Ex Parte MABASHI-ASAZUMA et al

Patent Trial and Appeal Board

Jan 2, 2019

14504195 (P.T.A.B. Jan. 2, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/504,195 10/01/2014 HIDEAKI MABASHI-ASAZUMA
110 7590 01/03/2019
DANN, DORFMAN, HERRELL & SKILLMAN
1601 MARKET STREET
SUITE 2400
PHILADELPHIA, PA 19103-2307
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
3309-P06081USOO 1049
EXAMINER
BROWN, MINDY G
ART UNIT PAPER NUMBER
1636
MAIL DATE DELIVERY MODE
01/03/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HIDEAKI MABASHI-ASAZUMA and
DONALD L. JARVIS 1
Appeal2018-000093
Application 14/504, 195
Technology Center 1600
Before ULRIKE W. JENKS, JOHN G. NEW, and DAVID COTTA,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants identify The University of Wyoming as the real party-in-
interest. App. Br. 3.
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Application 14/504, 195
SUMMARY
Appellants file this appeal under 35 U.S.C. § I34(a) from the
Examiner's Final Rejection of claims 1-11, 18-21, 23, 24, and 25 as
unpatentable under 35 U.S.C. 103(a) over the combination of Jarvis (US
6,461,863 Bl, October 8, 2002) ("Jarvis") and Sandig et al. (US
2012/0214975 Al, August 23, 2012) ("Sandig"). 2
We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to compositions for reducing
fucosylation of glycoproteins in insect cells and methods of use of such
compositions for the production of recombinant humanized proteins.
Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A recombinant baculovirus expression vector for
transient expression of GDP-4-dehydro-6-deoxy-D-mannose
reductase (RMD) for producing a protein of interest having a
stable fucose negative phenotype in an insect cell, said vector
comprising the following operably linked components,
2 The Examiner also rejected claims 11 and 24 as unpatentable under 35
U.S.C. § 112, second paragraph, for failing to particularly point out and
distinctly claim the subject matter. Final Act. 3. The Examiner has
withdrawn this rejection. See Advisory Act., August 19, 2016, at 4.
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i) an expression control sequence functional early in
infection operably linked to a codon optimized RMD
encoding nucleic acid, early expression of said RMD
reducing endogenous GDP-L-fucose levels; and
ii) an insertion site suitable for insertion of one or more
nucleic acids encoding at least one heterologous
protein of interest, having a stable fucose-negative
phenotype.
App. Br. 28 (emphasis added).
ISSUES AND ANALYSES
We adopt the Examiner's findings, reasoning, and conclusion that the
claims are prima facie obvious over the combined cited prior art. We
address the arguments raised by Appellants below.
A. Claims 1-11, 18-21, and 23-25
Issue 1
Appellants argue that the combined cited prior art fails to teach or
suggest all of the limitations of the claims on appeal. App. Br. 16.
Analysis
The Examiner finds that Jarvis teaches a recombinant baculovirus
expression vector for transient expression of an oligosaccharide-processing
enzyme in an insect cell. Final Act. 4 (citing Jarvis col. 1, 11. 18-19; col. 2,
11. 28--43; col. 51, 11. 31-32). The Examiner finds that Jarvis teaches a vector
comprising the following operably-linked components: an expression control
sequence functional early in infection operably linked to a codon optimized
an oligosaccharide-processing enzyme encoding nucleic acid; and an
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insertion site suitable for insertion of one or more nucleic acids encoding at
least one heterologous protein of interest. Id. at 4--5 (citing Jarvis col. 2, 11.
28--43; col. 10, 11. 9--13; col. 4, 11. 24--34).
The Examiner finds, however, that Jarvis fails to expressly teach
GDP-4-dehydro-6-deoxy-D-mannose reductase ("RMD"). Final Act. 6.
The Examiner finds that Sandig relates to oligosaccharide processing
enzymes, and teaches an expression unit encoding RMD. Id. ( citing Sandig
Abstr., ,r,r 30-33, 94). The Examiner concludes that it would have been
obvious to a person of ordinary skill in the art to modify the recombinant
baculovirus expression vector taught by Jarvis to include RMD to develop
recombinant baculovirus expression vectors for transient expression of
various oligosaccharide-processing enzymes, including RMD. Id. at 6-7.
The Examiner further concludes that, given the teachings of the prior art and
the level of ordinary skill in the art, a skilled artisan would have had a
reasonable expectation of success in practicing the claimed invention. Id. at
7.
Appellants point to their Specification to document their past efforts
attempting to block recombinant glycoprotein fucosylation in the
baculovirus-insect cell system, using an approach previously used to block
core al,6-fucosylation in Chinese hamster ovary ("CHO") cells genetically
transformed to overexpress RMD. App. Br. 16 (citing Spec. 30-32).
Appellants note that, although they were able to isolate Sf9 and Hi5â„¢
subclones that initially had fucose-negative phenotypes, and were able to
produce a non-fucosylated recombinant glycoprotein, the fucose-negative
phenotype of these cell lines was unstable, and that both insect cell lines
resulting from this original effort reverted to fucose-positive phenotypes
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after only a small number of passages in culture. Id. According to
Appellants, it was not until the allegedly novel baculoviral vectors of claims
1-3 were designed and tested that Appellants were able to achieve the goal
of producing a genetically stable baculovirus-insect cell system that could be
used to produce heterologous proteins of interest lacking fucosylation. Id. at
16-1 7. Appellants assert that this outcome was surprising, and in no way
predictable from the teachings of Jarvis or Sandig. Id. at 17.
Appellants argue that Jarvis teaches that early and late promoters are
interchangeable, and does not address temporal control of expression nucleic
acids within the vector to produce a desired result. App. Br. 17. Appellants
contend that another problem their invention overcomes is the inability of
the prior art to produce non-fucosylated antibodies which have higher levels
of effector function when expressed in the baculovirus-insect cell system,
and that this result was also not at all predictable from the teachings of Jarvis
and Sandig. Id.
Appellants therefore argue that there could have been no reasonable
expectation of success in combining the references, because Jarvis and
Sandig provide no basis for expecting that a recombinant baculovirus
expression vector having the ability to transiently express RMD immediately
after infection would successfully yield therapeutic proteins having a stable
fucose-negative phenotype. App. Br. 17. Appellants assert that the
importance of the timing of RMD expression cannot be overstated because it
was necessary to deplete endogenous cellular levels of GDP-fucose prior to
the onset of production of the foreign protein in baculovirus-infected cells.
Id. Appellants contend that neither Jarvis nor Sandig teaches or suggests to
a person of ordinary skill in the art any reasonable expectation of the
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successful functioning of the claimed baculovirus vector and kit for the
production of non-fucosylated products. Id.
Appellants further contend that Jarvis neither teaches nor suggests an
appreciation of any of the problems experienced by Appellants in the
development of their claimed invention. App. Br. 18. Notably, Appellants
argue, Jarvis teaches, in relevant part, a baculovirus expression vector
comprising at least a first glycosylation enzyme transcriptional unit
including a structural gene encoding an oligosaccharide-processing enzyme,
with the gene operatively positioned under the control of a baculoviral
immediate early, delayed early, early or late promoter. Id. (citing Jarvis col.
2, 11. 38--43). Appellants assert that this teaches nothing more than that any
one of the listed promoters would function equally well as any other in
practicing the Jarvis invention. Id. at 18-19. Furthermore, Appellants
argue, the baculoviral vectors of the present invention are designed to limit
or prevent fucosylation whereas the enzymes of Jarvis are designed to add
to, or modify oligosaccharide moieties on a target protein of interest. Id. at
19.
Appellants argue that, although Sandig acknowledges the problem of
high immunogenicity exhibited by the recombinant glycoproteins produced
by cell lines, Appellants assert that Sandig neither teaches nor suggests any
solution to that problem. App. Br. 19. Appellants contend that, like Jarvis,
Sandig reflects no preference for, or appreciation of the importance of
immediate RMD transient expression for successfully overcoming the
problems experienced by Appellants in the development of their invention.
Id. Therefore, Appellants argue, the motivation to combine the teachings of
the references cannot be found without impermissibly employing hindsight
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reconstruction of the invention using Appellants' Specification as a guide.
Id.
With respect to the Examiner's finding that Sandig teaches the general
conditions of the claimed invention, Appellants assert that there is nothing in
Sandig that would lead a person of ordinary skill in the art to construct a
recombinant baculovirus vector having a control sequence functional early
in infection and operably linked to a codon-optimized RMD-encoding
nucleic acid to produce one or more proteins of interest having a stable,
fucose-negative phenotype. App. Br. 19. Rather, Appellants argue, Sandig
exemplifies the introduction of a constitutively expressed RMD gene, which
the present inventors demonstrate is unsuccessful in a baculovirus-insect cell
system. Id.
Furthermore, Appellants argue, given that Jarvis teaches a nucleic
acid detection kit that lacks essential elements of Appellants' claims because
it does not include a baculoviral vector for early and transient expression of
RMD and a late promoter for driving expression of a therapeutic protein of
interest, Appellants assert that the Examiner cannot reasonably conclude that
claims 18-21 are rendered unpatentable over the teachings of the cited prior
art references. App. Br. 19-20.
We do not find Appellants' arguments persuasive. As an initial
matter, Appellants argue that the combined cited prior art references do not
teach all of the limitations of the claims, but Appellants, in their Appeal
Brief, do not expressly indicate which limitations of the claims are not
taught or suggested by the references. Rather, we understand the gravamen
of Appellants' arguments to be that a person of ordinary skill in the art
would have had no expectation of success in combining the teachings of
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Jarvis and Sandig, because the references provide no basis for expecting that
a recombinant baculovirus expression vector having the ability to transiently
express RMD immediately after infection, and with later expression of the
protein of interest, would successfully yield therapeutic proteins having a
stable fucose-negative phenotype. See App. Br. 17. In other words,
Appellants argue that the combined references would not lead a person of
ordinary skill in the art to understand the temporal separation of enzyme
expression and protein expression, as recited in some of the claims, e.g.,
independent claim 3. Appellants also argue that the Examiner has derived
the motivation for combining the references solely from the disclosures of
Appellants' Specification, and thus impermissibly employed hindsight
reasoning. See id. at 19. We find neither argument persuasive.
Appellants' claim 1 recites, in relevant part: "an expression control
sequence functional early in infection operably linked to a codon optimized
RMD encoding nucleic acid, early expression of said RMD reducing
endogenous GDP-L-fucose levels." Appellants assert that having the
expression control sequence be functional early in infection is essential to
the success of their claimed invention because, by that mechanism,
endogenous cellular levels of GDP-fucose are depleted prior to the onset of
production of the foreign protein in baculovirus infected cells. See App. Br.
17.
However, Jarvis teaches that:
The present invention overcomes the drawbacks in the
prior art by providing new and improved baculoviral expression
vectors, insect cell lines, compositions and various methods of
use. The invention first provides a baculovirus expression vector
characterized as: . . . comprising at least a first glycosylation
enzyme transcriptional unit, the transcriptional unit comprising a
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structural gene encoding an oligosaccharide processing enzyme,
the gene operatively positioned under the control of a
baculoviral immediate early, delayed early, early or late
promoter.
Jarvis col. 2, 11. 28--43 (emphasis added). In other words, Jarvis expressly
teaches that the baculovirus expression vector comprises the transfected
gene encoding an "oligosaccharide processing enzyme" that is operatively
positioned under the control of a baculoviral early promotor.
Furthermore, independent claim 3 additionally requires: "ii) an
insertion site suitable for insertion of one or more nucleic acids encoding at
least one heterologous protein of interest operably linked to a promoter
active later in infection for production of said protein(s) of interest having a
stable fucose-negative phenotype." Appellants contend that the references
do not teach that the protein of interest is operably linked to a promoter
active later in infection, i.e., temporally separated from the early promotion
of the synthesis of the enzyme gene. See, e.g., App. Br. 18; Reply Br. 4--5.
Indeed, Appellants argue, such is the key element of their invention. Id.
However, we find that Jarvis expressly teaches:
In particular aspects of the present invention, the vectors
further comprise a baculovirus structural gene, with gp64, p 10
and/or polyhedrin being preferred examples.
Certain embodiments of the present invention include at
least one heterologous structural gene encoding a selected
protein, the gene operatively positioned under the control of and
in frame with, a promoter. Preferred are baculoviral promoters,
more preferred are very late baculoviral promoters, and
particularly preferred are the polyhedron and/or plO promoter.
Alternatively the promoter is a promoter naturally associated
with the heterologous structural gene.
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Jarvis col. 4, 11. 24--42 (emphasis added). Jarvis thus teaches that expression
of the enzyme preferably promoted early in infection (see col. 2, 11. 28--43)
whereas the structural protein (i.e., the "protein of interest" of the claims) is
promoted preferably later following transfection. We agree with the
Examiner that a person of ordinary skill in the art would understand that
Jarvis thus teaches or suggests a temporal separation between early
promotion of the enzyme gene and later promotion of the gene encoding the
protein of interest, as recited in claim 3.
Although it is true that Jarvis does not teach RMD, Sandig teaches an
expression unit that comprises: "a polynucleotide comprising a [transfected]
nucleic acid sequence encoding an enzyme which uses GDP-6-deoxy-D-
lyxo-4-hexulose as a substrate, wherein the enzyme does not catalyze the
reaction which converts GDP-6-deoxy-D-lyxo-4-hexulose into GDP L-
fucose," and that, preferably, "the enzyme which uses GDP-6-deoxy-D-
lyxo-4-hexulose as a substrate is selected from the group consisting of GDP-
6-deoxy-D-lyxo-4-hexulose reductase (synonym[ous] with GDP-4-keto-6-
deoxy-D-mannose reductase, abbreviated RMD)." Sandig ,r,r 32, 33, 94.
Production of non-fucosylated glycoproteins is desirable because, as Sandig
teaches, such glycoproteins are less immunogenic:
The lack of fucose on glycoproteins has been shown to have
specific advantages. For example, in monoclonal antibodies,
immunoglobulins, and related molecules, it has been shown that
absense [sic] of the core fucose sugar from the N-glycan attached
to Asn297 of the Fe portion (CH2 domain) of immunoglobulins
increases or alters its binding to Fe receptors.
Id. at ,r 8. We therefore agree with the Examiner that a person of ordinary
skill in the art would have been motivated to combine the system of Jarvis
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with the gene for the enzyme taught by Sandig to produce non-fucosylated
glycoproteins of interest.
Appellants argue that a person of ordinary skill in the art would not
have had a reasonable expectation of success in combining the references
because, based on their experience, expression of the enzyme has to be
under control of a baculovirus early promoter. However, Appellants point to
no teaching of either Jarvis or Sandig that teaches or suggests that
combining the references could not reasonably be expected to be successful.
See, e.g., In re Langi, 795 F.2d 887,897 (Fed. Cir. 1985) (holding that only a
reasonable expectation of success, not absolute predictability, is necessary
for a conclusion of obviousness). More importantly, Jarvis expressly
teaches that expression of the enzyme gene can be under the control of a
baculoviral immediate early, delayed early, early or late promoter. See
Jarvis col. 2, 11. 42-53. We agree with the Examiner that a person of
ordinary skill in the art would reasonably expect success in combining the
teachings of Jarvis and Sandig to arrive at the claimed invention.
Nor are we persuaded by Appellants' argument that the Examiner
impermissibly arrived at a motivation to combine the references through
hindsight analysis. We have explained supra why a person of ordinary skill
would have been motivated to combine the references, i.e., to adapt the
system of Jarvis to transfect a structural enzyme that produces RMD, as
taught by Sandig. Furthermore:
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
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In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Because we have
found that the references establish a motivation to combine the references,
we cannot agree with Appellants that the Examiner impermissibly relied on
hindsight analysis to establish a motive to combine.
Issues 2 and 3
Appellants argue that a person of ordinary skill in the art would not
have been motivated to combine the references to arrive at the claimed
invention. App. Br. 20. Appellants also argue that a person of ordinary skill
in the art would have had no reasonable expectation of success in combining
the references. Id. at 22.
These arguments are essentially reiterative of those argued supra, and
we find them no more persuasive upon repetition. We consequently affirm
the Examiner's rejection on this ground.
B. Claim 3
Issue
Appellants argue claim 3 separately. App. Br. 22. Claim 3 recites:
3. A recombinant baculovirus expression vector for transient
expression of GDP-4-dehydro-6-deoxy-D-mannose reductase
(RMD) for producing a protein of interest having a stable fucose
negative phenotype in an insect cell, said vector comprising the
following operably linked components,
i) an expression control sequence functional early in infection
operably linked to a codon optimized RMD encoding nucleic
acid, early expression ofRMD reducing endogenous GDP-L-
fucose levels;
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ii) an insertion site suitable for insertion of one or more nucleic
acids encoding at least one heterologous protein of interest
operably linked to a promoter active later in infection for
production of said protein(s) of interest having a stable
fucose-negative phenotype.
Id. at 28. Appellants contend that the Examiner has not articulated a reason
by which a person of ordinary skill in the art would have been motivated to
combine the references. Id. at 23.
Analysis
Appellants again rely upon the arguments presented supra that the
Examiner has not articulated a reason by which a person of ordinary skill in
the art would have been motivated to combine the references. App. Br. 23.
We note that we have expressly addressed the limitations of claim 3 in our
analysis, supra. We are not persuaded by Appellants' argument, for the
reasons that we have explained, and we affirm the Examiner's rejection of
claim 3.
C. Claim 18 and its dependent claims 19--21
Issue
Appellants argue that the combined references neither teach nor
suggest a kit comprising at least one nucleic acid molecule encoding an
oligosaccharide processing enzyme. App. Br. 24.
Analysis
Appellants contend that the term "kit" appears only once in Jarvis.
App. Br. 24 ( citing Jarvis col. 11, 11. 25-37). Appellants argue that this
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single use of the term "kit" in Jarvis is insufficient as teaching or suggesting
the kit of claim 18. Id.
Appellants note that the Examiner acknowledges that Jarvis fails to
explicitly disclose a baculovirus comprising RMD driven by an immediate
early expression control sequence for stabilizing inhibition of fucosylation
and an insertion site for later expression of a non-fucosylated therapeutic
protein of interest. App. Br. 2 5. Appellants therefore dispute the
Examiner's contention that it would have been obvious to modify the nucleic
acid detection kit of Jarvis described above to include baculoviral vectors for
stabilizing inhibition of fucosylation for production of a non-fucosylated
protein of interest. Id.
The Examiner responds that the combination of Jarvis and Sandig
teaches the limitations of claims 18-21. Ans. 11. The Examiner finds that a
kit is comprised of parts or elements which are taught by the combination of
references and that a person of ordinary skill in the art would be motivated
to combine the elements so as to develop effective kits that can be used to
produce a protein of interest lacking fucose. Id.
We are not persuaded by Appellants' arguments. Claim 18 recites:
18. A kit for the production of at least one protein of interest
lacking fucose or with a reduced amount of fucose comprising at
least one recombinant baculovirus comprising at least one
nucleic acid molecule encoding the enzyme GDP-4-dehydro-6-
deoxy-D-mannose reductase (RMD) operably linked to an
immediate early expression control sequence for expression
early after infection, thereby reducing endogenous GDP-L-
fucose levels, and an insertion site for at least one additional
nucleic acid molecule encoding at least one protein of interest
operably linked to a control sequence for expression later in
infection for production of at least one protein of interest having
a stable fucose-negative phenotype due to early expression of
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said RMD mediated by said immediate early express10n
sequence.
Claim 18 thus recites no additional limiting structural requirements
for a "kit" than does independent composition claim 3, or the other claims
on appeal, other than the preambular language reciting the term "kit." We
cannot differentiate this from the "kit" recited in the relevant claims on
appeal at issue in AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042 (Fed. Cir.
2010), which included a "kit claim," included a limitation reciting: "a label
indicating administration by nebulization in a continuing regimen at a
frequency of not more than once per day." AstraZeneca, 633 F.3d at 1048.
However, this additional limitation notwithstanding, the Federal Circuit held
that, because the printed label added no patentable weight to the remaining
limitations, all of which were already known in the prior art, the claims were
invalid. Id. at 1065.
Here, the analysis is even simpler. Claim 18 and its dependents
provide no structural limitation regarding the constitution of the preambular
term "kit" beyond the limitations of the composition claims, e.g., claim 3,
that we have already concluded are obvious over the combined cited prior
art. Indeed, claim 18 and its dependents provide no limiting requirement
with respect to what actually may constitute a "kit" beyond the composition
of claim 3. Nor do the disclosures of Appellants' Specification enlighten us
as to what may constitute a "kit" beyond the limitations recited in claim 18,
claim 3, and the other claims on appeal. See Spec. 5.
We consequently agree with the Examiner's conclusion that the
limitations of claim 18 would have been obvious to a person of ordinary skill
in the art. We consequently affirm the Examiner's rejection of claim 18, and
dependent claims 19-21.
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DECISION
The Examiner's rejection of claims 1-11, 18-21, and 23-25 under 35
U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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