Ex Parte Fujiyama et al

Patent Trial and Appeal Board

Sep 20, 2016

11649720 (P.T.A.B. Sep. 20, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
11/649,720 01/04/2007
23628 7590 09/22/2016
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC A VENUE
BOSTON, MA 02210-2206
FIRST NAMED INVENTOR
Kazuhito Fujiyama
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.
P0850.70004US01 6512
EXAMINER
WORLEY, CATHY KINGDON
ART UNIT PAPER NUMBER
1662
NOTIFICATION DATE DELIVERY MODE
09/22/2016 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):
Patents_eOfficeAction@WolfGreenfield.com
WGS_eOfficeAction@WolfGreenfield.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte KAZUHITO FUJIYAMA, TA TSUJI SEKI, and
NAOYUKI TANIGUCHI1
Appeal2015-000604
Application 11/649,720
Technology Center 1600
Before FRANCISCO C. PRATS, TA WEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
transformed plant cell, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
STATEMENT OF THE CASE
Plant cells have been modified through genetic engineering to produce
proteins and glycoproteins. (Spec. 1--4.) "The advantage of using plant cells
or plants for the production of useful proteins [as compared to E.coli, for
1 Appellants identify the Real Party in Interest as Phyton Holdings, LLC.
(Br. 3.)
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Application 11/649,720
example,] is that plant cells and plants are capable of adding a sugar chain to
a protein [like animal cells do]." (Spec. 4-5.) However, "plants have a
sugar chain addition mechanism different from that of animals, particularly
that of humans." (Spec. 5.) The claimed invention relates to transforming a
plant cell with an animal al,6-fucosyl transferase, "which does not
originally exist in plant cells," and that provides "an animal-type sugar chain
adding function" to the plant cell (Spec. 9; Br. 15 (claim 1).)
Claims 1, 3, 9-12, and 17-22 are on appeal. 2 Claim 1 is
representative and reads as follows:
(Br. 15.)
1. A plant cell having an animal-type sugar chain adding
function, wherein the plant cell has an introduced DNA
encoding an animal al,6-fucosyl transferase, wherein the
fucosyl transferase transfers a fucose residue in an al,6-
linkage to a reducing terminal acetylglucosamine residue of
a sugar chain of a glycoprotein in a plant cell, and wherein
the glycoprotein in the plant cell is an antibody expressed in
the plant cell.
2 Claims 4-7 are also pending, but stand withdrawn from consideration.
(Appeal Br. 15-16.)
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Application 11/649,720
The following ground of rejection by the Examiner is before us on
review:
Claims 1, 3, 9-12, and 17-22 under 35 U.S.C. § 103(a) as
unpatentable over Chrispeels,3 Taniguchi,4 and Rishi. 5
DISCUSSION
The Examiner finds that Chrispeels teaches "that plants are well-
suited for the production of large amounts of glycoprotein [including
Immunoglobulin (IgG)] at a low cost" and that "it is desirable to employ a
strategy that will result in a recombinant glycoprotein that has more
mammalian-like glycans" such as "by adding new enzymes via
transformation of the plant to modify the enzyme complement of the Golgi."
(Ans. 3--4; Final Action 3--4.) The Examiner notes that Chrispeels also
teaches engineering plant cells using well known methods, such as gene
silencing, "to knock out genes that encode Golgi enzymes," such as fucosyl
transferase and xylosyl transferase. (Ans. 4-5; Final Action 4-5.) The
Examiner further notes that Chrispeels shows there are five differences
between the glycans of human glycoproteins synthesized in plants as
compared to those synthesized in humans:
1) al,3 fucose vs. al,6 fucose;
2) B 1,2 xylose vs. no xylose;
3 Chrispeels et al., The Production of Recombinant Glycoproteins with
Defined Non-Immunogenic Glycans, In: Transgenic Plants: A Production
System for Industrial and Pharmaceutical Proteins, John Wiley Pub., UK,
99-113 (1996).
4 Taniguchi et al., US 6,054,304, issued Apr. 25, 2000.
5 Rishi et al., Molecular Farming in Plants: A Current Perspective, 10 J.
Plant Biochem. & Biotech., 1-12 (2001).
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Application 11/649,720
3) absence of additional GlcNac on high mannose vs. j31,2 and j31,4
GlcNAc
4) absence of galactose vs. j31,4 galactose
5) absence of sialic acid vs. a2,3 sialic acid,
and states that it is necessary to "figure out how to minimize or eliminate the
differences." (Ans. 8-9.)
The Examiner further notes that Chrispeels teaches "successfully
express[ing] human GnT-1 in plant cells."6 (Ans. 4; Final Action 4.)
The Examiner recognizes that Chrispeels does not teach expressing
al,6-fucosyl transferase, a mammalian enzyme leading to glycans that
include fucose linked with a-1,6-linkages, rather than the plant glycans
having a-1,3-linkages. (Ans. 4; Final Action 4.) The Examiner concludes,
however, that modifying plant cells to include al,6-fucosyl transferase, to
address a known difference between plants and mammals, would have been
obvious in light of the prior art, including Chrispeels' suggestion of
"modification of plants' glycosylation machinery to bring it as close to
human-type glycosylation as possible." (Ans. 8.) The Examiner explains
that Taniguchi teaches "the production of recombinant a-1,6-fucosyl
transferase in COS-1 cells" and "suggest[ s] that the host cells can be plant
cells, such as tobacco cells, Arabidopsis cells, and the like," and Rishi
teaches "that plants are ideal candidates as host systems for producing
recombinant proteins; such as antibodies, enzymes, hormones, and vaccines"
6 GnT-1 refers to GlcNAc-transferase I, an enzyme active in the Golgi that is
key to complex glycan biosynthesis in both plant and animal cells.
( Chrispeels 10 3-104.)
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Application 11/649,720
and identifies a number of varying proteins successfully produced in plants.
(Ans. 5-6; Final Action 4-5.) The Examiner finds that in light of the level
of skill in the art of molecular biology, including being "well-versed in
techniques for heterologous expression of recombinant proteins," and the
foregoing art teachings, it would have been obvious to express the cDNA
encoding al,6-fucosyl transferase taught by Taniguchi in a plant cell as
taught by Chrisp eels to generate a transformed cell "coexpressing a-1, 6-
fucosyl transferase and a recombinant antibody of interest, such as an IgG."
(Ans. 6; Final Action 5-6.) The Examiner further finds that it would have
been obvious to further modify the "plants to knock out the endogenous a-
1,3-fucosyl transferase and B-1,2-xylosyl transferase, because Chrispeels []
specifically teach that it would be possible to knock out any enzyme in this
pathway and produce glycans without either plant-type fucose or xylose."
(Ans. 6-7; Final Action 6.) The Examiner notes that one of ordinary skill
would have had a reasonable expectation of success because not only is the
prior art "replete with examples of successfully producing recombinant
mammalian enzymes in plants," Taniguchi was "successful in producing
recombinant a-1,6-fucosyl transferase [and] specifically suggest[s] plant
cells as hosts [for producing recombinant al,6-fucosyl transferase]." (Ans.
7; Final Action 6.)
We agree with the Examiner's factual findings and conclusion that the
claimed transformed plant cell would have been obvious from Chrispeels,
Taniguchi, and Rishi.
We disagree with Appellants that the cited references would not have
motivated one of ordinary skill in the art to introduce al,6-fucosylation into
plant cells (Br. 6-8). In particular, we disagree with Appellants that none of
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Application 11/649,720
"Chrispeels, Taniguchi, and Rishi provides any insight as to potential
biological benefits that might result from al,6-fuc[ o ]se residues ofN-glycans
in a glycoprotein" (Br. 8). As the Examiner notes, Chrispeels provides such
insight. (Ans. 8-10.) In particular, Chrispeels delineates the following
differences in the plant and mammalian glycosylation machinery:
1) plants add al,3 fucose whereas animals add al,6 fucose;
2) plants add B 1,2 xylose whereas animals add no xylose;
3) plants do not add additional GlcNac on high mannose whereas
animals add Bl,2 and Bl,4 GlcNAc
4) plants do not add galactose whereas animals add Bl,4 galactose
5) plants do not add sialic acid whereas animals add a2,3 sialic acid.
(Chrispeels 101-104, 109-110; Ans. 8-9.) Chrispeels further suggests that
all of these differences should be "minimized or eliminated" if possible to
use plants as hosts for the production of recombinant glycoproteins.
( Chrispeels 101; Ans. 8-9.) The fact that Chrispeels discloses "knocking out
genes encoding Golgi enzymes to block the formation of immunogenic N-
glycans, and adding genes involved in sialylation to produce glycoproteins
having elongated half-life" (Br. 7) does not take away from Chrispeels' clear
suggestion to modify "plants' glycosylation machinery to bring it as close to
human-type glycosylation as possible" (Ans. 8), including eliminating the
plant function of adding al,3 fucose and conferring on the plant the function
of adding al,6 fucose. Regarding whether one of ordinary skill in the art
would have known and been motivated to express al,6-fucosyl transferase
in the Golgi of the plant cell, as the Examiner noted (Ans. 11 ), "Chrispeels
clearly teaches that the required substrate [for al,6-fucosyl transferase
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Application 11/649,720
expressed in a plant cell] is present in the Golgi of plant cells." (Chrispeels
102 (Fig. 2.3), 104 (Fig. 2.4).)
Moreover, we disagree with Appellants that the prior art teaches away
from the claimed invention because "at the time the instant application was
filed[] al,6 fucose was deemed as undesirable[,] at least in the context of
therapeutic antibodies." (Br. 9). Claim 1 does not require "an antibody
having antibody-dependent cell-mediated cytotoxic activity" (see Br. 15
(claim 1 )). Thus, that
US20020098527 explicitly states:
[0236] A host cell for producing an antibody having antibody-
dependent cell-mediated cytotoxic activity is preferably a cell
having a low enzyme activity or no enzyme activity relating to
a reaction in which fucose is added to N-acetylglucosamine
bound to the Fe region of the antibody. Emphasis added.
(Br. 9 (bold emphasis added)), does not teach away from the claimed
invention. "A reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be discouraged from
following the path set out in the reference, or would be led in a direction
divergent from the path that was taken by the applicant." In re Kubin, 561
F.3d 1351, 1357 (Fed. Cir. 2009) (quoting In re Gurley, 37 F.3d 551, 553
(Fed. Cir. 1994)). Since claim 1 does not have a requirement that the plant
cell producing an antibody has antibody-dependent cell-mediated cytotoxic
activity, the above quoted passage from US20020098527 cannot be said to
discourage one of ordinary skill in the art from adding al,6-fucosyl
transferase to a plant host cell to add fucose residues to a co-expressed
antibody in a-1,6-linkage. Likewise, in the absence of such a limitation, the
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Application 11/649,720
quoted passage does not lead one of ordinary skill in the art toward a
divergent path.
And, in any event, even as to a host cell for producing an antibody
having antibody-dependent cell-mediated cytotoxic activity, the US
20020098527 teaching cited by Appellants merely expresses a preference,
which is not a teaching away. See, e.g., DePuy Spine v. Medtronic, 567 F.3d
1314, 1327 (Fed. Cir. 2009) ("A reference does not teach away ... ifit
merely expresses a general preference for an alternative invention but does
not 'criticize, discredit, or otherwise discourage' investigation into the
invention claimed.") (quoting In re Fulton, 391 F .3d 1195, 1201 (Fed. Cir.
2004)).
Appellants' argument that there is "high unpredictability as to how a
mammalian glycosyltransferase would behave in plant cells [and] ... no
reasonable expectation that a-1,6-fucosylT [("al,6-fucosyl transferase")]
expressed in a plant cell [ c ]ould function to add fucose residues to a co-
expressed glycoprotein in a-1,6-linkage" (Br. 10-13) is also not well
founded. According to Appellants, Henquet7 "reflects that as of 2010, nine
years after filing of the instant application, the state of the art still viewed the
activity of mammalian glycosyltransferases in plant cells as highly
unpredictable and those skilled in the art lacked knowledge to predict how a
heterologous glycosyltransferase would behave in plant cells." (Br. 12.)
Appellants further point out that the subcellular location of the transferase,
i.e., in the Golgi, is important for its functioning because the transferase has
7 Henquet et al., Differential effects of human and plant N-
acetylglucosaminyltransferase I (GnTI) in plants, 19 Transgenic Res., 535-
547 (2010)
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Application 11/649,720
"rigid substrate requirements." (Br. 10-11.) According to Appellants,
because none of the references "provides any information as to the
subcellular localization of an a-1, 6-fucosyl transferase expressed in plant
cells" or how it "would behave inside the plant cells," there is "no evidence
showing whether al,6-FucT [("al,6-fucosyl transferase")] could successfully
integrate into the plant N-glycosylation machinery to form N-glycans
containing al,6-fucose residues inside the host plant cells." (Br. 11-12.)
Appellants thus contend that "a skilled person in the art, in view of the cited
references, would not have had a reasonable expectation that an al,6-FucT
[("al,6-fucosyl transferase")] expressed in plant cells would be located at a
desired subcellular position where it could get access to suitable
oligosaccharide substrates to exert its enzymatic activity." (Br. 12.)
While Henquet notes some unpredictability as to activity level of
mammalian glycosyltransferases in plants (Henquet 536), it does indicate
that the mammalian transferase integrated into the plant host cell and was
active (id.). We note that claim 1 does not require any particular level of
activity, just that the plant cell be transformed with al,6-fucosyl transferase
and that it "transfers a fucose residue in an al,6-linkage to a reducing
terminal acetylglucosamine residue of a sugar chain of a glycoprotein in a
plant cell" (Br. 15 (claim 1) ). Thus, even low levels of activity are
encompassed within the scope of the claims. Henquet suggests to one of
ordinary skill in the art that, at a minimum, low levels of al,6-fucosyl
transferase activity would be reasonably expected in the plant host cell upon
transformation of the cell with the mammalian enzyme. Moreover, as the
Examiner noted, to the extent that Henquet notes some failures, such "is not
sufficient for destroying a reasonable expectation of success." (Ans. 12.)
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Indeed, all that is required to establish a prima facie case of obviousness is a
reasonable expectation of success, not absolute predictability of success. In
re 0 'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988); see also Kubin, 561 F.3d
at 1360 (noting the Supreme Court in KSR Int'! Co. v. Teleflex Inc., 550 U.S.
398 (2007) "reinvigorated [the] perceptive analysis" that" '[o]bviousness
does not require absolute predictability of success ... all that is required is a
reasonable expectation of success"' (quoting 0 'Farrell, 853 F.3d at 903-
04)). We agree with the Examiner that the prior art cited by the Examiner
provides sufficient information for one of ordinary skill in the art to have
had a reasonable expectation of success that al,6-fucosyl transferase
expressed in a plant cell would function to add fucose residues to a co-
expressed glycoprotein in al,6-linkage.
Regarding whether one of ordinary skill in the art would have had a
reasonable expectation of getting al,6-fucosyl transferase to express in the
Golgi and be functional, the Examiner notes, and Appellant does not
challenge, that "many of the mammalian signal peptides function normally
in plant cells, and in the event that the mammalian al,6FucT [("al,6- fucosyl
transferase")] signal peptide did not function in plant cells, there were
numerous signal peptides known in the art which could be substituted in
order to direct the al,6FucT [("al,6- fucosyl transferase")] to the golgi of a
plant cell." (Ans. 11.) In fact, the Examiner notes that Bakker8 (a prior art
reference cited in Henquet (Henquet 536)) teaches that Bl,4 glactosyl
transferase, "the most important enzyme [in mammals] that is missing [in
8 Bakker et al., Galactose-extended glycans of antibodies produced
by transgenic plants, 98 PNAS, 2899-2904 (2001).
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plants] for conversion of typical plant N-glycan into mammalian-like N-
glycans" was stably expressed, and localized "correctly in the Golgi
apparatus" in tobacco plants and was "fully functional." (Ans. 13; Bakker
(Abs).)
For the foregoing reasons, Appellants do no persuade us that the
Examiner erred in rejecting claim 1 for obviousness over Chrispeels,
Taniguchi, and Rishi.
Claims 3, 9-12, and 17-22 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection of claims 1, 3, 9-12, and 17-22 under 35
U.S.C. § 103(a) as unpatentable over Chrispeels, Taniguchi, and Rishi.
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. § l.136(a).
AFFIRMED
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