Ex Parte Angov et al

Patent Trial and Appeal Board

Dec 15, 2012

11907584 (P.T.A.B. Dec. 15, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte EVELINA ANGOV, JEFFREY A. LYON,
and RANDALL L. KINCAID
__________

Appeal 2012-002430
Application 11/907,584
Technology Center 1600
__________

Before STEPHEN WALSH, ERICA A. FRANKLIN, and
ULRIKE W. JENKS, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the rejection of
claims directed to a method for preparing a synthetic gene for optimal
expression. The Patent Examiner rejected the claims for containing new
matter, for anticipation, and for obviousness. We have jurisdiction under
35 U.S.C. § 6(b). We affirm.
Appeal 2012-002430
Application 11/907,584

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STATEMENT OF THE CASE
Claims 1-7 and 28 are on appeal. Claim 1 is representative and reads
as follows:
l. A method for preparing a synthetic gene for optimal expression, in a
host cell, of a foreign protein encoded by a foreign gene comprising
(i) identifying all codons that are associated with segments in the
protein that separate defined domain structures and that are used more
frequently in the host cell than in the cell from which the foreign gene was
obtained; and
(ii) replacing said codons with synonymous host cell codons that are
used at the same frequency or less frequently in the host cell than in the
foreign gene.

The Examiner rejected the claims as follows:
I. claims 1-7 and 28 under 35 U.S.C. § 112, first paragraph, as failing to
comply with the written description requirement because they contain
new matter;
II. claims 1-7 under 35 U.S.C. § 102(b) as anticipated by Hatfield et al.
(US 5,082,767, issued Jan. 21, 1992); and
III. claim 28 under 35 U.S.C. § 103(a) as unpatentable over Hatfield and
Chen et al. (US 7,501,553 B2, issued Mar. 10, 2009, as a division of
Application No. 09/175,684, filed Oct. 20, 1998).

I
The Issue
The Examiner’s position is:
The specification as originally filed does not provide support
for the invention as now claimed: “segments in the protein that
separate defined domain structures” (claim 1). This is a new matter
rejection. The specification does not provide sufficient blazemarks nor
direction for the instant methods encompassing the above-mentioned
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Application 11/907,584

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limitations, as currently recited. The instant claims now recite
limitations which were not clearly disclosed in the specification as-
filed, and now change the scope of the instant disclosure as-filed.
Such limitations recited in the present claims, which did not appear in
the specification, as filed, introduce new concepts and violate the
description requirement of the first paragraph of 35 U.S.C. 112.

(Ans. 5.)
Appellants contend:
It is respectfully submitted that the expression "segments in the
protein that separate defined domain structures" will be clearly
understood by persons of skill in the art, and literal support for the
expression can be found at page 4, line 29 to page 5, line 3 of the
specification as filed, wherein it is stated:

Regions of coding sequence with slower translation rates may
contain clusters of infrequently used codons and appear to be
associated with unstructured intradomain segments in the
protein that separate defined domain structures such as alpha
helices and beta-pleated sheets. [Underlining added]

It is clear from this passage that the term "intradomain" was used to
indicate segments that separate defined domain structures, as
presently recited in amended claim 1. Therefore, it is respectfully
submitted that the change from "intradomain", as recited in the
originally filed claims, to "segments in the protein that separate
defined domain structures" is fully supported, is not new matter, and
satisfies the written description requirement.

(App. Br. 4.)
The issue with respect to this rejection is whether the present scope of
“segments in the protein that separate defined domain structures” is fully
supported by the original Specification.

Appeal 2012-002430
Application 11/907,584

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Findings of Fact
1. The originally-filed Specification stated:
Regions of coding sequence with slower translation rates may contain
clusters of infrequently used codons and appear to be associated with
unstructured intradomain segments in the protein that separate defined
domain structures such as alpha helices and beta-pleated sheets.
Temporary ribosomal "pausing" on the intradomain segment is
thought to allow the preceding nacent [sic] protein domain to
complete folding prior to continuing synthesis of the next domain.

(Spec. 4-5, literature citation omitted.)
2. During prosecution, the Specification passage quoted in FF 1 was
amended to replace the word “intradomain” with the word
“interdomain” as follows:
Regions of coding sequence with slower translation rates may contain
clusters of infrequently used co dons and appear to be associated with
unstructured intradomain interdomain segments in the protein that
separate defined domain structures such as alpha helices and beta-
pleated sheets. Temporary ribosomal "pausing" on the intradomain
interdomain segment is thought to allow the preceding nascent protein
domain to complete folding prior to continuing synthesis of the next
domain.

(Amendment filed June 24, 2009, literature citation omitted.)
3. The ordinary meaning of “domain” is found in a biochemistry
textbook:
within a single folded chain or subunit, contiguous portions of the
polypeptide chain often fold into compact local units called domains,
each of which might consist, for example, of a four-helix cluster or a
barrel or an antiparallel β sheet. . . .
The separateness of two domains within a subunit varies all the
way from independent globular domains joined only by a flexible
length of polypeptide chain, to domains with tight and extensive
Appeal 2012-002430
Application 11/907,584

5
contact and a smooth globular surface for the outside of the entire
subunit, as in the proteolytic enzyme elastase (Figure 2-35). . . .
Domains as well as subunits can serve as modular bricks to aid
in efficient assembly of the native conformation. Undoubtedly the
existence of separate domains is important in simplifying the protein-
folding process into separable, smaller steps, especially for very large
proteins.

(Zubay 86.)

Principles of Law
The test for determining compliance with the written description
requirement is whether the disclosure of the application as originally
filed reasonably conveys to the artisan that the inventor had
possession at that time of the later claimed subject matter, rather than
the presence or absence of literal support in the specification for the
claim language.

In re Kaslow, 707 F.2d 1366, 1375 (Fed. Cir. 1983).

Analysis
The claim phrase at issue is “segments in the protein that separate
defined domain structures.” The Specification did not set out a special
definition for the phrase “defined domain structures.” Neither Appellants
nor the Examiner provide a definition. The ordinary meaning, as a person of
ordinary skill in the art would interpret it, can be found in a biochemistry
textbook. A biochemistry textbook is evidence of general knowledge in the
art showing how a person of ordinary skill in art would understand “defined
domain structures” and the segments that separate them. The Zubay
1

1
Geoffrey Zubay, BIOCHEMISTRY, 2
nd
ed., pp. 86-87 (Macmillan Pub. Co.
1988).
Appeal 2012-002430
Application 11/907,584

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textbook states that a domain may contain secondary structures such as α
helices, a barrel, and β sheets. (FF 3.) Zubay states that multiple domains
may be joined by a flexible length of polypeptide chain. (Id.) Applying
those definitional facts to the claim phrase “defined domain structures,” we
find that a person of ordinary skill in the art would understand it to refer to at
least two kinds of structures. First, it would include the defined structure of
a domain as a whole. The Zubay text provided illustrations of defined whole
domain structures. For example, Zubay’s Fig. 2-34 compares two defined
domain structures in rhodanase; and Zubay’s Fig. 2-35 illustrates two
domains in elastase. Second, it would include defined structures within a
domain, e.g., α helices, a barrel, and β sheets.
It follows that a person of ordinary skill in the art would understand
the claim phrase “segments in the protein that separate defined domain
structures” as referring to (i) interdomain segments separating whole domain
structures, e.g., the “flexible length” segment Zubay identified as joining
domains; and (ii) intradomain segments separating structures like α helices
and β sheets within a domain.
The Specification as originally filed explicitly related only to
intradomain segments. (FF 1.) A later-filed amendment discarded
intradomain and replaced it with interdomain. (FF 2.) The Examiner found
that a person of ordinary skill in the art would understand these to be
distinctly different things. Appellants provide no basis, other than attorney
argument, to find error by the Examiner. Contrary to Appellants’
arguments, the Examiner’s statements and analysis were entirely consistent
with textbook principles. A person of ordinary skill in the art reading the
claim phrase “segments in the protein that separate defined domain
Appeal 2012-002430
Application 11/907,584

7
structures” without reference to the Specification would understand it to
include both interdomain and intradomain segments. The originally filed
Specification did not describe both kinds of segments and did not support
the full scope of that meaning. Even if a person of ordinary skill in the art
read the claim phrase with reference to the amended Specification’s term
“interdomain” and understood the claim as limited to interdomain segments,
that interpretation would also lack support in the originally filed
Specification, which only addressed intradomain segments. We find the
rejection must be affirmed for the reasons the Examiner provided.
Finally, we note that Appellants assert the term “intradomain” was
recited in originally filed claims. (App. Br. 4.) This appears to be an error.
In our review of the eleven originally filed claims, we cannot find the term
“intradomain.” However, we agree that the originally filed Specification
recited “intradomain” at least twice. (FF 1.)
Claims 2-7 and 28 have not been argued separately and therefore fall
with claim 1. 37 C.F.R. § 41.37(c)(1)(vii).

II
The Issue
Appellants dispute whether Hatfield disclosed every limitation of the
claims, and specifically whether Hatfield obtained its protein structural
information in the same way Appellants obtain their structural information.
According to Appellants:
The information provided in Hatfield et al. regarding the exact nature
of the DNA binding protein turn region would have to be based on
either crystal structure information, or NMR, otherwise it would be
putative. The approach that the present inventors developed utilizes
Appeal 2012-002430
Application 11/907,584

8
information from a compilation of sequences from the genetic
database to predict regions in nucleotide sequences that will select
codons in segments in the protein that separate defined domain
structures (alpha helices and beta-pleated sheets). Although secondary
structure predictive algorithms have been available for some years, the
method disclosed and claimed in the present application is the only
one that is based on identifying specific codon frequency usage and
information concerning the appearance of specific amino acids
predicted to occur more frequently in these segments in the protein
that separate defined domain structures. Accordingly, it is respectfully
submitted that Hatfield et al. does not disclose each and every element
of the claimed invention, and does not anticipate claims 1-7.

(App. Br. 4-5.)
Discussion
The Examiner found Appellants’ argument unpersuasive because the
claims do not recite a process step for obtaining structural information and
are not limited by how protein structural information is obtained. (Ans. 9.)
We agree: claim 1 presumes knowledge of protein structural information,
without regard to how the information is obtained. Appellants do not
dispute that Hatfield used the same structural information. We have
reviewed the Examiner’s fact-finding with regard to the method defined in
claim 1 and agree that the evidence supports it. (See Ans. 6 and 9-10.) The
rejection is affirmed.
Claims 2-7 have not been argued separately and therefore fall with
claim 1. 37 C.F.R. § 41.37(c)(1)(vii).

Appeal 2012-002430
Application 11/907,584

9
III
The Issue
Appellants contend: “Chen et al. fails to remedy the failure of
Hatfield to disclose substitutions of selected codons in segments in the
protein that separate defined domain structures. Thus, even if Hatfield and
Chen were combined, it would not result in the present invention.” (App.
Br. 5.)
Discussion
Contrary to Appellants’ argument, the evidence supports the
Examiner’s finding that Hatfield disclosed substitution of selected codons in
segments in the protein that separate defined domain structures. (See Ans.
6.) We have reviewed the Examiner’s additional fact finding and agree that
the evidence supports the findings and the legal conclusion of obviousness.
(See id. at 6-7 and 10.) The rejection of claim 28 is affirmed.

SUMMARY
We affirm the rejection of claims 1-7 and 28 under 35 U.S.C. § 112,
first paragraph.
We affirm the rejection of claims 1-7 under 35 U.S.C. § 102(b) as
anticipated by Hatfield.
We affirm the rejection of claim 28 under 35 U.S.C. § 103(a) as
unpatentable over Hatfield and Chen.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

Appeal 2012-002430
Application 11/907,584

10
AFFIRMED

Attachments: Form 892
Geoffrey Zubay, BIOCHEMISTRY, 2
nd
ed., pp. 86-87
(Macmillan Pub. Co. 1988).

alw

Notice of References Cited

Application/Control No.

11/907,584
Applicant(s)/Patent Under
Reexamination
Angov, Evelina
Examiner

Vogel, Nancy
Art Unit

1600

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Zubay, Geoffrey, BIOCHEMISTRY, 2
nd
ed., pp. 86-87 (Macmillan Pub. Co. 1988).

V

W

X

*A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).)
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U.S. Patent and Trademark Office
PTO-892 (Rev. 01-2001) Notice of References Cited Part of Paper No.
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SECOND EDITION
BOCHEM STRY

Coordinating Author
GEOFFREY ZUBAY
COLUMBIA UNIVERSITY
MACMILLAN PUBLISHING CONIPANY
New York
COLLIER MACMILLAN PUBLISHERS

London

Copyright © 1088 , Macmillan Publishing Company , a divis ion of Macmillan , Jil L .
Printed in the United States of America
l\1\ rights reserved. No part of this book m~y be reproduced or transmitted in uny fo r m o r by an)'
rn e ~ns, electronic or mechanical, including photocopying, recordi ng , or an y in formatioll ~turage
and retrieval system, without permission in wriling from the [Jl,bli , her.
Earlier edilion cupyright W, 1983 by Addison-Wesley Publis hing Comp any, Inc .
Portions o[ this uDok are re printed wilh the permission of The Benjami n/C ummings r ll b li~h ing
Company, Inc., frolll their text titled Genetics by Ceoffrey Zl.lbay
Macmillan Publishing Company
866 Third i\venue, New York, New York 10022
Cullier Ma~millan C"nuda, Inc.
Library of Congress Cataloging-ill-Publication Data
Zubay, Geoffrey [,.
lliochemistry.
Includes index.
1. Biuchemistry. 1. Title.
QP514.2.Z!J3 1988 574.1\l ' ~ (\7-28201
ISBN 0-02-432080-3
Printing: "1 2 3 4 5 6 7 8 Year: B 9 0 1 2 :3 4 5 6 7
86 PART I I MAJOR COMPONENTS OF THE CELL
Papain domain 1
Papain domain 2
Figure 2-33
Papa in, a protein in which the
domain s ar~' ver d ifferent from onn
:1 110 the r.
Figure 2-34
Rhodflnesp. d om a ins '1 and 2 as iln
eXil m p l0. o f f1 pTO loin with two
dumain ,; tha t reliem bl e encll other
e tre l1lel y .:10. r; ly . Rh od illHJSC is it liver
enzy me tha t de to xifi es cynn ide by
.ala lyzing the formiltion of thiocyanate
from thios u lfll t Ild cYaIli de.
Figure 2-35
chern tic bac bo ne drawing of the
·lasta e molCGlIie , showing the s imilar
,l3 -barrel s tru ct ures of tho t'~vo domains.
The ou ts ide surfJ ces of th e f3 barrels
are stip Ind .
has shown that they incorporate several different sorts of recurring tructural
arrangements . In general , these arrangements owe their origins to physica l
effects , some of \.vhich predispose the most stable conformations of the poly­
peptide chain, and some of which govern the formation of intimatel packed
tertiary structures.
Domains Are Functiona l Units of Tertiary Structure. Thp patterns of terti­
ary structure described in this and previous sections frequently constitute
the entire protein. HO\o\.lever, within fl single folded r. hain or subun it, contig­
uous portions of the polypeptide chain often fold into compact local units
called domains , each of which might consist , tor e ample, of a four-helix
cluster or a barrel or an antiparallc l f3 sheet Somelimes the domains w ithin a
protein are very different from ono another, as within the protease papain
(F igure 2-33), but often they resemble each other very c10s ly, as in rhoda­
nase (Figure 2-34).
The separateness of t\>\IO domains within a subuni t varies aJl the way
from independenl globular domains joined only by a fl ex ible length of poly­
peptide chain. to domaills with tight anc\ extensive contact and smooth
globular surface for the ou tside of the entire subunil, as in tho proteolytic
enzyme elastase (Figure 2-35). An inlermediate level of domain se~arate­
ness, characterized by a definite Ileck or cleft belv een the doma ins, is found
in phosphoglycerate kinase (Figure 2-36).
Domains as well as subunits can serve as mod u lar bricks to aid in effi­
cient assembly of the nalive conformalion. Undoubledly the existence of
separate domains is important in s implifying the protein-folding process
into separable , smaller steps. especially for very large proteins. There is no
strict upper limit on fo lding size. Indeed, known domains vary in size all the
way from about 4 0 residues to over 400.
Rhodanese domain 1 Rhodanese domain 2
Elastase
87 CHAPTER 2 I THE THREE-DIMENSIONAL STRUCTURES OF PROTEINS
Figure 2- 36
The d umbbell domain organization of
phosp h glycerate kinase, with a
re lative ly narrow neck between two
; ell-separated domains.
6 +· 6
E+G E·G
It 11
cO -+- Q=J

E' E' · G
Figure 2-37
Schemat ic re presentation of the
chQ:Jge in conformation of the
hexoki nase enzyme on binding
s h~ t rat . E and E' an: the inactive
nd ac tive co nformations of the
cuzv me , respectively. G is the sugar
substra te. Regions of protein or
substrate s illfac!! excluded from
t;OlLtac t wi th solvellt are indicated by a
il1kled line. (Adapted from W. S.
[j en nett El nd T. }\. Steitz, Glucose­
ind uc",d conformational change in
yea t hexokinase, Proc. f\Jatl. Acad.
S.; i. US A. 75:4848, 1978.)
Another important function of domains is to allow for movement. Com­
pletely flexible hinges would be impossible between subunits because they
would simply fall apart. However, flexible hinges can exist between cova­
lently linked domains. Limited flexibility between domains is often crucial
to substrate binding, allosteric cOllt.rol (discussed in Chapter 10), or assem­
bly of large structures. In hexokinase, the two domains within the individual
subunits hinge toward each other upon binding of the substrate gIll ose ~
enclosing it almost completely (Figure 2-37). In this manner glucose can be
bOllild in an environment that excludes water as a competing substrate (see
Chapter 14 for further details on the hexok.inase reaction).
Qualemary SlructUl'e Involves Subunit Interaction
i\lthough many globular proteins function as monomers biol ogical syst ems
abound with examples of complex protein assemblies (Table 2- 4) . This
higher-order organization of several globular subunits to form fu nctional
aggregate is referred to as the quaternary structUfJ:l of the pro tein . Protein
quaternary structures call. be classified into two types. One type involves the
assembly o£ different kinds of subunits. Examples range from cli meTic mole­
cules that contain different molecular subunits to complex assemblies such
as ribosomes (which also contain ribonucleic acid as a structural compo­
nent). The organization of these sorts of quaternary structures depends on
the specific nature of each interaction occurring between the different mo­
lecular subunits and their neighbors. Each intermolecular interaction gener­
aUy occurs only once within a given aggregate arrangement, so th t th over­
all complex struclure has a highly ilTegular geometry.
A second observed pattern of quaternary stru cture is lypified in molecu­
lar aggregates composed of mu ItipJe copies of one or more different kinds of
subunits. Owing to the recurrence of specific structural interactions between
the subunits, such aggregates typically form regular geometric arrangements.
Structures of this type are found most frequently in the coa ts tha t surround
viruses. Satellite tobacco necrosis virus and tobacco mosaic virus r e exam­
ples of these (see Table 2-4). The protein tllhulin (life Figure 2- 12e) is an­