Ex Parte Lyons et al

Patent Trial and Appeal Board

Mar 27, 2013

11508655 (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.
11/508,655 08/23/2006 Katelynne Lyons LOR-136.1 D1
(9720/98011)
4811
7590 03/27/2013
Edward P.Gamson
Suite 2200
120 S. Riverside Plaza
Chicago, IL 60606-3945
EXAMINER
LUCAS, ZACHARIAH
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
03/27/2013 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 2011-005352
Application 11/508,655
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
immunogenic recombinant chimeric hepatitis B core particles. The
Examiner has rejected the claims as lacking written descriptive support, as
obvious, and under nonstatutory obvious-type double patenting. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

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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 47-85 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief (App. Br. 59-75).
The Examiner has rejected the claims as follows:
I. claim 47-85 under 35 U.S.C. 112, first paragraph, as
introducing new matter and lacking descriptive support;
II. claims 47-71 under 35 U.S.C. § 103(a) as unpatentable over
Pumpens1 in view of Ulrich,2 Page,3 Zlotnick,4 Zheng,5 and
Birkett;6
III. claims 72-85 under 35 U.S.C. § 103(a) as unpatentable over
Pumpens in view of Ulrich, Page, Zlotnick, Zheng, and Birkett,
and further in view of Neirynck,7 He,8 and Goodman;9

1 P. Pumpens et al., Hepatitis B Virus Core Particle as Epitope Carriers, 38
INTERVIROLOGY 63-74 (1995).
2 Rainer Ulrich et al., Core Particle of Hepatitis B Virus as Carrier for
Foreign Epitopes, 50 ADVANCES VIRUS RES. 141-182 (1998).
3 Mark Page et al., WO 01/98333 A2, published Dec. 27, 2001.
4 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. NAT’L. ACAD. SCI. 9556-9561
(1997).
5 Jian Zheng et al., The Structure of Hepadnaviral Core Antigens, 267 J.
BIOLOGICAL CHEMISTRY 9422 (1992).
6 Ashley J. Birkett, US 6,231,864 B1, issued May 15, 2001.
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Application 11/508,655

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IV. claims 47-71 as unpatentable under obvious-type double
patenting over claims 1-22 of co-pending U.S. Patent
Application No. 11/507,083;
V. claims 47-82 as unpatentable under obvious-type double
patenting over claims 1-45 of U.S. Patent No. 6,942,866 and
claims 1-45 of U.S. Patent No. 7,361,352 in view of Zheng and
Zlotnick;
VI. claims 47-82 as unpatentable under obvious-type double
patenting over claims 1-22 of Birkett in view of Page and
Zheng.

I.
The Issue: Written Description10
A. New Matter
The Examiner takes the position that the claims contain new matter.
Specifically, the Examiner finds that the Specification does not have support
for “[t]he cited conditions in Claim 47, ‘being more stable on storage by size
exclusion chromatography at 1 mg/mL using 50 mM NaPO4, pH 6.8 . . . .’”
(Ans. 4 (emphasis omitted).)

7 Sabine Neirynck et al., A Universal Influenza A Vaccine Based on the
Extracellular Domain of the M2 Protein, 5 NATURE MED. 1157 (1999).
8 Qing He et al., Calcium Phosphate Nanoparticle Adjuvant, 7 CLINICAL &
DIAGNOSTIC LABORATORY IMMUNOLOGY 899-903 (2000).
9 Michael G. Goodman et al., US 4,539,205, issued Sep. 3, 1985.
10 The Examiner withdrew the new matter rejection of claims 47-85, under
35 U.S.C. § 112, first paragraph, with respect to the limitation of “5 percent
conservatively substituted amino acid residues in the HBc sequence”
(Ans. 2).
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4
Appellants direct attention to the thermal stability protocol found in
the Specification as showing descriptive support for the 50 mM NaPO4
claim limitation. (App. Br. 15).
The issue presented is whether the storage condition of particles at a
concentration of 1 mg/mL using 50 mM NaPO4, pH 6.8 is disclosed in the
originally filed Specification.
We find that Appellants have the better position. The Specification
provides a thermal stability protocol in which “[p]urified particles were
diluted to a concentration of 0.5-1 mg/mL using 50 mM NaPO4, pH 6.8 and
allowed to incubate at 4ºC, room temperature, or 37ºC.” (Spec. 175, see
Example 6.) Thus, the Specification disclosed diluted HBc chimer particles
in a 50 mM NaPO4 buffer at the desired pH, but did not test the stability of
the particles by size exclusion chromatography. The physical properties that
can be attributed to the particles in a particular buffer, at a particular
concentration and pH are an inherent feature of the particle, thus, any
discussion with respect to the assay is immaterial to the property of the
particle. In other words, the behavior of the particles on a size exclusion
chromatography column is an unknown property that is, nevertheless,
inherently present in the particles described in the thermal stability protocol
method. We reverse the rejection based on new matter.

B. Lack of Descriptive Support for the Genus Claimed
The Examiner takes the position that the Specification does not
provide sufficient written descriptive support for the claimed stabilized HBc
particles, citing MPEP § 2163 in support (Ans. 5). The Examiner finds that
“substitution of a single amino acid can have an unpredictable effect on the
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5
assembly of HBc particles.” (Id. at 7.) The Examiner further asserts that the
Specification has shown that particle formation is unpredictable when
replacing one or both cysteine residues, at position 48 and 107, in addition to
making conservative substitutions in the HBc sequence. (Id.) “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 6.) The Examiner points
to Example 14 of the Specification in support of the position that there is
unpredictability in the HBc particle formation and stability. “Example 14
shows 7 of 24 tested HBc chimers were able to yield particles, but 17 of 24
tested HBc chimers cannot form particles.” (Id.) It is the Examiner’s
position that:
[T]he specification has illustrated that it is not certain which
HBc chimers, “in which one or both cysteines residues at
positions 48 and 107 is replaced by another residue” [e. g.
Claim 47 (a)], and contain “5% conservative substituted amino
acid residues in the HBc sequence” [e.g. Claim 47 (ii)], would
form more stable particles “than are particles formed otherwise
identical HBc chimer molecules that contain both cysteine
residues at positions 48 and 107” as claimed.
(Id. at 7 (emphases omitted) (brackets in original).)
Appellants assert that the Specification provides direction with regard
to the substitutions within the HBc sequence. (App. Br. 13-14.) Appellants
contend that the Specification teaches that the “substitutions are to be
conservative, that guidance as to proper substitutions can be obtained with
LASERGENE software and the like, and that the region of substitution is in
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the non-helical portion of the molecule, within residues 2-15 and 24-50, to
assure particle formation.” (Id. at 14.)
The issue with respect to this rejection is: Does the Specification
describe HBc particles that have one or more cysteine residues at position 48
and 107 replaced in addition to containing 5% conservative substitutions?
After considering all the evidence and arguments, we agree with
Appellants’ position that the disclosure in the Specification sufficiently
describes the chimeric particles. “[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. 13; 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
for at least two weeks at 37ºC (Spec. 191).
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
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7
particles (Ans. 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. In addition, the
Specification provides 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.”
(Spec. 192.) 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.
The Issue
The Examiner takes the position that the claimed HBc immunogenic
particles are obvious in view of Pumpens, Ulrich, Page, Zlotnick, Zheng,
and Birkett. The Examiner finds that Pumpens disclosed:
These chimers contain an HBc sequence of at least about 130 of
the N-terminal 150 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 fused epitopes
encoded by inserted heterologous linkers in HBc chimer vectors
(see page 69, left col., 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 teach: (1) adding
a C-terminal cysteine residue to stabilize HBcΔ particles; (2) replacing one
or both cysteine residues at positions 48 and 107 by another residue; and (3)
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Application 11/508,655

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incorporating a chemically reactive linker residue for a conjugated hapten
(id.). The Examiner relies on the additional references for these teachings.
The Examiner concludes that it would have been obvious to:
[M]odify the HBcΔ chimeras taught by Pumpens by the
addition of a cysteine to the C-terminus of the molecule to
enhance the stability of the HBcΔ capsid as taught by Page and
Zlotnick. The skilled artisan would have been motivated to do
so because viral RNA-free and stable HBcΔ proteins are a
desirable epitope carrier (vaccine) as indicated by Ulrich.
There would have been a reasonable expectation of success
because both Zlotnick and Page illustrate that HBcΔ particles or
HBcΔ chimeras are free of viral RNA, while still capable of
self-assembly, and the addition of a heterologous cysteine
residue to an HBcΔ C-terminal truncation results in the
enhanced stability of HBcΔ capsid particles.
It would also have been obvious to one of ordinary skill
in the art at the time the invention was made to modify native
HBcΔ carrier by replacing native Cys48 and/or Cys107 of HBc
by another residue because native Cys48 and Cys107 are not
essential for HBc dimer formation, as taught by Zhang [sic],
and replacing Cys48 and Cys107 will not affect particle
assembly, as shown by Zlotnick.
It would also have been obvious to one of ordinary skill
in the art at the time the invention was made to modify the
HBcΔ chimeras by containing chemically-reactive linker
residues given the knowledge that HBc chimeras containing
chemically-reactive linker residues for a conjugated hapten on
HBc have been successfully made as taught by Birkett.
(Id. at 11-12.)
Appellants assert that a prima facie case has not been made.
Appellants’ position is that ordinary artisan would not look to using C-
terminally truncated HBc molecules as immunogens because Pumpens
disclosed that “that capsids formed by C-terminally truncated HBc
monomers are less stable than are the corresponding full-length protein
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Application 11/508,655

9
particles.” (App. Br. 24.) According to Appellants, Pumpens teaches away
from making truncated molecules (id.), and 25% of the molecules made in
Pumpens did not form particles (id. at 25). Appellants take the position that
“Page does not teach the substitution of Cys48 and Cys107 nor the retention
of Cys61 as claimed here.” (Id. at 27.)
The important structural feature is the absence of one or
both cysteines at positions 48 and 107 and the presence of the
Cys at position 61 of the HBc portion of the chimeric protein
providing a more stable particle than an “otherwise identical”
chimer containing both cysteines at positions 48 and 107.
(Id. at 30.) Appellants acknowledge that “Ulrich reports that HBc chimer
stability needs improvement for use as a vaccine carrier is the sole relevant
teaching, but does not make the claims obvious.” (Id. at 25.) The disclosure
of Ulrich goes to long felt need, but does not address the particular
composition claimed (id.).
Claims 47 and 54 require, in pertinent part, an HBc immunogenic
particle having an HBc sequence where “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 82 requires the
substitution of the cysteine at position 48 by another residue.
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?

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Appeal 2011-005352
Application 11/508,655

11
FF 3. 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 4. Pumpens disclosed that “[a]lthough capsids formed by C-
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 5. 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 carriers 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 6. Zlotnick disclosed the addition of a C-terminal cysteine residue.
Figure 1 is depicted below:
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Appeal 2011-005352
Application 11/508,655

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(Zlotnick 9556 (citation omitted).)
FF 8. 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. 10-11.)
FF 9. 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
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. 10-11.)
FF 10. 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.
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(Page 2, ll. 21-28; Ans. 10.)
FF 11. 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]. Cys107 is a free thiol buried within the particle
structure, whereas Cys48 is present partly as a free sulfhydryl
which is exposed at the surface of the particle. Cys61 is always
and Cys48 is partly involved in interchain disulfide bonds with
the identical residues of another monomer, whereas Cys163 is
always involved in a disulfide bond with the Cys183 of a
different monomer.
(Zheng Abstract; Ans. 11.)
FF 12. 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 removed the internal cysteine residues at 48, 61, and 107 in the
16-kD HBcAg molecule. The following cysteine mutations were made:
Cys48, Cys61, Cys107, Cys48, and Cys61 while retaining cysteine at Cys107,
Cys48, and Cys107 while retaining the cysteine at Cys61 (id. at 9424-9425).
FF 13. Birkett disclosed “a strategically modified hepatitis B
core (HBc) protein that is linked to a pendent hapten through chemically-
reactive amino acid residue inserted into the HBc sequence.” (Birkett col. 4,
ll. 8-11; Ans. 11.)

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) (citation
omitted). “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 using C-terminally
truncated HBc monomers for the production of particles because they are
less stable than full length protein (App. Br. 24), and Pumpens disclosed
“that 25% of the HBc constructs made were unable to assemble into capsid
particles” which would discourage the ordinary artisan because they would
be poor candidates. (Id. at 25.)
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 acid residues
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 4). Additionally, Table 1 of Pumpens shows
particles as epitope carrier 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
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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
particles. This means that it would be more likely, than not, that an 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
insertion of foreign sequences provides a stabilizing effect.
Appellants assert that the Examiner “alleged that the addition of a
single heterologous Cys at the C-terminus of Cp*150 (Cys-less HBcΔ +Cys)
‘can promote capsid assembly,’ That statement is true as far as it goes, but is
misleading for several reasons and is another red herring argument.” (App.
Br. 28-29 (citation omitted)). “[N]owhere in the disclosure of Zlotnick are
the same two molecules made and analyzed, with the only difference being
the existence of a C-terminal cysteine on one of the molecules.” (Id. at 29.)
Appellants additionally assert that “[t]he article states that binding of Au11
to Cp*150 induces capsid assembly, and suggests that this binding of Au11
may induce small changes in molecular surfaces near the C-terminus that
dock together when dimers polymerize and stimulate the assembly process.”
(Id. at 32.) “Zlotnick does NOT teach one skilled in the art that a C-terminal
cysteine lends to increased stability as the Answer has asserted.” (Reply Br.
13-14.)
We are also not persuaded by these arguments. Zlotnick disclosed
that
[t]he capsid protein of hepatitis B virus, consisting 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
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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 140-149 of the HBc core are
involved in the assembly and formation of particles (FFs 3, 7) while the
presence of the cysteine stabilizes the formed particles (FFs 8, 10, 11).
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 3,
7), and this sequence was present in both of 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; FF 8.) 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).
We are not persuaded by Appellants’ assertion that gold labeling
induces capsid assembly and that C-terminal terminal cysteines are not
important (App. Br. 32-33). We find Zlotnick discloses that “less than 20%
of the protein is [gold] labeled” (Zlotnick 9559); that means only 1 in 5
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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
stabilization seen by the experiments using the 3.5 M urea conditions are due
to the disulfide bond formation and not due to an 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 (FF 8).
In addition, Zlotnick at Figure 1B suggests having a cysteine at position 150
as well as 61 in order to stabilize the dimer (FF 6).
Zheng discloses the production of HBcAg particles and dimer
formation, with mutations in the cysteine residues at positions 48, 61, and
107 (FF 12). Unlike the cysteine mutation discloses in Zlotnick, where all
three cysteine 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 12).
Appellants assert that according to Zheng “it is irrelevant whether
cys48, cys61 and cys107 form disulfide bonds or not. They are not essential
for core particle formation.” (Reply Br. 16; see also App. Br. 33.)
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 12). Furthermore, Zheng
disclosed that Cys107 is not available for disulfide bond formation because
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the residue is buried in the structure, while, when present, Cys61 is always
involved in interchain disulfide bonds (id.). Cys48 is sometimes involved
with interchain disulfide bond formation with a Cys48 from another monomer
(id.). In contrast, 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 of a non-
naturally occurring C-terminal cysteine stabilizes the capsid once it has
formed. The involvement of the C-terminal cysteine residues in capsid
stabilization is also taught by Page (FF 10). Thus, the combination of
Zheng, Zlotnick, and Page suggests that disulfide bond formation stabilizes
the formed capsid, but only those cysteine residues that are involved in
interchain disulfide bonding as disclosed by Zheng would be important to
retain for particle stability. We agree with the Examiner’s conclusion that
[i]n addition to Zlotnick, Page also teaches that C-terminal
cysteines can stabilize HBcΔ particles. Thus, the knowledge
that C-terminal cysteines can stabilize HBcΔ particles was
known by one of ordinary skill in the art at the time the claimed
invention was filed as evidenced by both Zlotnick and Page.
(Ans. 27 (citation omitted).)
The Examiner finds that “Zhang [sic] 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
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HBc dimer.” (Ans. 30-31 (emphasis omitted).) We find that Zheng
specifically taught mutating the wild type 16 kDa HBcAg, a truncated core
protein that is capable of forming particles, and that “mutations of both
Cys48 and Cys107 results in only dimers (Fig. 3, lane 7) due to the disulfide
bond between Cys61s, the only remaining cysteine” (Zheng 9424-25).
Retaining the cysteines for the purpose of stabilizing the HBc core particle
in the immunogenic composition of Pumpens merely combines elements that
are known in the art for the same purpose. (Ans. 11-12, 32.) “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, in
view of Ulrich, Page, Zlotnick, Zheng, and Birkett renders obvious the
chimeric cysteine stabilized HBc molecules of claim 47. We thus affirm the
rejection of claim 47 under 35 U.S.C. § 103(a) as being obvious, and as
claims 48-71 were not separately argued, and therefore stand with claim 47,
we affirm the rejection as to those claims as well. Arguments not made are
waived. See 37 C.F.R. § 41.37(c)(1)(vii).

III.
The Issue
The Examiner takes the position that the invention was prima facie
obvious because “all claimed adjuvants are well known in the art for their
application to enhance the immunogenicity of antigens, and have been used
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for human application, they are obvious choices for use as the adjuvant of
the instant HBcΔ vaccine.” (Ans. 13.)
Appellants assert that:
[t]here is neither motivation nor direction in the art for a
combination of the proper disclosures of these teachings, let
alone the selection of disclosures to replace Cys48 and Cys107,
while keeping Cys61, to make obvious a claimed more stable
chimeric immunogen. Thus, even the most obvious adjuvants
cannot make these claims obvious.
(App. Br. 38.)
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,
and in which the cysteine at residue position 61 is present” as required by
the claims?

Analysis
As discussed above, we have found no error in the Examiner’s reason
for combining Pumpens in view of Ulrich, Page, Zlotnick, Zheng, and
Birkett, as applied to claims 47-71. Claims 72-85 include additional
limitations directed to the addition of adjuvant (claim 70), such as alum
(claim 72), small peptide adjuvants (claim 73), oil emulsion (claims 75, 76,
and 82), squalene (claim 78), a sorbitan or mannide C12-C24 fatty acid ester
(claims 79, 80, and 81), while claims 83-85 are directed to methods of
inducing an immune response in a host animal. The Examiner takes the
position that He, Goodman, and Neirynck teach these elements. The
Examiner concludes that
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[s]ince all claimed adjuvants are well known in the art for
their application to enhance the immunogenicity of antigens,
and have been used for human application, they are obvious
choices for use as the adjuvant of the instant HBcΔ vaccine.
Therefore, the invention as a whole was clearly prima facie
obvious to one of ordinary skill in the art at the time the
invention was made.
(Ans. 13.)
We conclude that the preponderance of the evidence of record
supports the Examiner’s conclusion that the combination of Pumpens, in
view of Ulrich, Page, Zlotnick, Zheng, and Birkett, and further in view of
He, Goodman, and Neirynck renders obvious the chimeric cysteine
stabilized HBc molecules of claims 72-85. We thus affirm the rejection of
claims 72-85 under 35 U.S.C. § 103(a) as being obvious. Arguments not
made are waived. See 37 C.F.R. § 41.37(c)(1)(vii).

IV.
The Examiner takes the position that the claims 47-71 are
unpatentable under nonstatutory obvious-type double patenting over co-
pending Application 11/507,083 because the “instant Claims 47-71 (genus)
would be anticipated by Claims 1-22 of '083 (species); and the instant
Claims 72-82 would be obvious in view of Neirynck, He, and Goodman.”
(Ans. 14.)
Appellants do not argue the merits of this rejection, but note that that
the filing of a terminal disclaimer is premature. (App. Br. 38.) Therefore,
we summarily affirm, and will not further discuss, this rejection. See MPEP
§ 1205.02 (“If a ground of rejection stated by the examiner is not addressed
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in the appellant’s brief, that ground of rejection will be summarily sustained
by the Board.”).

V.
The Examiner takes the position that claims 47-82 are unpatentable on
the ground of nonstatutory obvious-type double patenting over claims 1-45
of Birkett ‘86611, and claims 1-45 of Birkett ‘35212 in view of Zheng and
Zlotnick. (Ans. 34.)
Appellants take the position that “[t]he combined teachings do not
make the invention obvious as none at all teaches or suggests the presence of
Cys61 and replacement of Cys48 and/or Cys107, nor the resulting enhanced
stability.” (App. Br. 39; Reply Br. 21.)
We are not persuaded. Birkett ‘866 is directed to recombinant HBc
core chimer molecules comprising plasmodium epitopes, while Birkett ‘352
is directed to HBc core chimer molecules comprising influenza epitopes.
The Examiner acknowledges that “neither ‘866 nor ‘352 teach replacing one
or both cysteine residues at positions 48 and 107 by another residue.” (Ans.
14.) The Examiner relies on Zheng and Zlotnick for this teaching. We
agree with the Examiner’s position that it would have been obvious combine
Birkett’s ‘866 and ‘352 particles given the teaching of Zheng that discloses
HBcAg mutant proteins in which either the Cys 48 and/or 107 are replaced
by another amino acids while maintaining the Cys 61 (FF 12) in conjunction
with the teaching of Zlotnick that acknowledges C-terminal cysteine is

11 Ashley J. Birkett, US 6,942,866 B2, issued Sep. 13, 2005.
12 Ashley J. Birkett et al., US 7,361,352 B2, issued Apr. 22, 2008.
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involved in stabilizing particles after they have formed (FF 10). The
Examiner concludes that
[o]ne of ordinary skill in the art would be motivated to do so
and have a reasonable expectation of success because they
would recognize that replacing unnecessary Cys48 and Cysl07
with other amino acid residues could facilitate Cys61 and C-
terminal Cys to form inter-chain disulfide bonds with the
identical residues of another monomer.
(Ans. 15.) “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.
With regard to the enhanced stability, since the production of the
chimeric particles having the desired mutations is obvious over the cited art,
it would also be expected that they would exhibit the feature of having
enhanced stability in a particular buffer system.
Accordingly, we affirm this rejection.

VI.
The Examiner takes the position that claims 47-82 are unpatentable on
the ground of nonstatutory obvious-type double patenting over claims 1-22
of Birkett in view of Page and Zheng. (Ans. 15-16.)
Appellants contend that “[t]his combination of art does not make
obvious the present invention because none teaches or suggests the presence
of Cys61 and replacement of Cys48 and/or Cys107, nor the resulting
enhanced stability.” (App. Br. 39-40.) Appellants cite Sanofi-Synthelabo v.
Apotex, Inc. 550 F .3d 1075 (2008) for the position that “[t]he Court found
that the later-claimed compound, clopidogrel, was neither anticipated nor
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obvious, side-stepping its own precedent that an issued patent claim is
deemed to be enabled to its full breadth.” (Reply Br. 22.)
We are not persuaded by the Appellants contention that the Court is
abandoning the precedent of the presumption of validity. The Court found
that “[t]he evidence at trial well supported the finding that the result of this
separation of enantiomers was unpredictable.” Sanofi-Synthelabo at 1090.
We find no evidence in this record that Appellants have shown unexpected
or unpredictable results based on the claimed compositions.
We are not persuaded by Appellants’ argument that the cited art does
not teach the cysteine replacements. Birkett’s claim 1 is directed to HBc
chimer particles comprising about 125 of the N-terminal amino acids,
including an insertion in the immunodominant loop comprising a chemically
reactive linker residue (Birkett col. 89, ll. 2-14.). The Examiner
acknowledges that the claims of Birkett “do not teach replacing one or both
cysteine residues at positions 48 and 107 by another residue, nor adding a C-
terminal cysteine residue to C-terminal-truncated HBc.” (Ans. 16.) The
Examiner relies on Zheng and Page to provide this teaching. As discussed
in detail above, Zheng disclosed the production of an HBcAg molecule in
which the cysteine at position 48 and 107 are mutated while retaining the
cysteine at position 61 (FFs 11, 12). Page teaches that the C-terminal
cysteine is required for stabilizing the particle (FF 10). We agree with the
Examiner’s position that the combination would be obvious given the
teaching of Zheng that discloses HBcAg mutant proteins in which either the
Cys 48 and/or 107 is replaced by another amino acid while maintaining the
Cys 61 (FF 12) in conjunction with the teaching of Page that acknowledges
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C-terminal cysteine is involved in stabilizing particles (FF 10). The
Examiner concludes that
knowledge that HBc chimera containing chemically-reactive
linker residues can be used for a conjugated epitope as taught
by Claims 1-22 of '864, given the knowledge that HBcΔ
chimeras are free of viral RNA, while still being capable of
self-assembly and the addition of a heterologous cysteine
residue to an HBcΔ C-terminal truncation results in dimer
formation and enhanced stability, as taught by Page, and also
given the knowledge that native Cys48 and Cys 107 are not
essential for HBc dimer formation, as taught by Zhang.
(Ans. 16.)
With regard to the enhanced stability, since the production of the
chimeric particles having the desired mutations is obvious over the cited art,
it would also be expected that they would exhibit the feature of having
enhanced stability in a particular buffer.
Accordingly, we affirm this rejection.

SUMMARY
We reverse the rejection of claims 47-85 under 35 U.S.C. 112, first
paragraph, as (a) introducing new matter and (b) lacking written descriptive
support for the substituted HBc particles.
We affirm the rejection of claims 47-71 under 35 U.S.C. § 103(a) as
unpatentable over Pumpens in view of Ulrich, Page, Zlotnick, Zheng, and
Birkett.
We affirm the rejection of claims 72-85 under 35 U.S.C. § 103(a) as
unpatentable over Pumpens in view of Ulrich, Page, Zlotnick, Zheng, and
Birkett, and further in view of Neirynck, He, and Goodman.
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We affirm the rejection of claims 47-71 as unpatentable under
obvious-type double patenting over claims 1-22 of co-pending U.S. Patent
Application No. 11/507,083.
We affirm the rejection of claims 47-82 as unpatentable under
obvious-type double patenting over claims 1-45 of U.S. Patent No.
6,942,866 and claims 1-45 of U.S. Patent No. 7,361,352 in view of Zheng
and Zlotnick.
We affirm the rejection of claims 47-82 as unpatentable under
obvious-type double patenting over claims 1-22 of Birkett in view of Page
and Zheng.

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

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