[] comprises cloning each of a lentivirus transfer construct,
gag, pol, an envelope protein and rev respectively into the same or different

1 Appellant identifies the real party in interest as Trizell Limited. Appeal Br.
1. We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a).
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baculoviruses, and transducing a producer cell with the or each baculovirus.”
Spec. 2:18–21.
Claims 1–17 are on appeal. Claims 1, 8, and 12, reproduced below,
are the independent claims:
1. A method comprising:
a. Transducing a mammalian cell in vitro with a
recombinant baculovirus comprising a transfer construct
comprising a packaging genome of a second virus along
with a therapeutic transgene to make a transduced
mammalian producer cell comprising a transfer construct
containing the packaging genome of the second virus
along with the therapeutic transgene; and then
b. Culturing said transduced mammalian producer
cell in culture media, and harvesting from said
transduced mammalian producer cell and/or culture
media the second virus having the therapeutic transgene.

8. A mammalian cell transduced by a recombinant
baculovirus having at least one nucleic acid sequence coding
for a second virus obtained from a virus which in its wild state
has a single stranded genome, said second virus being
replication-deficient and having a therapeutic transgene.

12. A mammalian producer cell transduced with a
recombinant baculovirus, said mammalian producer cell
producing viral vector able to transfect a human cell which is
not actively dividing, said viral vector produced by a said
mammalian producer cell being substantially free of insect cell
membrane.

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The claims stand rejected as follows:
Claims 1–7 and 11–17 under 35 U.S.C. § 112, second paragraph, as
indefinite (Final Action2 6–7);
Claims 1–8 and 12–17 under 35 U.S.C. § 112, first paragraph, for lack
of adequate written description (Final Action 3);
Claims 9 and 10 under 35 U.S.C. § 112, fourth paragraph, as being in
improper dependent form (Final Action 10);
Claims 1–17 under 35 U.S.C. § 102(b) as anticipated by Leblois-
Prehaud3 (Final Action 11);
Claims 15–17 under 35 U.S.C. § 102(b) as anticipated by Schauber4
(Final Action 18);
Claims 1–17 under 35 U.S.C. § 103(a) as obvious based on Schauber,
Leblois-Prehaud, and Kingsman5 (Final Action 20); and
Claims 1–14, provisionally, for obviousness-type double patenting
based on claims 1–7 and 10 of application 12/522,646 (Final Action 35–36).
OPINION
Definiteness
“Packaging genome”
The Examiner concludes that the metes and bounds of claim 1 are
unclear because the claim recites “a packaging genome of a second virus.”
Final Action 7. The Examiner speculates that this limitation could refer to “a

2 Office Action mailed March 14, 2018.
3 US 6,387,670 B1; issued May 14, 2002.
4 US 6,863,884 B2; issued Mar. 8, 2005.
5 WO 98/55640; published Dec. 10, 1998.
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genome of a second virus to be packaged or an already packaged genome of
a second virus.” Id. The Examiner states that the limitation was interpreted,
for purposes of examination, “to refer to a genome of a second virus to be
packaged in the mammalian producer [cell].” Id.
Appellant argues that “[a] packaging genome is what the name
suggests - a genome (set of genes) coding for the various polypeptides
required to package the virus. The instant application describes one at e.g.,
2:19–20, in teaching gag-pol. . . . gag-pol is a packaging genome. The
artisan understands this.” Appeal Br. 4.
We agree with the Examiner that claim 1 is indefinite. The
Specification does not include the term “packaging genome.” The sentence
including the passage pointed to by Appellant as a description of a
packaging genome reads as follows: “According to the present invention, a
method of generating a lentivirus vector, comprises cloning each of a
lentivirus transfer construct, gag, pol, an envelope protein and rev
respectively into the same or different baculoviruses, and transducing a
producer cell with the or each baculovirus.” Spec. 2:18–21.
This passage describes a lentivirus transfer construct, gag, and pol as
three different components that can be cloned either into the same
baculovirus or into different baculoviruses, which can be transduced into a
producer cell in order to generate a lentivirus vector. Claim 1, however,
recites a “baculovirus comprising a transfer construct,” where the “transfer
construct compris[es] a packaging genome of a second virus.” The cited
passage does not describe a transfer construct as comprising any of the other
recited genes, nor does it describe gag and pol as a packaging genome.
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Claim 1 does not state that the recited packaging genome includes or
requires gag and pol, nor does the Specification support that interpretation,
since the passage that Appellant points to states that gag and pol can be
cloned into different baculoviral vectors, and suggests that each of (a) a
lentivirus transfer construct, (b) gag, (c) pol, (d) an envelope protein, and
(e) rev, are transduced into a producer cell in the disclosed method. See also
Spec. 2:29–30 (“To perform the method of the invention, the baculovirus(es)
must comprise a lentivirus transfer construct, gag, pol, a suitable envelope
protein and rev.”). The cited description therefore does not support
Appellant’s position that a skilled artisan would recognize that gag and pol
are a “packaging genome” because they encode the polypeptides required to
package a virus.
In addition, claim 1 is not limited to a method in which the “second
virus” is a lentivirus, while the passage in the Specification that Appellant
points to specifically describes a “method of generating a lentivirus vector.”
Spec. 2:18–19 (emphasis added). Thus, even if the evidence supported
Appellant’s argument that a skilled artisan would recognize gag-pol as an
example of a packaging genome, the record provides no guidance regarding
what a “packaging genome” means in the context of viruses other than
lentiviruses.
In summary, Appellant has not pointed to a specific definition of a
“packaging genome” in the Specification, nor has Appellant pointed to
evidence showing that “packaging genome” has a specific definition that is
known and accepted by those skilled in the art. Therefore, the scope of claim
1, even when read in light of the Specification, is unclear. The rejection of
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claim 1 under 35 U.S.C. § 112, second paragraph, is affirmed. Claims 2–7
depend from claim 1 and are indefinite for the same reason.
Claim 11
The Examiner states that, “[i]n claim 11, it is unclear what is
encompassed by the limitation ‘Obtaining the recombinant baculovirus of
Claim 8’. It is not[ed] that claim 8 is now directed to a mammalian cell
transduced by a recombinant baculovirus.” Final Action 7.
Appellant “does not here appeal the rejection of claim 11 as unclear.”
Appeal Br. 5. We therefore affirm the rejection of claim 11 under 35 U.S.C.
§ 112, second paragraph.
“Substantially free”
The Examiner concludes that claim 12 is indefinite because the term
“substantially free” is a relative term that “is not defined by the claim, the
specification does not provide a standard for ascertaining the requisite
degree, and one of ordinary skill in the art would not be reasonably apprised
of the scope of the invention.” Final Action 7.
Appellant argues that the “instant inventors teach to express virus in
human producer cells. See Specification 7:2. The resulting virus is thus
enveloped in human cell membrane.” Appeal Br. 5. Appellant also points
out that “‘[s]ubstantially free’ . . . reads on no insect membrane at all.” Id. at
6.
We reverse this basis of the rejection. Terms of degree are not per se
indefinite. “Such broadening usages as ‘about’ must be given reasonable
scope. . . . Although it is rarely feasible to attach a precise limit to ‘about,’
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the usage can usually be understood in light of the technology embodied in
the invention.” Modine Manufacturing Co. v. U.S. ITC, 75 F.3d 1545, 1554
(Fed. Cir. 1996).
Here, the Examiner has not disputed Appellant’s position that a viral
vector produced by a mammalian cell, as recited in claim 12, would be
expected to be enveloped in human cell membrane, and thus would be
expected to be entirely free of insect cell membrane. In fact, the Examiner
stated that “it is unclear how a produced viral vector in a mammalian cell
transduced with a recombinant baculovirus in claim 12 would even contain
any minute amount of an insect cell membrane.” Final Action 8. This
statement confirms that those skilled in the art would have no reason to
expect the viral vector produced by the cell of claim 12 to comprise any
insect cell membrane.
In short, the disputed limitation merely states that the viral vector
produced by the claimed cell is “substantially” free of a contaminant that
would not be expected to be present at all, and therefore does not make the
scope of the claimed mammalian producer cell unclear to those of ordinary
skill in the art.
Claims 12–14
Claims 12–14 stand rejected as indefinite, on the basis that they omit
essential elements, specifically “a recombinant baculovirus encoding a
genome of a viral vector/virus comprising a transgene along with the
necessary components for packaging said viral vector/virus (e.g., gag, pol,
rev, env for a lentiviral vector).” Final Action 8.
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Appellant argues that, although “[c]laim 12 is broader than the
inventors’ specific examples,” and “many of the specific embodiments in the
examples are not mentioned in claim 12,” the elements of claim 12
interrelate and therefore the claim is not indefinite. Appeal Br. 7–8.
We reverse this basis of the rejection. Claim 12 recites the structural
limitations of (a) a “mammalian producer cell,” (b) “transduced with a
recombinant baculovirus,” and the functional limitations that (c) the cell
“produc[es] viral vector able to transfect a human cell which is not actively
dividing,” and (d) the “viral vector produced by a [sic] said mammalian
producer cell [is] substantially free of insect cell membrane.”
The Examiner has not explained why a skilled artisan would be
unable to determine which mammalian cells are encompassed by the claim
language. See In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997) (“A
patent applicant is free to recite features of an apparatus either structurally or
functionally. See In re Swinehart, . . . 439 F.2d 210, 212 . . . (CCPA 1971)
(‘[T]here is nothing intrinsically wrong with [defining something by what it
does rather than what it is] in drafting patent claims.’).” (bracketed material
in original)). While the functional limitations of claim 12 might make the
claim broader than it would be if it included the limitations suggested by the
Examiner, “breadth is not to be equated with indefiniteness.” In re Miller,
441 F.2d 689, 693 (CCPA 1971).
“Obtaining the viral vector . . .”
Claims 15–17 stand rejected as indefinite, on the basis that it is
unclear what is encompassed by “[o]btaining the viral vector” of one of
claims 12–14. Final Action 8. The Examiner notes that claims 12–14 are
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directed to “a mammalian producer cell transduced with a recombinant
baculovirus to produce a viral vector able to transfect a human cell which is
not actively dividing,” and states that it is unclear whether the obtained viral
vector is in the form of a mammalian producer cell or is free of the
mammalian producer cell. Id.
The Examiner states that, for purposes of prosecution, the limitation
will be interpreted “to refer to any viral vector that is produced/generated
from a mammalian producer cell transduced with a recombinant baculovirus
encoding necessary components/elements for said viral vector.” Id. at 8–9.
Appellant agrees that this interpretation of the claim language is correct.
Reply Br. 56 (“Appellants do not disagree with the Examiner’s suggested
interpretation.”).
In short, the Examiner and Appellant agree that “obtaining the viral
vector” of claims 12–14, as recited in claims 15–17 respectively, means
obtaining the viral vector that is produced by the mammalian producer cell
defined by claims 12–14. We therefore reverse the rejection of claims 15–17
under 35 U.S.C. § 112, second paragraph.
Written Description
“Packaging genome”
Claims 1–7 stand rejected as lacking adequate written description,
because the recitation of transducing a mammalian cell with a “recombinant
baculovirus comprising a transfer construct comprising a packaging genome
of a second virus along with a therapeutic transgene” (claim 1), encompasses

6 After page 1, the pages of the Reply Brief are unpaginated but we refer to
them as if they were consecutively numbered beginning with page 1.
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“transducing a mammalian cell in vitro with a recombinant baculovirus
comprising a transfer construct comprising a genome of a second virus
that is already packaged (packaging genome) along with a therapeutic
transgene to make a transduced mammalian producer cell.” Final Action 3–
4.
The Examiner finds that the Specification does not describe
a transfer construct comprising an already
packaged/packaging genome of a second virus. This is
evident by the teachings of the instant specification that
disclose that the mammalian producer cell is also transduced
with recombinant baculovirus(es) encoding a suitable
envelope protein, gag, pol and rev to generate functional
and packaged lentiviruses.
Id. at 4.
Appellant argues that “none of the claims mention ‘already-packaged
packaging genome,’ much less require one.” Appeal Br. 8.
We will affirm this basis of the rejection. It is true that none of the
claims on appeal states that a “packaging genome” encompasses a packaged
viral genome, or part of one. However, as discussed above, neither the
claims nor the Specification make clear what is required or excluded by the
term “packaging genome.”
In its arguments regarding definiteness, in fact, Appellant seems to
suggest that “packaging genome” is broad enough to encompass a packaged
viral genome, or at least part of one. See Reply Br. 1: “[T]he Examiner
argues that the term [“packaging genome”] ‘may imply a genome that is
packaged.’ The Examiner is correct: the term ‘packaging genome’
encompasses a packaging genome which is in a viral capsid.”
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Under that apparently agreed-upon interpretation, claim 1
encompasses a method of transducing a mammalian cell with a recombinant
baculovirus comprising a transfer construct that itself comprises a packaging
genome (of a second virus) in a viral capsid.
Regarding this embodiment, Appellant argues that,
assuming the claims required it, the specification in fact teaches
an “already-packaged packaging genome.” gag-pol is a
packaging genome. The specification teaches to put gag-pol on
a plasmid (pBAC-gag-pol) . . . [and] to package that plasmid in
a baculovirus. pBAC-gag-pol packaged in baculovirus thus
becomes an “already-packaged packaging genome.”
Appeal Br. 8–9.
This argument is unpersuasive because, as discussed above with
respect to claim definiteness, the evidence of record does not support
Appellant’s position that a skilled artisan would recognize gag-pol as a
“packaging genome.” In addition, and even if gag-pol were recognized as
one example of a packaging genome, claim 1 requires not simply a
baculovirus comprising a packaging genome, but a baculovirus comprising a
transfer construct that comprises a packaging genome. Even under
Appellant’s interpretation, therefore, the description that is relied upon does
not describe the disputed claim limitation. We therefore affirm the rejection
of claim 1, and dependent claims 2–7, under 35 U.S.C. § 112, first
paragraph, for lack of adequate written description.
Claim 8
The Examiner reasons that the recitation in claim 8 of “‘[a]
mammalian cell transduced by a recombinant baculovirus’ . . .
encompasses any mammalian cell, including a mammalian cell in vitro . . .
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and in vivo (e.g., a mammalian cell in an animal),” as long as it includes
the nucleic acid recited in claim 8. Final Action 4. The Examiner finds that
“[t]he as-filed specification at best has a written support for an in vitro
mammalian cell being transduced with a recombinant baculovirus.” Id. at 5.
Appellant points to the “Summary of claimed subject matter” section
of the Appeal Brief for the argument with respect to this rejection:
“Applicant’s brief says that mammalian cell is supported in the specification
at e.g., 2:6–7, 1:14 and 4:5, and transduction with recombinant baculovirus
is supported in the specification at e.g., 3:15–16. See Appeal Brief (July
2018) at 2:25–26.” Reply Br. 6.
We affirm the rejection. For written description, “an adequate prima
facie case must . . . sufficiently explain to the applicant what, in the
examiner’s view, is missing from the written description. . . . When no such
description can be found in the specification, the only thing the PTO can
reasonably be expected to do is to point out its nonexistence.” Hyatt v.
Dudas, 492 F.3d 1365, 1370 (Fed. Cir. 2007). Here, the Examiner has
pointed out that, while the Specification describes mammalian cells
transduced with baculovirus in vitro, a description of such cells in vivo is
missing from the Specification. Final Action 4–5.
The burden is then shifted to Appellant “to cite to the examiner where
adequate written description could be found, or to make an amendment to
address the deficiency.” Hyatt v. Dudas, 492 F.3d at 1371. Appellant has
pointed to the Specification at page 1, line 14; page 2, lines 6–7; page 3,
lines 15–16; and page 4, line 5. Reply Br. 6.
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We have reviewed the cited passages in the Specification but fail to
find any description of a mammalian cell in vivo, transduced with a
recombinant baculovirus. Appellant therefore has failed to identify written
descriptive support for the limitation the Examiner finds to be missing from
the Specification. We affirm the rejection of claim 8 under 35 U.S.C. § 112,
first paragraph.
“Substantially free of insect cell membrane”
The Examiner reasons that the recitation in claim 12 of a viral vector
“substantially free of insect cell membrane” encompasses
an embodiment of a viral vector produced by a mammalian
producer cell containing/comprising a minute amount of
insect cell membrane (substantially free of insect cell
membrane does not mean completely free of insect cell
membrane). There is no written support in the as-filed
specification for this embodiment encompassed by the new
limitation.
Final Action 5.
Appellant again points to the “Summary of claimed subject matter”
section of the Appeal Brief for the argument with respect to this rejection:
“Applicant’s brief says that viral vector is supported in the specification at
e.g., Figure 2, mammalian producer cell is supported in the specification at
e.g., 2:6–7, 1:14 and 4:5, and substantially free of insect cell membrane is
supported in the specification at e.g., 8:8. See Appeal Brief (July 2018) at
3:3–8.” Reply Br. 7.
We have reviewed Figure 2 and the cited passages in the Specification
but fail to find any description of a viral vector, produced by a mammalian
producer cell, comprising any amount of insect cell membrane. Appellant
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therefore has failed to identify written descriptive support for the limitation
the Examiner finds to be missing from the Specification. We affirm the
rejection of claim 12, and dependent claims 13–17, under 35 U.S.C. § 112,
first paragraph.
Dependent claim format
Claims 9 and 10 stand rejected as being in improper dependent form,
because they are directed to the “recombinant baculovirus of claim 8,” while
claim 8 is directed to a “mammalian cell transduced by a recombinant
baculovirus.” Final Action 10. The Examiner thus finds that claims 9 and 10
do not include all of the limitations of claim 8, from which they depend. Id.
Appellant agrees that the preambles of claims 9 and 10 have a
typographical error. Reply Br. 7. We therefore affirm the rejection of claims
9 and 10 under 35 U.S.C. § 112, fourth paragraph.
Anticipation by Leblois-Prehaud
The Examiner finds that Leblois-Prehaud discloses
a method for producing any recombinant virus (e.g.,
adenovirus, adeno-associated virus and retrovirus) based on
the use of one or more baculoviruses for providing the
complementary functions . . . for the defective recombinant
genome in competent host cells such as 293 cells and
derivatives thereof, and purifying the recombinant virus in
the supernatant of competent host cells.
Final Action 11–12.
The Examiner finds that Leblois-Prehaud also discloses that “a
recombinant viral genome (e.g., an exemplary defective recombinant
adenovirus, including replication defective recombinant minimum
adenovirus or adenovirus defective for E1 and E3) can also be
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introduced into competent host cells in the form of another recombinant
baculovirus,” and that the recombinant viruses produced in its method can
include therapeutic transgenes. Id. at 12. The Examiner concludes that,
[s]ince at least the recombinant AAV containing a therapeutic
gene (including recombinant AAV in which the entire coding
regions of Rep and Cap are replaced by nucleic acids of
interest; see at least col. 3, lines 5–7) and generated by the
method of Leblois-Prehaud et al that is able to transfect both
dividing and non-dividing human cells in vitro, ex vivo or in
vivo; and that wild-type AAV has a single-stranded DNA
genome; the teachings of Leblois-Prehaud et al meet every
limitation of the instant claims.
Id. at 12–13.
Appellant argues, among other things, that Leblois-Prehaud does not
disclose a second virus having a therapeutic transgene, as required by
independent claims 1 and 8. Appeal Br. 23. Appellant also argues that
Leblois-Prehaud does not disclose a “virus which can transduce a human cell
‘which is not actively dividing,’” as required by claim 12. Id. at 21.
We agree with Appellant that the Examiner has not shown that
Leblois-Prehaud discloses the method or cells defined by the claims on
appeal. “[U]nless a reference discloses within the four corners 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, it
cannot be said to prove prior invention of the thing claimed and, thus, cannot
anticipate under 35 U.S.C. § 102.” Net MoneyIN, Inc. v. VeriSign, Inc.,
545 F.3d 1359, 1371 (Fed. Cir. 2008). “[I]t is not enough that the prior art
reference . . . includes multiple, distinct teachings that the artisan might
somehow combine to achieve the claimed invention.” Id.
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Here, the Examiner has not pointed to a disclosure in Leblois-Prehaud
that includes all of the limitations of any of the independent claims on
appeal, arranged as in the claims, with no need to combine different
teachings within the reference. Claim 1 is directed to a method that requires
transducing a mammalian cell with “a recombinant baculovirus comprising a
transfer construct comprising a packaging genome of a second virus along
with a therapeutic transgene.” The Examiner has identified the disclosure in
Leblois-Prehaud of a recombinant baculovirus that provides complementary
functions for a defective viral genome in a host cell (Final Action 11), and
the disclosure of genes that could potentially be used therapeutically (id. at
12). However, the Examiner has not identified a disclosure in Leblois-
Prehaud of transducing a mammalian cell with a specific recombinant
baculovirus that includes all of the elements recited in claim 1, culturing the
transduced cell, and harvesting a second virus having the therapeutic
transgene, as required by the claim. The Examiner therefore has not shown
that Leblois-Prehaud anticipates claim 1 or its dependent claims.
The Examiner relies on the adeno-associated virus (AAV) disclosed
by Leblois-Prehaud as the “virus which in its wild state has a single stranded
genome” recited in claim 8 and the virus “able to transfect a human cell
which is not actively dividing” recited in claim 12. Final Action 12–13. The
Examiner has not, however, pointed to a specific description in Leblois-
Prehaud of a mammalian cell transduced by a recombinant baculovirus
having a nucleic acid sequence coding for a replication-deficient AAV
having a therapeutic transgene, as would be required to meet all of the
limitations of claim 8. Nor has the Examiner pointed to a specific description
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in Leblois-Prehaud of a mammalian cell transduced with a recombinant
baculovirus, where the mammalian producer cell produces an AAV vector,
as would be required to meet all of the limitations of claim 12. We therefore
reverse the rejection of independent claims 8 and 12, and the claims that
depend from them, as anticipated by Leblois-Prehaud.
In summary, the Examiner has not persuasively shown that Leblois-
Prehaud identically discloses, without any need for picking and choosing, a
method or a cell that meets all of the limitations of the claims on appeal. See
Gechter v. Davidson, 116 F.3d 1454, 1457 (Fed. Cir. 1997) (“Under 35
U.S.C. § 102, every limitation of a claim must identically appear in a single
prior art reference for it to anticipate the claim.”). The rejection under
35 U.S.C. § 102(b) based on Leblois-Prehaud is therefore reversed.
Anticipation by Schauber
Claims 15–17 stand rejected as anticipated by Schauber. Claim 15 is
representative of the rejected claims. As noted above in the discussion of
claim definiteness, the Examiner and Appellant agree that the recitation in
claim 15 of “[o]btaining the viral vector of Claim 12” refers to “any viral
vector that is produced/generated from a mammalian producer cell
transduced with a recombinant baculovirus encoding necessary
components/elements for said viral vector.” Final Action 8–9; Reply Br. 5.
Thus, claim 15 requires obtaining a viral vector as recited in claim 12—i.e.,
one that (a) is able to transfect a human cell which is not actively dividing,
and (b) is substantially free of insect cell membrane—and transducing a
human patient’s cells with said viral vector.
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The Examiner finds that Schauber teaches
a lentiviral packaging system . . . comprising at least: (i) a
first vector comprising a gag, a pol, or gag and pol genes; (ii)
a second vector comprising a functionally modified or
heterologous envelope gene . . . ; and (iii) a third vector
comprising a rev gene; and a producer cell comprising the
packaging system and a lentiviral transfer vector comprising
a transgene.
Final Action 18. The Examiner finds that Schauber teaches that “packaging
or producer cells include human cells or cell lines known in the art.” Id.
at 18–19. Finally, the Examiner finds that Schauber teaches that the
transgene in its system can be a therapeutic gene, which can be delivered in
vivo or ex vivo to human cells. Id. at 19.
The Examiner concludes that the viral vector taught by Schauber
meets the limitations of the vector in claim 12 because it “is able to transfect
both dividing and non-dividing human cells and is free of insect cell
membrane (no insect cell is utilized in the production of the recombinant
lentiviral vector).” Id. “Therefore, methods for delivering a transgene,
including a therapeutic transgene, to a cell in vivo or ex vivo using the
same recombinant lentiviral vector to treat humans as taught by Schauber
et al have the same method steps and starting materials as those of” claim
15. Id..
We agree with the Examiner that Schauber anticipates claim 15.
Schauber discloses a retroviral packaging system and “a producer cell that
comprises the packaging system of the invention and a retroviral transfer
vector comprising a transgene.” Schauber 3:5–6, 22–24. In a working
example, Schauber states that “[t]he VSV-G and baculovirus (AcNPV) gp64
envelope genes were subcloned into a mammalian expression vector” and
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used for “[l]arge-scale production of pseudotyped vectors . . . as follows:
low passage 293T cells were expanded and seeded at 5.75 x 108 cells per cell
factory.” Id. at 27:39–40; 28:16–20. 293T cells are human embryonic kidney
cells. Id. at 4:37–38. Thus, Schauber describes production of viral vectors
using mammalian producer cells, which would necessarily be free of insect
cell membrane.
In the same example, Schauber states that “pseudotyped HIV vector
particles were prepared and tested for their ability to transduce three human
cell lines.” Id. at 29:10–13. “The results . . . demonstrate[d] that gp64-
pseudotyped vector was infectious on all three cell lines.” Id. at 29:21–22.
Schauber thus discloses that its vectors are able to transfect human cells, and
HIV is a lentivirus that can transduce non-dividing cells. See Spec. 1:6–8:
“Lentiviruses, such as Human Immunodeficiency Virus I, are promising
tools for gene therapy due to their ability to transduce and integrate into the
genome of both dividing and non-dividing cells.”
The viral vectors disclosed by Schauber meet all of the limitations of
the viral vectors required by claim 15, and Schauber discloses transducing
human cells with its viral vectors. Although claim 15 recites “[t]ransducing a
human patient’s cells with said viral vector,” the broadest reasonable
interpretation of “a human patient” encompasses any human and therefore “a
human patient’s cells” encompasses human cells generally. We therefore
find that Schauber anticipates claim 15.
Appellant argues:
Claim 12 requires a mammalian cell transduced with a
recombinant baculovirus. . . . [C]laims 15–17 depend from
claim 12. Claims 15–17 thus each require a mammalian cell
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transduced with a recombinant baculovirus. The Examiner has
already found that Schauber does not teach this. See Office
Action (March 2018) at 20:1–4. Schauber therefore cannot
anticipate claims 15–17.
Appeal Br. 25–26.
This argument is unpersuasive because, as discussed above, the step
of “[o]btaining the viral vector of Claim 12,” as recited in claim 15, simply
requires obtaining a viral vector having the properties recited in claim 12.
The mammalian producer cell, which is defined in claim 12 based on its
production of the same vector, plays no part in the method of claim 15 and is
therefore irrelevant to the steps of that method. Appellant in fact agreed with
the Examiner’s interpretation of the “obtaining” claim limitation as merely
requiring “any viral vector that is produced/generated from a mammalian
producer cell transduced with a recombinant baculovirus encoding necessary
components/elements for said viral vector.” Final Action 8–9 (emphasis
added); Reply Br. 5
In summary, Schauber discloses a method meeting all of the
limitations of claim 15. We affirm the rejection of claim 15 under 35 U.S.C.
§ 102(b) based on Schauber. Claims 16 and 17 fall with claim 15. 37 C.F.R.
§ 41.37(c)(1)(iv).
Obviousness
Claims 1–17 stand rejected as obvious based on Schauber, Leblois-
Prehaud, and Kingsman. The Examiner relies on Schauber for the teachings
discussed above. Final Action 20–21. The Examiner finds that Schauber
does not teach “each of a lentivirus transfer construct, gag, pol, an
envelope protein and rev being cloned into different baculoviruses and
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transducing a mammalian producer cell for generating a recombinant
replication-deficient lentivirus particle comprising a therapeutic transgene.”
Id. at 21.
The Examiner finds that Leblois-Prehaud teaches a method for
producing recombinant viruses “based on the use of one or more
baculoviruses for providing the complementary functions (e.g., gag, pol
and/or env for the retrovirus . . .) for the defective recombinant genome
in competent host cells,” including mammalian (293) host cells. Id. at 21–
22. The Examiner also finds that Leblois-Prehaud suggests therapeutic
transgenes. Id. at 22–23. The Examiner finds that “Kingsman also taught at
least the production of retroviral particles, including HIV particles, in a
baculovirus expression system (see at least the abstract). Kingsman taught
specifically expression of HIV gag-pol, VSV-G and an HIV-based vector
genome in a baculovirus expression system.” Id. at 23.
The Examiner concludes that it would have been obvious
to modify a lentiviral vector production method of Schauber et
al by also at least cloning Gag/Pol, Rev, VSVG and a lentivirus
transfer construct into at least 4 separate baculoviruses and
introducing the recombinant baculoviruses into a producer cell
such as 293T cells to generate a recombinant replication-
deficient lentivirus particle comprising a therapeutic transgene,
in light of the teachings of Leblois-Prehaud et al and Kingsman.
Id.
We reverse this rejection with respect to claims 1–11. “An examiner
bears the initial burden of presenting a prima facie case of obviousness.” In
re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). The test of
obviousness is “whether the teachings of the prior art, taken as a whole,
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would have made obvious the claimed invention.” In re Gorman, 933 F.2d
982, 986 (Fed. Cir. 1991).
Here, we conclude that the Examiner has not persuasively shown that
the cited references would have made obvious the inventions defined by the
independent claims on appeal. Claim 1 requires, among other things, “a
recombinant baculovirus comprising a transfer construct comprising a
packaging genome of a second virus.” Claim 1. As discussed above in the
context of indefiniteness, the meaning of a “packaging genome” is unclear
from the record. The Examiner suggests that it might mean “a genome of a
second virus to be packaged in the mammalian producer” (Final Action 7) or
“a genome of a second virus that is already packaged (packaging
genome)” (id. at 3–4). Appellant argues that a packaging genome is “a
genome (set of genes) coding for the various polypeptides required to
package the virus.” Appeal Br. 4.
However, the record lacks a definition of “packaging genome” or
evidence showing that those skilled in the art recognize a definite meaning
for the term. Because it is unclear what structure is required by the claim
language, we are unable to determine whether the cited references would
have made obvious an invention encompassed by claim 1, and dependent
claims 2–7. We therefore reverse the rejection of claims 1–7 under 35
U.S.C. § 103(a). See In re Steele, 305 F.2d 859, 862 (CCPA 1962).
Independent claim 8 requires, among other things, a recombinant
baculovirus having a nucleic acid sequence “obtained from a virus which in
its wild state has a single stranded genome, said second virus being
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replication-deficient.” Claim 8. The Examiner concludes that it would have
been obvious, based on Schauber, Leblois-Prehaud, and Kingsman, to
clon[e] Gag/Pol, Rev, VSVG and a lentivirus transfer construct
into at least 4 separate baculoviruses and introducing the
recombinant baculoviruses into a producer cell such as 293T
cells to generate a recombinant replication-deficient lentivirus
particle comprising a therapeutic transgene.
Final Action 23. The Examiner’s explanation of the rejection, however, fails
to address how the cited references would have made obvious the “single
stranded genome” and “replication-deficient” limitations of claim 8. We
therefore reverse the rejection of claim 8, and dependent claims 9–11, under
35 U.S.C. § 103(a).
We affirm the § 103(a) rejection with respect to claims 12–17. Claim
12 is directed to a “mammalian producer cell transduced with a recombinant
baculovirus, said mammalian producer cell producing viral vector able to
transfect a human cell which is not actively dividing, said viral vector
produced by a said mammalian producer cell being substantially free of
insect cell membrane.” Claim 12.
As discussed above with regard to the anticipation rejection of claims
15–17, Schauber teaches the production of lentiviral (HIV) vectors in 293T
(human embryonic kidney) cells. Schauber 28:16–20; 4:37–38. Schauber
also discloses that its pseudotyped HIV vector particles were able to
transduce human cells. Id. at 29:10–13, 21–22. And HIV is an example of a
virus that is able to transfect cells that are not actively dividing. Spec. 1:6–8.
However, Schauber does not disclose mammalian producer cells, transduced
with a recombinant baculovirus, that produce the viral vectors, as claimed.
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Leblois-Prehaud teaches a system for producing recombinant viral
vectors. Leblois-Prehaud 1:6–11. “The system of the invention is based on
the use of a baculovirus to provide the complementation functions.” Id. at
4:54–56. For example, “[t]he baculovirus may also comprise the gag, pol
and/or env regions of a retrovirus. A baculo-gag/pol/env thus makes it
possible to complement, in a line of competent cells, a retroviral genome
lacking any coding viral sequence.” Id. at 7:32–35.
Leblois-Prehaud teaches that “it was possible, with a recombinant
baculovirus, to infect cells of human origin such as immortalized embryonic
cells . . . [with] a very high transduction efficiency.” Id. at 5:55–59. Leblois-
Prehaud discloses that its baculovirus-based system has several advantages:
(a) “since the baculovirus does not replicate in human cells, the viral
preparation obtained is not contaminated by the baculovirus” (id. at 5:28–
30); (b) “the baculovirus constitutes an inert vector which can be
advantageously used for the transfer and expression of virus
complementation functions into mammalian, particularly human, cells” (id.
at 5:63–66); (c) “the large cloning capacity” of baculovirus (id. at 6:1); and
(d) “the advanced development of the technology of the baculovirus” (id. at
6:2–3).
We agree with the Examiner that it would have been obvious to a
person of ordinary skill in the art to modify Schauber’s retroviral packaging
system to use the baculovirus vectors taught by Leblois-Prehaud to express
the retroviral complementation functions (e.g., gag, pol, and an envelope
protein) in a mammalian producer cell (e.g., immortalized human embryonic
cells). Leblois-Prehaud provides sufficient reason to combine its teachings
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with Schauber’s, because Leblois-Prehaud teaches that its baculovirus-based
system has the advantage of allowing expression of virus complementation
functions in human cells without baculovirus contamination of the resulting
viral preparation, as well as the large cloning capacity of baculoviral vectors
and the advanced state of baculovirus technology.
Appellant argues that Leblois-Prehaud is non-enabled because it
“recommends using fibroblast, A549 and HepG2 producer cells. But those
cell lines don’t work.” Appeal Br. 27, citing Airenne Decl.7 ¶ 6. Dr. Airenne
states:
Carbonell (1987) teaches that baculovirus can penetrate
mammalian fibroblast cells and human A549 lung carcinoma
cells, yet is not able to transduce (evoke transgene expression
in) such cells. Our own unpublished development work
similarly shows baculovirus is not able to transduce HepG2
cells for the purpose in the patent (simultaneous transduction
with very high MOI and/or several viruses).
Airenne Decl. ¶ 6.
Even assuming that fibroblast, A549, and HepG2 cells would not
work in Leblois-Prehaud’s baculovirus-based system, however, Appellant’s
argument fails because Leblois-Prehaud suggests a variety of other cell
types. Leblois-Prehaud states:
Advantageously, the cells used are hepatic, muscular,
fibroblastic, embryonic, nerve, epithelial (pulmonary) or ocular
(retinal) cells. There may be mentioned, by way of nonlimiting
example, the cells 293 or any derived cell comprising an
additional complementation function (293E4, 293E2a, and the
like), the A549 cells, the HuH7 cells, the Hep3B cells, the

7 Declaration under 37 C.F.R. § 1.132 of Kari Airenne, filed Oct. 3, 2017.
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HepG2 cells, the human retinoblastic cells (HER, 911), the
HeLa cells, the 3T3 cells or the KB cells.
Leblois-Prehaud 16:15–21 (emphasis added). Thus, Leblois-Prehaud
specifically suggests using the 293 cells that are also used by Schauber (see
Schauber 28:16–20), and Appellant has presented no evidence, or even
argued, that 293 cells would not be suitable host cells for use in Leblois-
Prehaud’s system.
Appellant also argues that Leblois-Prehaud is non-enabling because
“baculovirus cannot infect human cells.” Appeal Br. 27, citing Airenne Decl.
¶ 4. Dr. Airenne states: “Baculovirus cannot infect mammalian cells. This
was true on the critical date. This remains true today.” Airenne Decl. ¶ 4.
This argument is unpersuasive. Appellant’s argument appears to be
based on their definition of “infection” as requiring viral replication in the
host cell. Appellant states that “[i]nfection requires the virus replicate in the
host cell, forming progeny which then spread to neighboring cells. . . .
Baculovirus cannot replicate in human cells.” Appeal Br. 9, footnote 5.
Leblois-Prehaud, however, relies on a different definition of “infection,”
because it expressly states that one of “the advantages of the system of the
invention” is that “since the baculovirus does not replicate in human cells,
the viral preparation obtained is not contaminated by the baculovirus.”
Leblois-Prehaud 5:23–30 (emphasis added).
Thus, when Leblois-Prehaud states that “the applicant has shown that
it was possible, with a recombinant baculovirus, to infect cells of human
origin such as immortalized embryonic cells” (id. at 5:55–57), it is not using
“infect” to indicate viral replication. Rather, Leblois-Prehaud characterizes
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baculovirus as “an inert vector” useful for “transfer and expression” of virus
complementation functions in human cells. Id. at 5:63–66.
Appellant also argues that Leblois-Prehaud “admonishes to avoid
Schauber’s gag, pol and env. Leblois says, ‘In the recombinant vectors
derived from retroviruses, the gag, pol and env genes are generally
deleted.’” Appeal Br. 28, citing Leblois-Prehaud 3:8–9.
This argument is unpersuasive. The section quoted by Appellant refers
to retroviral vectors that contain a transgene. The full sentence reads: “In the
recombinant vectors derived from retroviruses, the gag, pol and env genes
are generally deleted, completely or in part, and replaced by a heterologous
nucleic acid sequence of interest.” Leblois-Prehaud 3:8–11. Leblois-Prehaud
also states that, because the recombinant vectors lack gag, pol, and env, “the
production of these various recombinant viruses involves the possibility of
transcomplementing the functions deleted from the genome.” Id. at 16–19.
Leblois-Prehaud states that, in its system, “[t]he baculovirus may also
comprise the gag, pol and/or env regions of a retrovirus. A baculo-
gag/pol/env thus makes it possible to complement, in a line of competent
cells, a retroviral genome lacking any coding viral sequence.” Id. at 7:32–35.
Thus, Leblois-Prehaud also requires production of gag, pol, and env to
generate retroviral vectors.
Appellant argues that Leblois-Prehaud “also warns that Schauber’s
293 encapsidation cells ‘hardly make it possible to avoid the production of
replicative contaminant viruses.’” Appeal Br. 28, citing Leblois-Prehaud
4:9–10. Similarly, Appellant argues that Leblois-Prehaud “complains
Schauber’s cell lines ‘do not allow . . . in a satisfactory manner for an
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industrial use, very highly defective viral genomes’”; “warns that Schauber’s
encapsidation lines are ‘difficult, expensive and restrictive at the industrial
level to construct and to validate’”; and “complains that Schauber’s cell lines
do not enable one to ‘obtain very high recombinant retrovirus titres.’”
Appeal Br. 28–29, citing Leblois-Prehaud 4:11–15, 5–7, 30–32.
These arguments are unpersuasive, because Leblois-Prehaud does not
refer to Schauber’s 293 cell line in the relevant discussion. Leblois-Prehaud
states:
Various lines have also been described for the production
of defective retroviruses, generally capable of expressing the
gag, pol and env genes. Such lines are, for example, the PA317
line (U.S. Pat. No. 4,861,719), the PsiCRIP line
(WO90/02806), the GP+envAm-12 line (WO89/07150), the
BOSC line (WO94/19478) and the like.
Leblois-Prehaud 3:59–64. Leblois-Prehaud does not cite Schauber’s U.S.
Patent No. 6,863,884, and Appellant has not provided a persuasive basis for
concluding that Leblois-Prehaud’s discussion in the cited passages pertained
to Schauber as well as the specifically cited lines.
In addition, the discussion cited by Appellant refers to drawbacks of
prior art systems, not Leblois-Prehaud’s baculovirus-based system. Leblois-
Prehaud expressly states that its baculovirus system “makes it possible to
overcome these disadvantages.” Leblois-Prehaud 4:52–54. Thus, if a skilled
artisan would have read the cited disadvantages as applying to Schauber’s
system, they would have provided further reason to modify Schauber’s
system by using Leblois-Prehaud’s baculovirus-based system.
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Appellant argues that “Leblois requires VSV-G. Schauber at 1:61–63
warns that Leblois’ VSV-G is cytotoxic to producer cells, thus lowering
producer cell yield.” Appeal Br. 29.
This argument is unpersuasive for several reasons. First, Appellant
points to no basis for the position that Leblois-Prehaud requires using
VSV-G. Leblois-Prehaud states that its baculovirus “may also comprise the
gag, pol and/or env regions of a retrovirus” (Leblois-Prehaud 7:32–33) and
therefore suggests an envelope protein in general, rather than VSV-G
specifically. Second, Schauber discloses that the problem referred to in the
passage cited by Appellant can be solved by expressing VSV-G under the
control of a repressible or inducible promoter. Schauber 1:65 to 2:5. Finally,
Schauber’s invention involves “pseudotyping of retroviruses with
baculoviral envelope proteins,” which “provides an alternative to
pseudotyping retroviruses with VSV-G.” Id. at 3:1–4. Thus, combining the
components of Schauber’s retroviral packaging system with Leblois-
Prehaud’s baculovirus vectors avoids the known drawback of using VSV-G.
For the reasons discussed above, we affirm the rejection of claim 12
under 35 U.S.C. § 103(a) based on Schauber, Leblois-Prehaud, and
Kingsman. Claims 13–17 fall with claim 12 because they were not argued
separately. 37 C.F.R. § 41.37(c)(1)(iv).
Provisional Obviousness-type Double Patenting
Claims 1–14 stand provisionally rejected based on obviousness-type
double patenting based on claims 1–7 and 10 of application 12/522,646.
Final Action 35–36. Appellant does not present any arguments regarding the
provisional double patenting rejection in the Appeal Brief or Reply Brief.
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We therefore affirm it. See 37 C.F.R. § 41.37(c)(1)(iv) (The Appeal Brief
must contain “[t]he arguments of appellant with respect to each ground of
rejection.”); MPEP § 1205.02 (9th Ed., Rev. 08.2017 (Jan. 2018)) (“If a
ground of rejection stated by the examiner is not addressed in the appellant’s
brief, appellant has waived any challenge to that ground of rejection and the
Board may summarily sustain it.”).
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–7, 11–17 112, second
paragraph
Definiteness 1–7, 11 12–17
1–8, 163-9-
2–17
112, first
paragraph
Written Description 1–8, 12–17
9, 10 112, fourth
paragraph
Dependent Form 9, 10
1–17 102(b) Leblois-Prehaud 1–17
15–17 102(b) Schauber 15–17
1–17 103(a) Schauber, Leblois-
Prehaud, Kingsman
12–17 1–11
1–14 Provisional
Obviousness-type
Double Patenting
1–14
Overall
Outcome
1–17
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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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED