Ex Parte Lyons et al

Patent Trial and Appeal Board

Mar 27, 2013

10732862 (P.T.A.B. Mar. 27, 2013)

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.
10/732,862 12/10/2003 Katelynne Lyons LOR-136.0 (9720/88881) 9117
24628 7590 03/28/2013
Husch Blackwell LLP
Husch Blackwell Sanders LLP Welsh & Katz
120 S RIVERSIDE PLAZA
22ND FLOOR
CHICAGO, IL 60606
EXAMINER
LUCAS, ZACHARIAH
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
03/28/2013 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte KATELYNNE LYONS, ASHLEY J. BIRKETT, and
JAY A. HARON
____________

Appeal 2011-005451
Application 10/732,862
Technology Center 1600
____________

Before TONI R. SCHEINER, LORA M. GREEN, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to a
recombinant hepatitis B core molecule. The Examiner has rejected the
claims as lacking written descriptive support, lacking enablement, as
obvious, and under nonstatutory obvious-type double patenting. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

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STATEMENT OF THE CASE
The Specification is directed to the production of an “immunogen for
a vaccine or inoculum comprised of a recombinantly engineered
hepadnavirus nucleocapsid protein; i.e., a hepatitis B core (HBc) chimeric
protein . . . that self-assembles into particles after expression by a host cell.”
(Spec. 12.)
Claims 1-47 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief (App. Br. 60-79). Claims 1, 11, 25, and 47 are
independent claims.
The following grounds of rejection are before us for review:
The Examiner has rejected the claims as follows:
I. claims 1-47 under 35 U.S.C. 112, first paragraph as failing to
comply with the written description requirement;
II. claims 1-47 under 35 U.S.C. 112, first paragraph as failing to
comply with the enablement requirement;
III. claims 1-6, 8-14, 16-28, 30-42, and 46 under 35 U.S.C.
§ 103(a) as unpatentable over Pumpens
1
in view of Zlotnick
2

and Zheng;
3

IV. claims 1-6, 8-28, and 30-46 under 35 U.S.C. § 103(a) as
unpatentable over Page,
4
Birkett,
5
both in view of Zheng;

1
P. Pumpens et al., Hepatitis B Virus Core Particles as Epitope Carriers, 38
INTERVIROLOGY 63-74 (1995).
2
A. Zlotnick et al., Localization of the C Terminus of the Assembly Domain
of Hepatitis B Virus Capsid Protein: Implications for Morphogenesis and
Organization of Encapsidated RNA, 94 PROC. NATL. ACAD. SCI. USA 9556-
9561 (1997).
3
Jian Zheng et al., The Structure of Hepadnaviral Core Antigens, 267 J.
BIOLOGICAL CHEMISTRY 9422-9429 (1992).
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V. claims 1-46 as unpatentable under obvious-type double
patenting over (1) claims 1-78 of 09/930,915; (2) claims 1-53 of
10/787,734 (now US Pat. No. 7,361,352); (3) claims 1-22, 25,
26 of 11/507,083;
VI. claims 1-6, 8-28, and 30-46 as unpatentable under obvious-type
double patenting, as being obvious over claims 1-19 of Birkett
in view of Page and Zheng.

I. - WRITTEN DESCRIPTION
The Examiner takes the position that even “[s]ubstitution of a
single amino acid can result in an unpredictable effect on the assembly of
HBc particles.” (Ans. 6.) “Support for a genus is generally found where the
Appellant has provided a sufficient number of examples so that one skilled
in the art would recognize from the specification the scope of what is being
claimed, or provided a function and a structure correlating with that
function.” (Id. at 5.) The Examiner takes the position that the Specification
does not provide sufficient written description for the claimed stabilized
HBc particles, citing MPEP 2163 (id. at 4). To support the Examiner‟s
position that there is uncertainty in the art, the Examiner cites to Example 14
of the Specification where only 7 out of 24 chimers yielded particles, and 14
chimers lost their ability to form particles altogether (id. at 5-6).
The issue with respect to this rejection is: Does the Specification
describe HBc chimer sequences that have up to 5% mutations in the amino
acid sequence of SEQ ID NO: 1?

4
Mark Page et al., WO 01/98333 A2, published Dec. 27, 2001.
5
Ashley J. Birkett, US 6,231,864 B1, issued May 15, 2001.
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After considering all the evidence and arguments, we agree with
Appellants‟ position that the disclosure in the Specification sufficiently
describes the chimeric sequences. “[T]he written description requirement
does not demand either examples or an actual reduction to practice; a
constructive reduction to practice that in a definite way identifies the
claimed invention can satisfy the written description.” Ariad
Pharmaceuticals, Inc. v Eli Lilly and Co., 598 F.3d 1336, 1352 (Fed. Cir.
2010).
Here, Appellants rely on the prior art to satisfy the description
requirement by citing to the LASERGENE software, that provides guidance
with regard to conservative and non-conservative substitutions (Spec. 74),
and the description of regions in the HBc that can accommodate
conservative substitutions (App. Br. 18, 19; Spec. 25, 73). We find that the
Specification guides the artisan to make conservative substitutions to the
non-helical portion of the HBc molecule as well as make changes to the
cysteine residues so that particle formation is retained. In addition, the
Specification has provided examples of HBc mutants that not only have
retained their ability to make particles but also have been shown to be stable
at 37ºC (Spec. 186).
The Examiner cites Example 14 of the Specification as experimental
evidence that shows only 7 out of 24 HBc chimer molecules are able to form
particles (Ans. 5-6), to support the position that there is unpredictability in
the art. We are not persuaded, and find that this experimental evidence
where almost 30% of the HBc chimer molecules retain their particle forming
ability is evidence of reduction to practice of the claimed invention. Further,
the Specification provides that “all particles (except non-C terminally
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stabilized controls) that were incubated at 37°C were entirely disulfide
bonded after a period of 7 days.” (Spec. 192.) These results are consistent
with what was already known in the art (see below FFs 10, 12, 13). In
addition, the Specification provides that the “C48S/C107S epitope-carrying
particles behaved in a manner similar to their wild type counterparts,
signifying that these mutations did not affect particle assembly.” (Spec.
193.) This evidence further supports Appellants‟ position that the
Specification provides sufficient descriptive support to meet the written
description requirement of the subject matter presently claimed.
Accordingly, we reverse the Examiner‟s rejection.

II. - ENABLEMENT
The Examiner takes the position that the Specification does not
provide the ordinary artisan with sufficient guidance to make the invention
commensurate in scope with the claims. (Ans. 7-8.) Specifically, the
Examiner finds that “[t]he scope of [the] claims encompasses a large number
of HBc chimers that contain 5% substitutions variously arranged along the
sequence of SEQ ID No: 1.” (Id.) The Examiner finds that “a single amino
acid can create problems resulting from changes in conformation that can't
be adequately predicted in advance.” (Id. at 8.) The Examiner concludes
that “the specification does not enable those of skill in the art to make the
claimed invention commensurate in scope.” (Id.)
The issue with respect to this rejection is: Does the Specification
provide guidance on how to make a HBc particle that has up to 5%
mutations in the amino acid sequence and shows increased stability?

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Findings of Fact
FF 1. Example 13 of the Specification shows particle formation of
chimers carrying cysteine mutations. Table 12 is reproduced below:

(Spec. 190.)
FF 2. The Specification provides that:
[A]ll particles (except non-C terminally stabilized controls) that
were incubated at 37°C were entirely disulfide bonded after a
period of 7 days. Of particular note was the fact that the C-
terminally stabilized C48S/C107S chimer appeared to be
entirely disulfide bonded at day zero, whereas its C48/C107
counterpart was not and did not reach the same level of cross-
linking achieved by the C48S/C107S chimers during the period
of study.
(Spec. 192.)
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FF 3. Example 14 of the Specification characterizes the formation of
particles from clones with mutations of the cysteine residues and carrying
epitopes. Table 13 is reproduced below:

(Spec. 194-195.)
FF 4. The Specification provides that “[s]ubstitutions, other than in
the immunodominant loop of Domain II or at the termini, are preferably in
the non-helical portions of the chimer molecule and are typically between
residues 2 to about 15 and residues 24 to about 50 to help assure particle
formation.” (Spec. 75.)
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Appellants assert that not all permutations of the generic claim need to
be operable in order to meet the enablement requirement, citing In re
Angstadt, 537 F.2d 498 (CCPA 1976). Here, computer guidance can help
determine “which amino acid residues can be substituted, inserted or deleted
without abolishing biological activity or particles formation can be found
using computer programs known in the art such as LASERGENE.” (App.
Br. 19.) Appellants further assert “that substitutions are preferably in the
non-helical portions of the molecule between residues 2-15 and 24-50 to
help assure particle formation.” (Id.) In support, Appellants point to Table
13 of the Specification, that shows particles with an inserted cysteine residue
at the C-terminus are more stable. (Id. at 17.)
“[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed invention
without „undue experimentation.”‟ Genentech, Inc. v. Novo Nordisk, A/S,
108 F.3d 1361, 1365 (Fed. Cir. 1997)(quoting In re Wright, 999 F.2d 1557,
1561 (Fed. Cir. 1993)). “That some experimentation may be required is not
fatal; the issue is whether the amount of experimentation required is
„undue.”‟ In re Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991). Some
experimentation, even a considerable amount, is not “undue” if, e.g., it is
merely routine, or if the specification provides a reasonable amount of
guidance as to the direction in which the experimentation should proceed.
See In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Here, after considering all the evidence and arguments, we agree with
Appellants that based on the disclosure in the Specification, the skill in the
art, the state of the prior art, and the breadth of the claims, a skilled artisan
would not have had to resort to undue experimentation to arrive at the
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claimed recombinant hepatitis C core protein molecules. Although it is
recognized that not all mutations in the HBc core protein will result in a
particle (Spec. 6, 7), we find that Appellants have disclosed several cysteine
substituted HBc chimer molecules that produce particles as recited in
claim 1 (FF 1). Even though the Specification did not produce a chimer
molecule with 5 percent of the amino acid sequence substituted in SEQ ID
NO: 1, we find that the totality of the evidence, however, still weighs in
Appellants‟ favor (FFs 1-3). Even if not all cysteine substituted chimer
particles will be stable for 14 days, this claim limitation can easily be
assessed by the ordinary artisan. Additionally, the Specification provides
guidance to where in the chimer molecule substitutions may be made and
what areas should be avoided for substitutions (FF 4).
We find that the state of the art at the time of the claimed invention
would have allowed the ordinary artisan to make substitutions in the amino
acid sequence of HBc. The issue is whether the experimentation required to
arrive at the claimed invention is undue. We find that it would not have
been undue to make the mutations as claimed, given the guidance in the
Specification (FFs 1-4) and what the ordinary artisan would have known at
the time of the claimed invention given the state of the art in the field of
HBc chimer molecules (Spec. 1-12).
Accordingly, we reverse the non-enablement rejection.

III.
The Issue
The Examiner takes the position that the claimed Hbc immunogenic
particles are obvious in view of Pumpens, Zlotnick, and Zheng. The
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Examiner finds that Pumpens disclosed:
These chimers contain an HBc sequence of at least about 130 of
the 150 N-terminal amino acid residues of the HBc molecule
(See for instance Fig. 1, pg. 64) that include a peptide-bonded
heterologous epitope (Table 1, page 66) or a heterologous linker
residue which code for epitope present in the HBc
immunodominant loop at positions 76 through 85 (see page 69,
col. 1, last paragraph). Pumpens discloses that HBc chimeras
with C-terminal truncations are capable of self-assembly and do
not bind or 'pack' nucleic acids in their capsid particles (page
67, col. 1).
(Ans. 9.) The Examiner recognizes that “Pumpens does not explicitly teach
replacing one or both cysteine residues at positions 48 and 107 by another
residue and adding a C-terminal cysteine residue to achieve the stabilizing
effect.” (Id. at 10.) The Examiner relies on the additional references for
these teachings. The Examiner concludes that it would have been obvious
to:
[M]ake a C-terminal truncated HBcΔ chimera containing an
epitope at its N-terminus, immunodominant loop, or C-terminal
region, or containing two epitopes is these areas, in which
native Cys48 and/or Cysl07 are conservatively replaced by
another residue, and a heterologous cysteine is added at the C-
terminus of HBcΔ. One of ordinary skill in the art would have
been motivated to do so and would have reasonable expectation
of success that such HBcΔ chimera would be capable of
incorporating foreign epitopes, and be free of viral nucleic acid
binding and with enhanced stability, given the knowledge
HBcΔ chimeras are free of viral RNA, while still capable of
self-assembly as taught by Zlotnick, and a various of HBcΔ
chimera containing an epitope(s) at its N-terminus,
immunodominant loop, or/and C-terminal region have been
successfully made as taught by Pumpens, given the knowledge
that the addition of a heterologous cysteine residue to an HBcΔ
C-terminal truncation results in dimer formation and enhanced
stability, as taught by Zlotnick, and also given the knowledge
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that native Cys48 and Cysl07 are not essential for HBc dimer
formation, as taught by Zhang.
(Ans. 11.)
Appellants assert that a prima facie case has not been made based on
the combination of Pumpens, Zlotnick, and Zheng (App. Br. 33; Reply Br.
22.)
Claims 1, 11, and 47 require, in pertinent part, an HBc immunogenic
particle having an HBc sequence were “one or both cysteine residues at
positions 48 and 107 is replaced by another residue, and in which the
cysteine at residue position 61 is present;” while claim 25 requires the
substitution of the cysteine at position 48 by another residue and maintaining
the cysteines at position 61 and 107.
The issue presented is: Has the Examiner established by a
preponderance of the evidence that it is obvious to make an HBc particle
having “one or both cysteine residues at positions 48 and 107 . . . replaced
by another residue, and in which the cysteine at residue position 61 is
present” as required by the claims?

Additional Findings of Fact
FF 5. We adopt the Examiner‟s findings of fact and conclusions
concerning the disclosure of the prior art. We highlight the following
findings for discussion purposes.
FF 6. Pumpens disclosed regions for insertion in the HBc core
protein. Figure 1 is reproduced below:
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(Pumpens Fig. 1; Ans 9.) Fig. 1 depicts a homology based model of HBc
protein, the β-sheets are designated, and regions permissive to insertions are
indicated as heavy lines, and arrows are directed toward insertion sites,
specifically showing internal insertions, N-terminal insertions, and C-
terminal insertions. (Pumpens Fig. 1; Ans. 9.)
FF 7. Pumpens disclosed that up to 39 C-terminal amino acids, out of
a total 183, can be deleted from the sequence and still retain particle
assembly. “These HBcΔ capsids are indistinguishable from native HBc
particles by electron cryomicroseopy [] but fail to pack nucleic acid and
appear as empty shells.” (Pumpens 67; Ans. 9.)
FF 8. Pumpens disclosed that “[a]lthough capsids formed by C-
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terminally truncated HBc monomers are less stable than the corresponding
full-length protein particles [], foreign insertions are not only possible but
also exert a stabilizing effect on chimeric HBcΔ derivatives especially in the
case of internal insertions.” (Pumpens 67; Ans. 9.)
FF 9. Pumpens disclosed examples of “HBV core particles as carriers
of epitopes inserted at N-terminus of HBc protein (full length)” (Pumpens
Table 1; Ans. 9), “HBV core particles as carries of internally inserted
epitopes.” (Pumpens Table 2; Ans. 9), and “HBV core particles as carriers
of epitopes inserted at C-terminus of full-length and C-terminally truncated
HBc protein” (Pumpens. Table 3; Ans. 9).
FF 10. Zlotnick disclosed the addition of a C-terminal cysteine
residue. Figure 1 is depicted below:

(Zlotnick 9557.)
Fig. 1 Schematics of Cp sequences (a) and disulfide
bonding (b). (a) The constructs are referred to as Cp followed
by the number of the C-terminal residue, thus, Cp149 is a 149-
residue protein. In Cp*149 the cysteines found in the native
sequence, residues 47, 61, and 107, are mutated to alanine.
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Cp*150 has arginine 150 replaced by a C-terminal cysteine.
The protamine domain of Cp183, residues 150-183, is shaded.
The Cp183 construct has eight N-terminal residues (hatched
box) derived from a cloning vector (29). (b) Shown are
silhouettes of two Cp150 dimers connected by a disulfide bond
between Cys-150 residues. Each molecule also contains an
intradimer disulfide bond linking its two Cys-61 residues across
the dyad axis.
(Zlotnick 9557.)
FF 11. Zlotnick disclosed:
Using Cp constructs progressively truncated from the C
terminus, we found that residues 138-149 play an influential
role in morphogenesis in vitro. About 95% of the capsids
assembled from a 149-residue Cp (CpI49) have the T = 4
morphology; decreasing to ≈20% for Cp140. Further truncating
the protein by two residues renders it incapable of assembly.
(Zlotnick 9556 (citations omitted).)
FF 12. Zlotnick disclosed that “Purified Cp*149 and Cp*150
assemble into capsids under the same conditions as other Cp constructs.”
(Zlotnick 9558.) “These [cysteine] bonds stabilize the quaternary structure
of the capsid, as attested by the observation that oxidized Cp*150 capsids-
unlike CP*149 capsids or reduced Cp*150 capsids-are resistant to
dissociation by 3.5 M urea (Fig. 2b).” (Zlotnick 9558; Ans. 25.)
FF 13: Zlotnick provides:
[W]hen Cp proteins are stored in a low ionic strength, high pH
buffer they do not polymerize. . . . However, when stored in
this buffer without DTT, Cp*150 dimers assemble into capsids,
as determined by negative stain electron microscopy and
analytical ultracentrifugation. A high proportion of the protein
in these capsids is disulfide-bonded (Fig. 2a). These data show
that disulfide bond formation by Cp* 150 can promote capsid
assembly. Without disulfide formation, higher-order structures
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do not accumulate in storage buffer, i.e., the rate for
dissociation is greater than the rate of association. Formation of
these disulfide bonds stabilizes complexes against dissociation.
(Zlotnick 9558; Ans. 25.)
FF 14. Zheng disclosed that:
[D]isulfide bonds are not essential for core particle formation.
No intra-chain disulfide bonds occur [when there is no cysteine
present]. Cys
l07
is a free thiol buried within the particle
structure, whereas Cys
48
is present partly as a free sulfhydryl
which is exposed at the, surface of the particle. Cys
61
is always
and Cys
48
is partly involved in interchain disulfide bonds, with
the identical residues of another monomer, whereas Cys
163
is,
always involved in a disulfide bond with the Cys
183
of a
different monomer.
(Zheng Abstract; Ans. 10.)
FF 15. Zheng disclosed the elimination of cysteine residues in a
16-kD HBcAg molecule, the 39 C-terminal amino acids have been deleted
and the molecule retains particle formation (Zheng, 9422). Zheng
sequentially mutated the internal cysteine residues at position 48, 61, and
107 in the 16-kD HBcAg molecule. The following cysteine mutations were
made: Cys
48
, Cys
61
, Cys
107
, Cys
48
and Cys
61
while retaining cysteine at
Cys
107
,

Cys
48
and Cys
107
while retaining the cysteine at Cys
61
(id. at 9424-
9425).

Principle of Law
“Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in isolation,
but for what it fairly teaches in combination with the prior art as a whole.”
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In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). “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).

Analysis
Appellants assert that Pumpens teaches away from the present
invention because the elimination of N-terminal amino acids results in a
disappearance of chimeric particles (App. Br. 25), citing that “25% of the
HBc constructs made were unable to assemble into capsid particles” (id.).
We are not persuaded by this argument. A prior art reference is said
to teach away from an Applicant‟s invention “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 Gurley, 27 F.3d 551, 553
(Fed. Cir. 1994). Pumpens disclosed that the portion of the “HBc sequences
required for self-assembly was later located between amino acids 139 and
144” (Pumpens 66). Although Pumpens recognizes that truncated HBc
monomers may be less stable, the reference, more importantly, also
recognizes that “foreign insertions are not only possible but also exert a
stabilizing effect on chimeric HBcΔ derivatives especially in the case of
internal insertions” (FF 8). Additionally, Table 1 of Pumpens shows
particles as epitope carriers where the epitopes are inserted at the N-terminus
of a full length HBc protein, and a total of 12 out of 16 constructs formed
particles. The argument that 25% of the chimers did not form particles is not
persuasive because the data indicate that 75% of the chimers do form
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particles. This means that it would be more likely, than not, that a HBc
chimeric construct will form particles, as required by the present claims.
Thus, contrary to Appellants‟ position, the ordinary artisan reading Pumpens
would not be discouraged from using HBc chimer particles because the
artisan would know that the insertion of foreign sequences provides a
stabilizing effect.
Appellants assert that Zlotnick also teaches away from the present
invention because “Zlotnick[„s] molecules have no cysteines, but rather the
substitution of all of Cys48, Cys61, Cysl07, and Arg150 for alanines.”
(App. Br. 25.) According to Appellants, “HBc chimer having a cysteine at
the 150 position that is bonded to a gold cluster is „unimpaired in its ability
to form capsids.‟ This teaches one of skill in the art that this molecule,
although it has no free C-terminal cysteine, was able to form capsids.” (Id.
at 26.) “Zlotnick emphasized that purified Cp*149 and Cp*150 assembled
into capsids under the same conditions as did other Cp constructs, with or
without DTT.” (Id.) Appellants contend that “Zlotnick suggests that other
forces are at work besides cysteine binding in terms of capsid assembly.”
(Id. at 31.) “All in all, Zlotnick does not provide valid support for the
premise that C-terminal cysteines enhance stability.” (Id.)
We are also not persuaded by these arguments. Zlotnick disclosed
that “[t]he capsid protein of hepatitis B virus, consist[s] of an „assembly‟
domain (residues 1-149) and an RNA-binding „protamine‟ domain (residues
150-183) . . . . The C terminus of the assembly domain (residues 140-149)
functions as a morphogenetic switch, longer C termini favoring a higher
proportion of the larger capsids.” (Zlotnick Abstract.) Assembly and
stability are two separate and distinct requirements. The amino acid residues
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140-149 of the HBc core are involved in the assembly and formation (FFs 7,
11) of particles while the presence of the cysteine stabilizes the formation of
particles (FF 12). Thus, it is not surprising that CP*149 and CP*150
assemble into capsids, because the ordinary artisan at the time the invention
was made would have known that amino acids 139-144 are required for
particle assembly (FFs 7, 11), and this sequence is present in both if
Zlotnick‟s CP*149 and CP*150 constructs. Because the amino acid
sequence from 139-144 does not contain any cysteine residues, it is also not
surprising that removing cysteine residues from the HBc sequence would not
affect the assembly of the capsid particles. However, that does not mean
that cysteine residues are not important for stabilizing the particle once they
have formed.
When reduced CP*150 capsids were stored without DTT for 2
days, >90% of the protein oxidized to form disulfide-bonded
dimers (Fig. 2a). These bonds stabilize the quaternary structure
of the capsid, as attested by the observation that oxidized
Cp*150 capsids-unlike CP*149 capsids or reduced Cp*150
capsids-are resistant to dissociation by 3.5 M urea (Fig. 2b)
(Zlotnick, 9558). Oxidized CP*150, those with disulfide dimers, form
particles that are resistant to treatment with 3.5 M urea as shown on SDS-
Page and by size exclusion chromatography (Zlotnick, Fig. 2; Ans. 10).
We are not persuaded by Appellants assertion that gold labeling
induces capsid assembly. We find Zlotnick discloses that “less than 20% of
the protein is [gold] labeled” (Zlotnick, 9559), that means only 1 in 5
molecules contains an Au11 at the C-terminal cysteine. That leaves 4 out of
every 5 molecules free to form disulfide dimers. Even though Au11 may
promote polymerization of CP*150, “[t]he Au11 has a single reactive
maleimide group and cannot crosslink proteins” (Zlotnick, 9558), the
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stabilization seen by the experiments using the 3.5 M urea conditions would
be due to the disulfide bond formation and not due to any artifact of the Au
label as suggested by Appellants. The important teaching from Zlotnick is
that adding a cysteine to the C-terminus stabilizes the dimers once they are
formed, when compared to particles that do not have cysteine bonds. In
addition, Zlotnick at figure 1B suggests having a cysteine at position 150 as
well as 61 in order to stabilize the dimer (FF 10).
Appellants assert that “[i]t further cannot be agreed with that Zheng
teaches interchain disulfide bonds are involved in the formation of HBc
capsid dimers as alleged in the Action.” (App. Br. 32.) “Zheng clearly does
not teach that cys61 and cys183 are required for core particle formation as
alleged.” (Reply Br. 23.)
Zheng discloses the production of HBcAg particles and dimer
formation, with mutations in the cysteine residues at positions 48, 61, and
107 (FF 14). Unlike the cysteine mutations disclosed in Zlotnick, where all
three cysteines were replaced by alanine, Zheng disclosed making targeted
individual mutations at position 48 and 107 while retaining the cysteine at
61, as well as making a targeted mutation at position 48 while retaining the
cysteines at position 61 and 107 (FF 15). Just because certain residues are
not important for particle formation does not mean that these same residues
are not important for particle stabilization. We find that Zheng disclosed
dimer formation even in the absence of intra-chain disulfide bonds (FF 14).
Furthermore, Zheng disclosed that Cys107 is not available for disulfide bond
formation because the residue is buried in the structure, while, when present,
Cys61 is always involved in interchain disulfide bonds (id.). While Cys48 is
sometimes involved with interchain disulfide bond formation with a Cys48
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from another monomer (id.). In contrast, the Cys183 is always disulfide
bonded to another Cys183 of another molecule (id.). Thus, Zheng tells the
ordinary artisan that Cys 61 and Cys183 are always involved in disulfide
bonding in the HBc core protein.
The combination of Zheng and Zlotnick would lead the ordinary
artisan to conclude that although none of the four naturally occurring
cysteine residues are involved in capsid formation, the presence, however, of
a C-terminal cysteine stabilizes the capsid once it has formed. Specifically,
Zlotnick teaches that the “[f]ormation of disulfide bonds stabilizes the
complex from dissociation” (FF13), thereby driving the reaction rate toward
capsid assembly. The Examiner finds that “Zhang teaches that Cys48 and
Cys107 are not essential for formation of an interchain disulfide bond with
another monomer because mutations of Cys48 and Cys107 do not affect
formation of HBc dimers, while Cys61 is important for formation and
maintaining an HBc dimer.” (Id. at 30.) We agree with the Examiner and
find that Zheng specifically taught mutating the wild type 16 kDa HBcAg, a
truncated core protein that is capable of forming particles; and that “Zhang
teaches that Cys48 and Cys 107 are not essential for formation of an
interchain disulfide bond with another monomer because mutations of Cys48
and Cys107 do not affect formation of HBc dimers, while Cys61 is
important for forming and maintaining an HBc dimer.” (Ans. 30.) Because
disulfide bond formation stabilizes the formed capsid, only those cysteine
residues that are involved in interchain disulfide bonding, as disclosed by
Zheng, would be important to retain for the stabilization of the particle.
We agree with the Examiner‟s conclusion that “Zlotnick teaches that
„bond formation by Cp*150 can promote capsid assembly‟ and „stabilizes
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complexes (capsid particle) against dissociation‟ . . . . This experiment by
itself teaches that C-terminal cysteines are important for HBcΔ capsid
formation and stability.” (Ans. 27-28.) We also agree with the Examiner‟s
finding that “Pumpens teaches immunogenic compositions and vaccines
using recombinant HBc chimer molecules of a variety of lengths up to about
380 or 600 amino acid residues in length” (Ans. 9) as well as with the
Examiner‟s finding that “Cys61 is important forming and maintaining an
HBc dimer” (Ans. 30). “The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR, 550 U.S. at 416.
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that the combination of Pumpens,
Zlotnick, and Zheng, renders obvious the chimeric cysteine stabilized HBc
molecules of claim 1. We thus affirm the rejection of claim 1 under 35
U.S.C. § 103(a) as being obvious, and claims 2-6, 8-28, and 30-46 were not
separately argued and fall with claim 1. Arguments not made are waived.
See 37 C.F.R. § 41.37(c)(1)(vii).

IV.
The Issue
The Examiner takes the position that the claimed HBc particles are
obvious over Page, Birkett, and Zhang. According to the Examiner “Page
teaches „[t]he removal of the arginine repeats residues [responsible for] the
binding of nucleic acid, whilst retention of the C-terminal cysteine allows
for the formation of a disulphide [sic] bond which in the native structure is
important for the formation of a stable particle.‟” (Ans. 12.) Birkett teaches
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the incorporation of heterologous linker residues while Zhang provides
HBcAg mutants where the cysteine residues have been replaced (id. at 13).
Specifically, “Zheng teaches that the native Cys107 is buried within the
particle structure and is not involved in HBc capsid formation. The native
Cys61 and Cys183 are always, and Cys48 is partially, involved in inter-
chain disulfide bonds with the identical residues of another monomer.” (Id.
at 10.) The Examiner concludes that:
It would have been obvious to one of ordinary skill in the
art to make a C-terminal truncated HBcΔ chimera containing an
epitope(s) at its N-terminus, immunodominant loop, or/and C-
terminal region, wherein a heterologous linker residue for a
conjugated epitope is present in the HBc immunodominant loop
between amino acid residues 76 and 85, wherein a cysteine is
added at their C-terminus, and native Cys48 and/or Cysl07 are
conservatively replaced by another residue. One of ordinary
skill in the art would have been motivated to do so and would
have reasonable expectation of success, given the knowledge
that HBcΔ chimeras are capable of incorporating foreign
epitope(s) at their N-terminus, immunodominant loop, or/and
C-terminal region, and also capable of forming viral RNA-free
capsid, as taught by Page, given the knowledge that
addition/retention of C-terminal cysteines allows the formation
of a stable HBcΔ dimer particle as taught by Page, given the
knowledge that HBc chimera containing a chemically-reactive
linker residues for a conjugated hapten at their
immunodominant loop have been successfully made, as taught
by Birkett, and also given the knowledge that native Cys48 and
Cys107 are not essential for HBc dimer formation, as taught by
Zhang.
(Id. at 13.)
The issue is: Has the Examiner established by a preponderance of the
evidence that it is obvious to make an HBc particle having “one or both
cysteine residues at positions 48 and 107 . . . replaced by another residue,
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23
and in which the cysteine at residue position 61 is present” as required by
the claims?

Additional Findings of Fact
FF 16. Page disclosed that:
[A] clone in which one or more of the arginine repeats of
HBcAg is removed but in which the C-terminal cysteine is
retained. The removal of the arginine repeats reduces binding
of nucleic acid, whilst retention of the C-terminal cysteine
allows the formation of a disulphide bond which in the native
structure is important for the formation of a stable particle. The
deleted repeat(s) may be replaced with sequences encoding T -
helper, B or CTL epitopes from bacterial or viral pathogens,
parasites, allergens or cancer associated antigens. This is made
possible by insertion of a suitable cloning site in place of the
deleted region.
(Page 2; Ans. 12.)
FF 17. Page disclosed that:
There are three preferred regions for insertion of the
epitopes, namely the C-terminus in place of deleted arginine
repeat(s), the e1 loop and the N-terminus. These three regions
all tolerate well insertion of foreign sequences. When an
epitope is placed in the e1 loop of HBcAg, it may be inserted in
the sequence of amino acid residues 68 to 90, 69 to 90, 71 to
90, 75 to 85 or 78 to 83. Most preferred is to insert the epitope
between residues 79 and 80 or 80 and 81. HBcAg residues
from the e1 loop may be deleted in proteins of the invention, so
that the inserted epitope may replace all or part of the sequence
of the loop.
(Page, 10-11.)
FF 18. Birkett disclosed “a strategically modified hepatitis B
core (HBc) protein that is linked to a pendent hapten through chemically-
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24
reactive amino acid residue inserted into the HBc sequence.” (Birkett, col.
4, ll. 8-11; Ans. 11.)

Analysis
Appellants assert that the Examiner has not presented a prima facie
case based on the combination of references because the “signpost[s] are
lacking.” (App. Br. 36.) “Page does not teach the importance of the
retention of cys61 as is present in the claimed chimeric particles.” (Id. at
35.) “Birkett does not teach substitution of cysteines 48 and/or 107 with
another amino acid.” (Id.)
We are not persuaded by Appellants‟ argument. “In determining
whether obviousness is established by combining the teachings of the prior
art, the test is what the combined teachings of the references would have
suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d
1573, 1581 (Fed. Cir. 1995) (internal quotations omitted). According to the
Examiner:
Zhang teaches: “A single mutation at Cys
48
produced only
dimers with no detectable monomers (Figure 3, lane 3);
mutation of Cys
61
alone resulted in the production of both
dimers and monomers (Fig.3, lane 4) .... mutations of both
Cys
48
and Cys
l07
results in only dimers (Para 3, right col. and
also see Figure 3, lane 7) due to the disulfide bond between
Cys
61
s” . . . . By showing these results, Zhang teaches that
Cys48 and Cys 107 are not essential for formation of an
interchain disulfide bond with another monomer because
mutations of Cys48 and Cysl07 do not affect formation of HBc
dimers, while Cys61 is important for forming and maintaining
an HBc dimer. Moreover, these results also illustrate that
substitution of one or both Cys48 and/or Cys107 result in only
HBc dimers, rather than a mixture of dimers and monomers
(Para 2, right col. p. 9424, and Figure 3), which would have
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suggested to and motivated one of ordinary skill in the art to
substitute one or both native Cys48 and Cysl07, but maintain
Cys61, [e.g. Claim 47 (a)] in order to obtain unified HBc
dimers.
(Ans. 30.) Page teaches that the retention of the C-terminal cysteine residue
is important for particle stability (FF 17) and that insertions can be tolerated
at the C-terminus, N-terminus and the e1 loop (Ans. 31; FF 18). Under KSR,
it is obvious to substitute one element for another as long as it produces
predictable result. KSR at 416. We agree with the Examiner‟s conclusion
that the ordinary artisan would have been motivated to:
[M]odify HBcΔ by incorporating these features in order to
improve the stability of HBc chimers. There would have been
reasonable expectation of success, given the knowledge that
HBcΔ chimeras are capable of incorporating foreign epitope(s)
at their N-terminal, immunodominant loop, or/and C-terminal
region, and also capable of forming viral RNA-free capsid, as
taught by Page, given the knowledge that addition/retention of
C-terminal cysteines allows formation of a stable HBcΔ dimer
particle as taught by Page, given the knowledge that HBc
chimera containing a chemically-reactive linker residues for a
conjugated hapten at their immunodominant loop have been
successfully made, as taught by Birkett, and also given the
knowledge that native Cys48 and Cys107 are not essential for
HBc dimer formation, as taught by Zhang.
(Ans. 31-32.)
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that the combination of Pumpens,
Birkett, and Zheng renders obvious the chimeric cysteine stabilized HBc
molecules of claim 1. We thus affirm the rejection of claim 1 under 35
U.S.C. § 103(a) as being obvious, and claims 2-6, 8-28, and 30-46 were not
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26
separately argued and fall with claim 1. Arguments not made are waived.
See 37 C.F.R. § 41.37(c)(1)(vii)

V.
The Examiner rejected claims 1-46 under the judicially created
doctrine of obvious-type double patenting
6
as being unpatentable over (1)
claims 1-78 of 09/930,915; (2) claims 1-53 of 10/787,734 (now US Pat.
7,361,352); (3) claims 47-85 of 11/508,655. (Ans. 14.)
Appellants do not argue the merits of the rejections, but note that they
will consider submitting a terminal disclaimer once allowable subject matter
is indicated, believing that it is premature to deal with the terminal
disclaimer. (App. Br. 36.) Therefore, we summarily affirm, and will not
further discuss, this rejection. See MANUAL OF PATENT EXAMINING
PROCEDURE § 1205.02 (“If a ground of rejection stated by the examiner is
not addressed in the appellant's brief, that ground of rejection will be
summarily sustained by the Board.”).

VI.
The Examiner rejected claims 1-6, 8-28, and 30-46 on the grounds of
nonstatutory obvious-type double patenting as being unpatentable over
claims 1-19 of Birkett, in view of Page and Zheng. (Ans. 14.)
Appellants do not argue the merits of the rejections, but note that they
will consider submitting a terminal disclaimer once allowable subject matter

6
Applications 10/805,913, 10/806,006 and 11/507,083 are now abandoned,
rendering moot the double patenting rejections over these Applications.
(Ans. 14.)
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27
is indicates, believing that it is premature to deal with the terminal
disclaimer. (App. Br. 37.) Therefore, we summarily affirm, and will not
further discuss, this rejection. See MANUAL OF PATENT EXAMINING
PROCEDURE § 1205.02 (“If a ground of rejection stated by the examiner is
not addressed in the appellant's brief, that ground of rejection will be
summarily sustained by the Board.”).

SUMMARY
We reverse the rejection of claims 1-47 under 35 U.S.C. 112, first
paragraph as failing to comply with the written description requirement.
We reverse the rejection of claims 1-47 under 35 U.S.C. 112, first
paragraph as failing to comply with the enablement requirement.
We affirm the rejection of claims 1-6, 8-14, 16-28, 30-42, and 46
under 35 U.S.C. § 103(a) over Pumpens, in view of Zlotnick, and Zheng.
We affirm the rejection of claims 1-6, 8-28, and 30-46 under 35
U.S.C. § 103(a) over Page and Birkett, in view of Zheng.
We affirm the rejection of claims 1-46 under obvious type double
patenting over (1) claims 1-78 of 09/930,915; (2) claims 1-53 of 101787,734
(now US Pat. 7,361,352); and (3) claims 47-85 of 11/508,655.
We affirm the rejection of claims 1-6, 8-28, and 30-46 under
obviousness-type double patenting, as being obvious over claims 1-19 of
Birkett in view of Page and Zheng.
Claims 7, 29, and 47 are presently free of rejection over the prior art.

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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. § 1.136(a).

AFFIRMED-IN-PART

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