Ex Parte WANG et al

Patent Trials and Appeals Board

Apr 25, 2019

13411733 - (D) (P.T.A.B. Apr. 25, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/411,733 03/05/2012
79683 7590 04/29/2019
OLIVE LAW GROUP, PLLC
Bentley J Olive
125 EDINBURGH SOUTH DRIVE
Suite 220
CARY, NC 27511
FIRST NAMED INVENTOR
LAI-XI WANG
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.
648-307-UTIL 7394
EXAMINER
ROONEY, NORA MAUREEN
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
04/29/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
docket@OLIVELA WGROUP.COM
eofficeaction@appcoll.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LAI-XI WANG, WEI HUANG, and
JOHN GIDDENS 1
Appeal2017-008191
Application 13/411,733
Technology Center 1600
Before ERIC B. GRIMES, JOHN G. NEW, and TA WEN CHANG,
Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of preparing a core-fucosylated glycopeptide or core-fucosylated
glycoprotein having a predetermined oligosaccharide moiety, which have
been rejected as anticipated and/or obvious. We have jurisdiction under
35 U.S.C. § 6(b ).
We AFFIRM.
STATEMENT OF THE CASE
"Fucosylated glycoproteins are an important class of biomolecules
that play crucial roles in many biological events such as cell adhesion, tumor
metastasis, pathogen infection, and immune response." (Spec. ,-J 90.) "Core
1 Appellants identify the Real Party in Interest as University of Maryland,
Baltimore. (Appeal Br. 3.)
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Application 13/411,733
fucosylation, ... the attachment of an a-1, 6-linked fucose to the innermost
GlcNAc moiety of asparagine (N)-linked glycans, is a natural modification
frequently found in natural and mammalian cell line-expressed N-
glycoproteins." (Id. ,i 6.) The Specification states that core fucosylation
"affects N-glycan conformations and regulates the interactions between N-
glycans and glycan-binding proteins," including for instance the binding of a
therapeutic antibody to target cells. (Id. ,i 7.) The Specification states,
however, that "a major problem in structural and functional studies of
fucosylated glycoproteins is their structural microheterogeneity," because
"[ n Jatural and recombinant fucosylated glycoproteins are typically produced
as a mixture of glycoforms that differ only in the structure of the pendent
oligosaccharides." (Id. ,i 90; see also id. ,i 9.)
According to the Specification, therefore, "there is a need for proper
and consistent glycosylation in developing core-fucosylated glycopeptides
and glycoproteins to be used for development and production of therapeutic
agents while reducing negative effects such as allergy problems or undesired
immune responses and conferring significant and consistent stability and
activity." (Id. ,i 11.) Further according to the Specification, "[t]he present
invention relates to the synthesis of fucosylated glycopeptides or
glycoproteins wherein a desired sugar chain is added to a fucosylated
GlcNAc-protein acceptor by transglycosylation to form structure defined
core-fucosylated glycopeptides or glycoproteins." (Id. ,i 12.) In particular,
according to the Specification, in one aspect the invention "provides for
novel transglycosylation activity of Flavobacterium meningosepticum
endoglycosidases ... Endo-F 1, Endo-F2, Endo-F3 and [certain] mutants
thereof," which "enable the transfer of an oligosaccharide (in the form of an
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Application 13/411,733
activated sugar oxazoline) en bloc to a fucosylated GlcNAc-peptide acceptor
to form a core-fucosylated glycopeptide." (Id. f 13.)
Claims 1-6, 8-10, and 13 are on appeal. Claim 1, the only
independent claim, is illustrative and reproduced below:
1. A method of preparing a core-fucosylated glycopeptide or core-
fucosylated glycoprotein having a predetermined oligosaccharide
moiety, the method comprising:
providing a core-fucosylated acceptor glycopeptide or core-
fucosylated acceptor glycoprotein comprising an asparagine-linked N-
acetylglucosamine (GlcNAc) residue linked to a core fucose residue,
wherein the core-fucosylated acceptor glycopeptide or core-
fucosylated acceptor glycoprotein is an alpha-1-6-fucosyl-GlcNAc-
peptide or an alpha-1-6-fucosyl-GlcNAc protein; and
enzymatically reacting the core-fucosylated acceptor
glycoprotein or core-fucosylated acceptor glycopeptide with an
activated oligosaccharide donor in the presence of at least one
endoglycosidase selected from the group consisting of
Endoglycosidase-F2 (SEQ ID NO: 2), Endoglycosidase-F2 Dl24A
mutant (SEQ ID NO: 4), Endoglycosidase-F2 Dl24Q mutant (SEQ ID
NO: 5), Endoglycosidase-F3 (SEQ ID NO: 3), Endoglycosidase-F3
Dl26A mutant (SEQ ID NO: 6), and Endoglycosidase-F3 Dl26Q
mutant (SEQ ID NO: 7), wherein the activated oligosaccharide donor
comprises an oxazoline covalently linked to a oligosaccharide moiety,
wherein the oligosaccharide moiety comprises a predetermined
number and type of sugar residues, and wherein the enzymatically
reacting covalently links the oligosaccharide moiety to the core-
fucosylated acceptor glycoprotein or core-fucosylated acceptor
glycopeptide; thereby providing the core-fucosylated glycoprotein or
core-fucosylated acceptor glycopeptide having the predetermined
oligosaccharide moiety.
(Appeal Br. 26 (Claims App'x).)
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Application 13/411,733
The Examiner rejects claims 1-6, 8-10, and 13 under pre-AIA
35 U.S.C. § 102(b) as being anticipated by or, in the alternative, under pre-
AIA 35 U.S.C. § 103(a) as being obvious over Defrees.2 (Ans. 3.)
DISCUSSION
Issue
The Examiner finds that Defrees teaches all of the limitations of
claims 1-6, 8-10, and 13. In particular, with respect to claim 1, the only
independent claim, the Examiner finds that Defrees teaches "using mutant
endoglycanases such as endo-H, endo-F2 and endo-F3 to remodel the
glycosylation pattern of glycopeptides," in particular by adding
oligosaccharide at an N-linked GlcNAc. (Ans. 3.) The Examiner also finds
that Defrees teaches that the glycosyl donor molecule in the enzymatic
reaction may include a 1,2 oxazoline moiety. (Id. at 4.) The Examiner
further finds that Defrees teaches that one of the glycopeptide that may be
modified using its method is Remicade, which is a core-fucosylated
glycopeptide recited in instant claim 8. (Id.) Finally, the Examiner finds
that De frees teaches that the wild type of Endo-F2 and Endo-F3 are taught
by Tarentino,3 which is incorporated by reference into Defrees, and the
Endo-F2 and Endo-F3 sequences disclosed in Tarentino are identical to SEQ
ID NO: 2 and SEQ ID NO: 3 recited in the claims. (Id. at 5.)
Appellants contend that Defrees "does not ... suggest that core-
fucosylated glycopeptides or core-fucosylated glycoproteins can serve as
2 Defrees et al., US 2005/0064540 Al, published Mar. 24, 2005.
3 A. L. Tarentino et al., Multiple Endoglycosidase F Activities Expressed by
Flavobacterium meningosepticum Endoglycosidase F2 and FJ, 268 J.
BIOLOGICAL CHEMISTRY 9702 (1993).
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Application 13/411,733
substrates for enzymatic transglycosylation as required by the instant
claims." (Appeal Br. 10 (emphasis added).) While Appellants do not
dispute that Remicade is core-fucosylated, Appellants contend that "the
mere listing of Remicade in [Defrees'] Table 1, as one of hundreds of
potential substrates proposed by Defrees," is not sufficient to render Defrees
an anticipatory reference. (Id. at 12.) Appellants further contend that the
"claimed methods include very specific amino acid changes at very specific
sites" of the recited endoglycosidases, whereas "Defrees ... merely
discloses a broad genus of possible [mutations]." (Id. at 15.) Finally,
Appellants contend that Defrees does not anticipate because, at best, "to find
all the claimed limitations[] one has to go on a hunting expedition through
the ... reference." (Id. at 10; see also id. at 15-16.)
Appellants contend that Defrees also does not render the claims
obvious, because a skilled artisan would not have had motivation to combine
the various elements disclosed in Defrees to arrive at the claimed invention
and thus the rejection is based on hindsight in an unpredictable field.
(Appeal Br. 24; see also id. at 19.) In particular, Appellants contend that
Defrees "provides no guidance for core-fucosylated substrates as required by
the instant claims" and also provides no guidance as to which wild-type or
mutated enzymes should be used to transglycosylate fucosylated peptide or
polypeptide substrates. (Id. at 16, 18, 19.) Appellants contend that, at best,
the Examiner "erroneously equated ['obvious to try'] with obviousness
under §103." (Id. at 18-19.)
Appellants do not separately argue the claims, and we therefore limit
our analysis to claim 1 as representative. The issue with respect to this
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rejection is whether a preponderance of the evidence of record supports the
Examiner's conclusion that claim 1 is obvious over Defrees.
Findings of Fact
1. Defrees teaches that "[h Jeterogeneity in the glycosylation of a
recombinantly produced glycopeptides arises because the cellular machinery
(e.g., glycosyltransferases and glycosidases) may vary from species to
species, cell to cell, or even from individual to individual," and "[t]he
substrates recognized by the various enzymes may be sufficiently different
that glycosylation may not occur at some sites or may be vastly modified
from that of the native protein." (De frees ,i 18.)
2. Defrees teaches "methods for modifying glycosylation patterns
of glycoproteins" and "glycoprotein compositions in which the
glycoproteins have a homogeneous glycosylation pattern." (Id. at Abstract.)
3. Defrees teaches that, typically, its methods are carried out by
glycosylating a polypeptide which comprises an Asn or an
Asp residue. The protein will generally be recombinantly
produced and may be first treated chemically or with an
appropriate enzyme (e.g., endoglycanase ... or protease)
to remove a portion of an existing carbohydrate structure.
The method can also utilize one or more steps in which an
appropriate acceptor moiety is ligated onto the peptide.
The methods of the invention include contacting the
polypeptide with an activated glycosyl donor molecule
(e.g., a species having a leaving group) and a mutant
endoglycanase (e.g., endo-H) under conditions suitable for
linking the activated glycosyl donor molecule to a
glycosyl acceptor on the polypeptide. If desired, the
glycosylation pattern of the peptide produced using the
method of the invention can be further elaborated using
glycosylation methods set forth herein, or known in the art.
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(Id. ,i 33; see also id. ,i 38 (explaining that invention provides methods for
producing glycopeptides having a particular glycosylation pattern,
comprising "contacting a ... glycopeptide having an acceptor for a mutant
endoglycanase of the invention with a glycosyl donor and the mutant
endoglycanase"), ,i 85 (stating that invention provides a method of
glycosylating a glycoprotein comprising "contacting [a] glycoprotein with
an activated glycosyl donor molecule comprising a GlcNAc residue and a
mutant endoglycanase ( endoglycosidase) under conditions suitable for the
linkage of the GlcNAc residue of said activated glycosyl donor to said
GlcNAc of said glycoprotein").)
4. Defrees refers to endoglycosidase as endoglycanase. (Id. ,i 85
(referring to the mutant enzymes useful for its invention as "endoglycanase
( endoglycosidase )").)
5. Defrees teaches that "[t]he mutant enzyme catalyzes the
reaction, usually by a synthesis step that is analogous to the reverse reaction
of the endoglycanase hydrolysis step." (Id. ,i 35.) In particular, "the
glycosyl donor molecule (e.g., a desired oligo- or monosaccharide structure)
contains a leaving group and the reaction proceeds with the addition of the
donor molecule to a GlcNAc residue on the protein." (Id.)
6. Defrees teaches that "[t]he particular glycosyl donor molecule
used in the methods of the invention is not a critical aspect of the invention"
and that "[a]ny desired carbohydrate structure can be added to a glycoprotein
using the methods of the invention." (Id. ,i 36.) However, Defrees teaches
that "the GlcNAc residue on the glycosyl donor molecule ... may comprise
a 1,2 oxazoline moiety." (Id. ,i 35; see also id. at claim 12.)
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7. Defrees teaches that "[t]he acceptor glycoprotein is also not a
critical aspect of the invention." (Id. ,i 37; see also id. ,i 38.) Instead,
Defrees teaches that "[t]he methods of the invention are practiced
successfully with substantially any peptide or glycopeptide" and that
"[ w ]hen the peptide or glycopeptide does not include an appropriate
acceptor moiety, it is within the scope of the present invention to add the
appropriate moiety by enzymatic and/or chemical methods." (Id. ,i 93.)
However, Defrees teaches that "[p ]referred glycoproteins to which ...
oligosaccharide are added contain an N-linked GlcNAc at which the addition
occurs. The terminal GlcNAc residue on the protein can be naturally
derived from the expression system or can be created prior to remodeling."
(Id. iJ 105.)
8. Defrees teaches that"[ e ]xemplary peptides that can be modified
using the methods of the invention" include the monoclonal antibody
Remicade. (Id. ,i 95.) The Examiner finds, and Appellants have not
disputed, that Remicade is also known as infliximab, which is a core-
fucosylated glycopeptide within the meaning of claim 1. (Ans. 4; Appeal
Br. 27 (Claims App'x, claim 8).)
9. Defrees teaches that the invention uses "mutant endoglycanases
such as endo-H, endo-F1, endo-F2, endo-F3, endo-D and PNGase-A to
remodel the glycosylation pattern of glycopeptides." (Defrees ,i 103.)
10. Defrees teaches that "[t]he wild type of these proteins cleave
the chitobiose core ofN-linked oligosaccharides between the GlcNAc
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Application 13/411,733
residues leaving one GlcNAc attached to the protein," as illustrated in
Defrees' Figure 1, reproduced below:
i golycoprotein
A-GlcNAc-GlcNAc-Asn .
1 Endo-Glycanse (H, A, F1_3)
8
glycoprotein
A-GlcNA<>-OH !1cNAc·AsO
A = remaining N-linked oligosaccharide structure
which is dependent on the specificy of the enzyme
used. B = H, fucose
FIG.1
(Id. ,i 104, Fig. l; see also id. at claim 23.) Figure 1 ofDefrees illustrates
the reaction catalyzed by endoglycanases such as Endo-F 2 and Endo-F 3
wherein the chitobiose core ofN-linked oligosaccharides is cleaved between
GlcNAc residues leaving one GlcNAc attached to the glycoprotein. (Id. ,i
104, Fig. 1.)
11. The Examiner finds, and Appellants have not disputed, that the
sequences of the wild type Endo-F 2 and Endo-F 3 disclosed in Defrees, as
evidenced by Tarentino, are identical to SEQ ID N0:2 and SEQ ID N0:3
recited in claim 1. (Ans. 5; Defrees ,i 104.)
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12. Defrees teaches that
[ m Jodifications of the active site amino acids or peptide
reengineering is used to improve the synthetic capabilities
of these enzymes with activated oligosaccharide
substrates. Initial attempts will be focused on altering the
hydrolytic capabilities of the enzyme by first changing the
either or both of the two acidic amino acids, asp and glu,
to another amino acid such as Ser, Ala, Asn or Gln.
(Id. ,i 105; see also id. ,i 107 ( stating that the invention is based on "the
observation that endoglycanases ... can be converted from a degradative
enzyme to a synthetic enzyme" and that "change in the catalytic activity is
induced by modifying amino acid residues of the enzyme to facilitate this
conversion"), ,i 108 ( explaining that enzymes mutated according to the
invention can "catalyze the coupling of modified glycosyl donor molecules
to modified acceptors"), ,i 117 (mutant enzymes of the invention are used to
couple modified glycosyl donors with glycosyl acceptors.)
13. De frees teaches that,
in general, the substitution [to create mutant enzymes of
the invention] will involve replacing a glutamic acid or
aspartic acid residue of the wild-type enzyme with alanine,
glycine, valine, leucine, isoleucine, serine, threonine,
cysteine, methionine, asparagine, glutamine, histidine,
proline, phenylalanine, or tyrosine. Preferably, the
substituted amino acid will have a side chain of
approximately equal or smaller size to the side chain of the
wild-type amino acid residue to avoid significant changes
to the size and shape of the active site.
(Id. iJ 108.)
14. Defrees teaches that
[t]he amino acids that are replaced [in the mutants] are
generally located within or proximate the active site, or a
water binding site. Exemplary substitutions include ...
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endo-F2, which includes an amino acid residue substituted
for an active site acidic amino acid residue selected from
Asp at position 124, Glu at position 126 and combinations
thereof; and endo-F3, which includes an amino acid
residue substituted for an active site acidic amino acid
residue selected from Asp at position 126, Glu at position
128 and combinations thereof.
(Id. ,i 103; see also id. at claims 5 and 6.)
15. Defrees teaches that a glycoprotein may be contacted with a
wild-type endoglycanase to cleave the carbohydrate structure from the
glycoprotein before the glycoprotein is glycosylated by being contacted with
a mutant endoglycanase. (Id. ,i,i 44, 100, 105, Fig. 3, claims 1, 23.)
16. Defrees teaches that "[ s Jubstrate specificity with regards to the
oligosaccharide will depend on which endoglycanase is modified and used."
(Id. ,i 105.) Defrees teaches that "[b]y using the different enzyme
specificities of the endoglycanases, any N-linked structure can be introduced
on the target glycoprotein using this methodology." (Id. ,i 106.)
Analysis
Defrees teaches a method for modifying glycosylation patterns of
glycoproteins (FF2, FF3), comprising reacting an acceptor glycoprotein
(FF3) with an activated glycosyl donor (FF3, FF5) in the presence of an
enzyme such as mutant Endo-F2 and Endo-F3 (FF3-5, FF9, FFl l-FF14), as
recited in claim 1. Defrees teaches that the result of the reaction is the
linkage of the glycosyl donor molecule ( e.g., a desired oligo- or
monosaccharide structure) to a GlcNAc residue on the glycoprotein. (FF2,
FF5.) Defrees teaches that its method may be used with any acceptor
glycoprotein, including core-fucosylated glycoproteins. (FF7, FF8.)
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Defrees teaches that the activated glycosyl donor may be an oligosaccharide
donor comprising a 1,2 oxazoline moiety. (FF5, FF6.) Thus, to arrive at the
claimed invention a skilled artisan merely needs to follow the explicit
suggestions of Defrees. "The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416
(2007). We therefore agree with the Examiner that claim 1 is obvious over
Defrees.
We address Appellants' arguments below. Only those
arguments timely made by Appellants in the briefs have been considered;
arguments not so presented in the Brief are waived. See 37 C.F.R.
§ 41.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474
(BP AI 2010) (informative) ("Any bases for asserting error, whether factual
or legal, that are not raised in the principal brief are waived.").
Appellants contend that Defrees does not anticipate because "to find
all the claimed limitations[] one has to go on a hunting expedition through
the ... reference." (Appeal Br. 10; see also id. at 15-16, Reply Br. 5, 6-7.)
We are not persuaded. The Examiner rejected the claims as anticipated by
and/or obvious over Defrees. Assuming for the sake of argument that the
rejection requires "picking, choosing, and combining various disclosures not
directly related to each other by the teachings of the cited reference," such
picking and choosing still would be proper as part of an obviousness
rejection. Cf In re Arkley, 455 F.2d 586, 587 (CCPA 1972).
Appellants contend that Defrees does not suggest that core-
fucosylated glycopeptides or glycoproteins can serve as substrates for
enzymatic transglycosylation. (Appeal Br. 10-12, 16, 19-20; see also Reply
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Br. 3-5.) We are not persuaded. As an initial matter, Defrees explicitly
includes Remicade as an exemplary peptide that can be modified by the
method of its invention, and Appellants do not dispute that Remicade is a
core-fucosylated glycopeptide within the meaning of claim 1. (FF8).
Furthermore, Defrees teaches that carbohydrate structure may be cleaved
from a glycoprotein using a wild-type endoglycanase before that
glycoprotein is glycosylated by the mutant endoglycanase of the invention.
(FF15.) Defrees provides a figure, Figure 1, that illustrates the reaction
catalyzed by such a wild-type endoglycanase, and the glycoprotein being
cleaved is shown to be fucosylated. (FFlO.) Thus, we find that Defrees
suggests core-fucosylated glycoprotein as a substrate for enzymatic
transglycosylation using the mutant enzymes of its invention.
Appellants contend that the listing of Remicade in Defrees' Table 1 is
insufficient to render claim 1 anticipated or obvious. (Appeal Br. 12, 16-17;
see also Reply Br. 5.) Appellants first contend that "the Defrees reference
DOES NOT state what type of reaction is occurring in any of the
components listed in Table l." (Appeal Br. 12, 16-17.)
We are not persuaded. Defrees states that "[ e ]xemplary peptides that
can be modified using the methods of the invention are set forth in Table l"
and includes Remicade in Table 1. (FF8.) Defrees also makes clear that the
methods of its invention include glycosylating an acceptor glycopeptide by
contacting it with a glycosyl donor and a mutant endoglycanase. (FF3.)
Therefore, we disagree with Appellants that Defrees does not state "what
type of reaction is occurring in any of the components listed in Table l ";
instead, we find that a skilled artisan would understand based on Defrees
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that Remicade (i.e., a core-fucosylated glycopeptide) can be a substrate for
enzymatic glycosylation as recited in claim 1.
We are likewise unpersuaded by Appellants' argument that Defrees
does not render claim 1 obvious because Remicade is listed as one of
"hundreds of possible substrate choices" and a skilled artisan would have no
reason to "'home in' on Remicade to represent a core-fucosylated
polypeptide substrate of the present invention." (Appeal Br. 13; see also
Reply Br. 5.) The use of Remicade or core-fucosylated glycopeptide
substrate in general is not nonobvious merely because Defrees teaches that
other types of glycopeptide can also act as substrate for the reactions taught
in the reference. In the context of a prior art patent that disclosed the
claimed combination as part of a disclosure of over a thousand effective
combinations of compounds, for instance, our reviewing court has explained
that "disclos[ing] a multitude of effective combinations does not render any
particular formulation less obvious. This is especially true because the
claimed composition is used for the identical purpose taught by the prior
art." Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir.
1989).
Appellants contend that Defrees "expressly states that the acceptor
glycoprotein is ... not a critical aspect of the invention.") (Appeal Br.
19; see also id. at 23, Reply Br. 4-5.) Thus, Appellants contend that Defrees
does not teach that the type of acceptor glycoprotein is a result-effective
variable and
never recognized that the acceptor glycoprotein could and should
include variable types of specific sugar component (e.g., a core
fucosyl group), or that such variable types of specific sugar
components and the placement thereof could have a marked effect on
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the activity and efficiency of an endoglycosidase used in
transglycosylation.
(Appeal Br. 19.)
We are not persuaded. Assuming for argument's sake that Appellants
have shown that the type of acceptor glycoprotein affects the activity and
efficiency of an endoglycosidase used in transglycosylation, "merely
discovering ... a new benefit of an old process cannot render the process
again patentable." In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). In
this case, Defrees already suggests the use of core-fucosylated glycoproteins
as a substrate for glycosylation reaction with mutated endoglycosidase; thus,
Appellants' alleged discovery that using core-fucosylated glycopeptides as
substrate affects the activity and efficiency of endoglycosidase does not
render the process non-obvious.4
Appellants contend that there are no examples in Defrees of
transglycosylation of fucosylated substrates and that Defrees "provides no
proof of the abilities of the endoglycosidases-F2 or F3 and mutants thereof
to transglycosylate fucosylated substrates as recited in the instant claims."
(Appeal Br. 20; see also id. at 24, Reply Br. 8.) Appellants also contend that
a skilled artisan would have had no reason to "make any modification to the
teaching of Defrees to arrive at the present invention" because, "prior to
4 Appellants cite to Ex Parte Collison, Appeal No. 2010-002734, 2012 WL
684056 (BPAI 2012) and In re Antonie, 559 F .2d 618 (CCPA 1977), in
support of their arguments. These cases are inapposite. They relate to
situations where an obviousness rejection is based on the notion that
discovery of optimum or workable ranges is obvious even if general
conditions of a claim are disclosed in the prior art. In this case, as discussed
above, Defrees does not merely disclose the "general conditions" of the
claim but explicitly suggests use of a core-fucosylated glycopeptide as a
substrate for its enzymatic glycosylation reaction.
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Appellant[s'] discovery, the ability of Endo F2 and Endo F3 and mutants
thereof to glycosylate ... core-fucosylated substrates was unknown."
(Appeal Br. 23-24; see also id. at 21-23.)
We are not persuaded. As discussed above, Defrees suggests using
Endo F2 and Endo F3 mutants to glycosylate glycopeptides, including core-
fucosylated glycopeptides. Even if Defrees does not provide a specific
example using a core-fucosylated glycopeptide as a substrate, it is well
settled that"[ a] reference may be read for all that it teaches," not just for its
examples or preferred embodiments. In re Mouttet, 686 F.3d 1322, 1331
(Fed. Cir. 2012). Moreover, "a prior art printed publication ... is
presumptively enabling barring any showing to the contrary by a patent
applicant or patentee." In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed.
Cir. 2012). Accordingly, claim 1 is not non-obvious merely because Defrees
does not provide an example or "proof' of transglycosylation of fucosylated
substrates.
Appellants contend that the inventors found that "endoglycosidase-F2
or -F3 and mutants thereof were only effective if the acceptor glycoprotein
included a fucose sugar attached to a GlcNAc glycan adjacent to the
protein" and that "Endo-F2 and Endo-[F]3 did not show transglycosylation
activity on the non-fucosylated GlcNAc." (Id. at 20; see also Reply Br. 4.)
We are not persuaded that this contention, even if true, renders claim
1 non-obvious. Assuming for the sake of argument that Appellants have
shown that Endo-F2 and Endo-F3 do not transglycosylate non-fucosylated
GlcNAc, this is not evidence that Defrees does not enable transglycosylation
of core-fucosylated glycopeptide using the mutant Endo-F2 and Endo-F3 of
Defrees' invention. Neither have Appellants persuasively argued that the
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ability of the claimed enzymes to transglycosylate core-fucosylated
glycopeptides is unexpected. Indeed, this is a result that one would expect
based on Defrees' teachings.
Appellants further contend that Defrees does not teach "which Endo
enzymes can be used for transglycosylation of core-fucosylated
substrates." (Appeal Br. 10; see also Reply Br. 6-7.) Appellants contend
that the "claimed methods include very specific amino acid changes at ~
specific sites" of the recited endoglycosidases, whereas "Defrees ... merely
discloses a broad genus of possible [mutations]." (Appeal Br. 14-15.)
Appellants contend that the Examiner's citation to Tarentino "does not add
to the scope of the Defrees reference" because "[t]he mere mention of wild
type Endo-F2 or Endo-F3 sequence is just another component with no
indication of how to combine with all the other aspects of the Defrees
reference" and because a skilled artisan would not "'home-in' on this one
single reference" out of the 180 references cited without hindsight. (Id. at
15; see also Reply Br. 7.)
We are not persuaded. Claim 1 recites, among other enzymes,
Endoglycosidase-F2 Dl24A and Dl24Q mutants and Endoglycosidase-F3
Dl26A and Dl26Q mutants, i.e., Endo-F2 and Endo-F3 wherein the aspartic
acid (Asp, D) in positions 124 and 126 of Endo-F2 and Endo-F3,
respectively, is substituted with an alanine (Ala, A) or a glutamine (Gln, Q).
Similarly, Defrees teaches that mutated endoglycosidase F2 and F3
catalyzes glycosylation of glycopeptides (FF3-FF5, FF9-FF14) and teaches,
as evidenced by Tarentino, Endo-F2 and Endo-F3 having the SEQ ID N0:2
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and SEQ ID NO: 3 recited in claim 1.5 (FFl 1.) Defrees further teaches
substituting the aspartic acid at position 124 of Endo-F2 and position 126 of
Endo-F3, as recited in claim 1. (FF14.) Finally, Defrees teaches that, in
general, the aspartic acid should be replaced with alanine, glycine, valine,
leucine, isoleucine, serine, threonine, cysteine, methionine, asparagine,
glutamine, histidine, proline, phenylalanine, or tyrosine and that the
substituted amino acid "will have a side chain of approximately equal or
smaller size to the side chain of the wild-type amino acid residue [(i.e.,
aspartic acid)] to avoid significant changes to the size and shape of the active
site." (FF 13.) Given the above, we find that Defrees suggests the mutations
recited in claim 1 (i.e., Endo F2 Dl24A and Dl24Q and Endo F3 Dl26A
and D l 26Q), even if it also suggests that the aspartic acid at position 124
and 126 of Endo-F2 and Endo-F3, respectively, may be substituted with
certain other amino acids as well. Cf Merck & Co., Inc., 874 F.2d at 807
( explaining that "disclos[ing] a multitude of effective combinations does not
render any particular formulation less obvious," especially where "the
5 We are not persuaded by Appellants' argument that a skilled artisan would
not "home in" on Tarentino and that it therefore does not add to the
obviousness rejection (Appeal Br. 15; Reply Br. 7), or that Tarentino does
not support the obviousness rejection because it only teaches "cleaving
bonds and not adding a bond which is necessary for transglycosylation"
(Reply Br. 7). Defrees itself teaches using mutated Endo F2 and Endo F3,
which are also recited in the claims, to catalyze the glycosylation of
glycopeptides (FF3-FF5, FF9-FF14), and Tarentino merely provides
evidence that the Endo F2 and Endo F3 discussed in Defrees have the same
amino acid sequence as recited in the claims (FF 11 ). Likewise, even if
Tarentino only teaches cleaving bonds rather than transglycosylation,
Defrees teaches glycosylation of glycopeptides using mutated Endo F2 and
Endo F3 enzymes. (See, e.g., FF3.)
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claimed composition is used for the identical purpose taught by the prior
art").
Appellants contend that Defrees does not render the claims obvious
because a skilled artisan would not have had motivation to combine the
various elements disclosed in Defrees to arrive at the claimed invention and
thus the rejection is based on hindsight in an unpredictable field. (Appeal
Br. 24; see also id. at 19, Reply Br. 4, 8.) Appellants contend that, at best,
the Examiner "erroneously equated ['obvious to try'] with obviousness
under §103." (Appeal Br. 18-19.)
We are not persuaded. As we have explained above, Defrees teaches
each limitation of claim 1, and combining these elements to arrive at the
invention of claim 1 requires no more than following the teachings in
Defrees itself. KSR Int'! Co., 550 U.S. at 416 (explaining that "[t]he
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results").
For the same reasons, we disagree with Appellants' contention that
the Examiner's obviousness rejection is based on the impermissible types of
obvious-to-try rationale. As explained in In re O 'Farrell, 853 F.2d 894
(Fed. Cir. 1988), an invention that is obvious to try is nevertheless
nonobvious when what would have been "obvious to try" would have been
( 1) "to vary all parameters or try each of numerous possible choices until
one possibly arrived at a successful result, where the prior art gave either no
indication of which parameters were critical or no direction as to which of
many possible choices is likely to be successful," or (2) "to explore a new
technology or general approach that seemed to be a promising field of
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experimentation, where the prior art gave only general guidance as to the
particular form of the claimed invention or how to achieve it." Id. at 903.
The obviousness rejection over Defrees is based on neither of these
impermissible obvious-to-try rationales. As discussed above, Defrees
indicated the parameters that are critical - i.e., the particular mutations for
the enzymes such as Endo F2 and Endo F3 - and also provided clear
directions as to the particular mutations that are likely to be successful.
Neither does Defrees merely provide "general guidance as to the particular
form of the claimed invention or how to achieve it." Instead, Defrees
provides specific examples of ( 1) glycopeptide substrates, including core-
fucosylated glycopeptide substrates (FF7, FF8, FFlO, FF15), (2) mutated
enzymes, including mutations recited in claim 1 (FF9, FF 11-14 ), and (3)
glycosyl donor, including one comprising an oxazoline moiety as recited in
claim 1 (FF6); as well as teachings regarding the expected glycosylation
reaction when the glycopeptide substrate is contacted with the mutated
enzyme and glycosyl donor (FF3.)
Accordingly, we affirm the Examiner's rejection of claim 1 as
obvious over Defrees. Claims 2-6, 8-10, and 13, which are not separately
argued, fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For the reasons above, we affirm the Examiner's decision rejecting
claims 1-6, 8-10, and 13 as obvious over Defrees.
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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. § l .136(a).
AFFIRMED
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