Ex Parte Gerngross

Board of Patent Appeals and Interferences

Nov 4, 2010

11271217 (B.P.A.I. Nov. 4, 2010)

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.
11/271,217 11/10/2005 Tillman U. Gerngross GFI/100 DIV4 8735
210 7590 11/05/2010
MERCK
P O BOX 2000
RAHWAY, NJ 07065-0907
EXAMINER
LIU, SAMUEL W
ART UNIT PAPER NUMBER
1656
MAIL DATE DELIVERY MODE
11/05/2010 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte TILLMAN U. GERNGROSS
__________

Appeal 2010-005042
Application 11/271,217
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to DNA
libraries. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, or for filing a request
for rehearing, as recited in 37 C.F.R. § 41.52, begins to run from
the “MAIL DATE” (paper delivery mode) or the
“NOTIFICATION DATE” (electronic delivery mode) shown on
the PTOL-90A cover letter attached to this decision.
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Application 11/271,217

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Statement of the Case
The Claims
Claims 1, 3-8, and 10-14 are on appeal. Appellants state that
“the Claims on appeal shall stand or fall together” (App. Br. 4). 37
C.F.R. § 41.37(c)(1)(vii). Independent claim 1 is representative
and reads as follows:
1. A DNA library comprising a plurality
of genetic constructs, each construct comprising
a nucleic acid encoding a catalytically active
fragment of a glycosylation enzyme selected from
the group consisting of glycosidases,
glycosyltransferases, nucleotide sugar transporters,
and nucleotide diphosphatases ligated in-frame to a
nucleic acid encoding a targeting sequence which
targets said catalytically active fragment to the
endoplasmic reticulum or Golgi apparatus of a host
cell,
said DNA library comprising at least two
different nucleic acids encoding targeting
sequences and at least two different nucleic acids
encoding catalytically active fragments
wherein the nucleic acid encoding the
catalytically active fragment is separately ligated
to each of at least two different nucleic acids
encoding targeting sequences to provide the
plurality of genetic constructs.
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The issue
The Examiner rejected claims 1, 3-8, and 10-14 under 35 U.S.C.
§ 103(a) as obvious over Chiba2, Zhu3, and Andersen4 (Ans. 3-9).
The Examiner finds that:
It would have been obvious to one of ordinary skill in the art
at the time the invention was made to prepare a DNA library,
library of yeast expression vectors wherein the vectors
encodes fusion proteins comprising the glycosylation enzyme
and ER-targeting or Golgi apparatus-targeting sequence. This
is because Chiba et al. have taught all structural elements
necessary for contracting the “DNA library” (e.g., the
expression vectors encoding the fusion protein wherein the
glycosylation enzyme (such as α-1,2-mannosidase) is fused
with ER- targeting sequence (such as “HDEL”) in order to
obtain proper cellular localization of said fusion proteins[)].
This is also because Zhu et al. have taught feasibility of
constructing the library of yeast expression vector which is
highly diverse (see abstract) and allows high throughput
screening for proteins in vivo including the "modifying
enzymes to catalyze post-translational modification.

(Ans. 5).
Appellant contends that “Chiba provides no indication as to whether
the enzymes were functional in sense that they were targeted to the correct
region of the ER or Golgi in a manner that would then enable the enzymes to
modify the glycosylation pattern on a glycoprotein as it passes through the
ER and Golgi” (App. Br. 5).

2 Chiba et al., Production of Human Compatible High Mannose-
type (Man5GlcNAc2) Sugar Chains in Saccharomyces Cerevisiae,
273 J. BIOLOGICAL CHEMISTRY 26298-26304 (1998).
3 Zhu et al., US 6,410,246 B1, issued Jun. 25, 2002.
4 Andersen et al., US 2007/0154591 A1, published Jul. 5, 2007.
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Appellant further contends Chiba does not:
suggest what the applicant has discovered: that construction
of genetically engineered host cells that can produce various
human-like N-glycans would be enhanced by constructing a
DNA library of expression vectors encoding fusion proteins
comprising glycosylation enzyme catalytic domains fused to
targeting sequences and screening host cells transformed
with the DNA library to identify host cells that express the
particular fusion protein combinations that produce the
desired N-glycan in high yield.

(App. Br. 7). Appellant contends that “Zhu does not teach using a DNA
library to construct a biosynthetic pathway in a cell that renders the cell
capable of producing proteins that have human-like N-glycans” (App. Br. 9).
Appellant contends that “for a person of ordinary skill in the art to
make the applicant’s currently claimed library, there needs to be something
in the combination of Chiba and Zhu that would suggest to the person skilled
in the art that the problem of building a glycosylation pathway in a cell can
be solved by making libraries of glycosylation enzyme catalytic domains
and targeting peptides” (App. Br. 13).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Chiba and Zhu render obvious the
claimed DNA library?
Findings of Fact (FF)
1. The Specification teaches that “[t]argeting sequences are well
known and described in the scientific literature and public databases, as
discussed in more detail below with respect to libraries for selection of
targeting sequences and targeted enzymes” (Spec. 26, ll. 21-23).
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2. The Specification teaches that in “a preferred embodiment, a
DNA library is then constructed by the in-frame ligation of a sub-library
including DNA encoding signal sequences with a sub-library including DNA
encoding glycosylation enzymes or catalytically active fragments thereof.
The resulting library includes synthetic genes encoding fusion proteins”
(Spec. 30, ll. 5-8).
3. Chiba teaches that the “expression of the A. saitoi α-1,2-
mannosidase in the ER was demonstrated by adding ‘HDEL’ to the C
terminus of the α-1,2-mannosidase open reading frame. The introduced α-
1,2-mannosidase was also shown to convert Asn-linked oligosaccharides
into Man5GlcNAc2” (Chiba 26299, col. 1).
4. Chiba teaches that “we are trying to construct the mammalian-
type glycosylation system in S. cerevisiae as a host to produce glycoprotein
therapeutics (Fig. 1). The first aim of this research was to convert the
mannan-type sugar chain of S. cerevisiae to a Man5GlcNAc2 sugar chain,
because it is an intermediate for hybrid- and complex-type sugar chains”
(Chiba 26298, col. 2).
5. Chiba teaches that “trimming of the mannose residues by α-1,2-
mannosidase requires α-mannosidase I. Several α-1,2-mannosidases have
been isolated from mammals, yeast, and fungi, and some mammalian α-1,2-
mannosidase genes have been cloned” (Chiba 26298, col. 2, citations
omitted).
6. Figure 1 of Chiba is reproduced below:
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“FIG. 1. Strategy for genetic manipulation of S. cerevisiae, and the
comparison of the N-glycosylation pathway in mammalian cells and S.
cerevisiae” (Chiba 26299).
7. Zhu teaches that:
A highly diverse library of yeast expression vectors
encoding a library of fusion proteins such as antibodies is
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provided. The yeast expression vector formed in the library
comprises: a first nucleotide sequence encoding a first
polypeptide subunit; a second nucleotide sequence encoding
a second polypeptide subunit; and a linker sequence
encoding a linker peptide that links the first nucleotide
sequence and the second nucleotide sequence. The first
polypeptide subunit, the second polypeptide subunit, and the
linker polypeptide are expressed as a single fusion protein
within the library of fusion proteins. The first and second
nucleotide sequences each independently varies within the
library of expression vectors. The library of fusion proteins
expressed by the library expression vectors can be used for
screening against target molecules such as proteins,
peptides, DNAs and small molecules in vitro and in vivo.

(Zhu, abstract).
8. Zhu teaches that the “expression vectors in the library of
transformed yeast cells comprise: a transcription sequence encoding an
activation domain or a DNA binding domain of a transcription activator; a
first nucleotide sequence encoding a first polypeptide subunit; a second
nucleotide sequence encoding a second polypeptide subunit; and a linker
sequence encoding a linker peptide that links the first nucleotide sequence
and the second nucleotide sequence” (Zhu, col. 4, l. 67 to col. 5, l. 7).
9. Zhu teaches that the “efficient methods for preparing extremely
diverse libraries of tester proteins, and selecting from these libraries proteins
with high affinity and specificity toward a target protein, peptide or DNA in
vivo” (Zhu, col. 13, l. 67 to col. 14, l. 3).
10. Zhu teaches that “[o]ptionally, the expression vector containing
an AD (or BD) domain may also include another expression unit which is
capable of expressing one or more proteins other than the fusion proteins
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encoded by V1 and V2, such as the scFv antibodies. These proteins may be
modifying enzymes such as . . . glycosylase” (Zhu, col. 30, ll. 56-61).
Principles of Law
“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’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id. at 417. Moreover, an “[e]xpress suggestion to substitute
one equivalent for another need not be present to render such substitution
obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982). As noted by the
Court in KSR, “[a] person of ordinary skill is also a person of ordinary
creativity, not an automaton.” 550 U.S. at 421.
Analysis
Chiba teaches that a number of different glycosylation enzymes are
involved in the human N-glycosylation pathway (see Fig. 1, FF 5-6). Chiba
teaches that “we are trying to construct the mammalian-type glycosylation
system in S. cerevisiae as a host to produce glycoprotein therapeutics (Fig.
1)” (Chiba 26298, col. 2; FF 4). As an initial step in studying the N-
glycosylation pathway, Chiba generates an expression vector where
“expression of the A. saitoi α-1,2-mannosidase in the ER was demonstrated
by adding ‘HDEL’ to the C terminus of the α-1,2-mannosidase open reading
frame. The introduced α-1,2-mannosidase was also shown to convert Asn-
linked oligosaccharides into Man5GlcNAc2” (Chiba 26299, col. 1; FF 3).
Zhu teaches “efficient methods for preparing extremely diverse
libraries of tester proteins, and selecting from these libraries proteins with
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high affinity and specificity toward a target protein, peptide or DNA in vivo”
(Zhu, col. 13, l. 67 to col. 14, l. 3; FF 9). Zhu teaches libraries which are
composed of two different elements joined to one another (FF 7-8).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary creativity would have predictably
applied Zhu’s library generation methods to the glycosylation enzymes and
localization signals of Chiba and the prior art (FF 1, 3). “[W]hen the
question is whether a patent claiming the combination of elements of prior
art is obvious,” KSR directs that “a court must ask whether the improvement
is more than the predictable use of prior art elements according to their
established functions.” KSR, 550 U.S. at 417. Here, the N-glycosylation
enzymes of Chiba are predictably cloned into libraries with appropriate
retention signals, for the established function of efficiently creating libraries
which can be used to study enzymes involved in the synthesis of human
sugar chains in yeast (FF 3-10).
Appellant contends that “Chiba provides no indication as to whether
the enzymes were functional in sense that they were targeted to the correct
region of the ER or Golgi in a manner that would then enable the enzymes to
modify the glycosylation pattern on a glycoprotein as it passes through the
ER and Golgi” (App. Br. 5).
We are not persuaded. Chiba teaches that “expression of the A. saitoi
α-1,2-mannosidase in the ER was demonstrated by adding ‘HDEL’ to the C
terminus of the α-1,2-mannosidase open reading frame. The introduced α-
1,2-mannosidase was also shown to convert Asn-linked oligosaccharides
into Man5GlcNAc2” (Chiba 26299, col. 1; FF 3). This is a specific teaching
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Application 11/271,217

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of the localization of a glycosylation enzyme into the ER and a
demonstration that the enzyme is functional.
Appellant further contends Chiba does not:
suggest what the applicant has discovered: that construction
of genetically engineered host cells that can produce various
human-like N-glycans would be enhanced by constructing a
DNA library of expression vectors encoding fusion proteins
comprising glycosylation enzyme catalytic domains fused to
targeting sequences and screening host cells transformed
with the DNA library to identify host cells that express the
particular fusion protein combinations that produce the
desired N-glycan in high yield.

(App. Br. 7). Appellant contends that “Zhu does not teach using a DNA
library to construct a biosynthetic pathway in a cell that renders the cell
capable of producing proteins that have human-like N-glycans” (App. Br. 9).
We are not persuaded. Appellant’s argument addresses each of the
references individually. The rejection, however, is based on the combined
teachings of the references; “[n]on-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references.” In re Merck & Co., 800 F.2d at
1097.
Appellant contends that “for a person of ordinary skill in the art to
make the applicant’s currently claimed library, there needs to be something
in the combination of Chiba and Zhu that would suggest to the person skilled
in the art that the problem of building a glycosylation pathway in a cell can
be solved by making libraries of glycosylation enzyme catalytic domains
and targeting peptides” (App. Br. 13).
Appeal 2010-005042
Application 11/271,217

11
We agree that a reason to form the claimed library is required. See
KSR at 418 (There must be “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does.”). However, in the instant case, the Examiner
has provided several reasons which would have prompted the ordinary
artisan to combine the teachings of Chiba and Zhu to form a library. The
Examiner finds that:
Considering (i) the number of the glycosylation enzymes
involved in the glycosylation pathway as depicted in Fig. 1
of Chiba et al., (ii) possible number of the ER- and Golgi-
targeting sequences for each of the enzymes thereof, and
further considering combination of the above two numbers,
one of ordinary skill in the art would have chosen the DNA
library as [a] screening mean[s].

(Ans. 8). The Examiner also finds that the ordinary artisan “would have
realized that the Zhu’[s] library of yeast expression vectors is suitable for
screening the proper ER and/or Golgi targeting sequence(s) necessary for
correct cellular localization of the glycosylation enzymes so as to properly
process the mammalian type sugar chains in the yeast” (Ans. 8).
Appellant argues that the “advantages of a library cited on page 5 of
the office action are not believed to be applicable to the currently claimed
library and the problem it is designed to solve” (App. Br. 10).
We are not persuaded. While it might be true that Appellant’s
purpose for forming the claimed library is different than the reason
suggested by Chiba and Zhu, that fact does not undermine the Examiner’s
prima facie case. See KSR, 550 U.S. at 419 (“In determining whether the
subject matter of a patent claim is obvious, neither the particular motivation
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nor the avowed purpose of the patentee controls. What matters is the
objective reach of the claim. If the claim extends to what is obvious, it is
invalid under § 103.”).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Chiba
and Zhu render obvious the claimed DNA library.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Chiba and Zhu. Pursuant to 37 C.F.R. §
41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 3-8 and 10-14
as these claims were not argued separately.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

dm

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