Ex Parte Birkett

Patent Trial and Appeal Board

Nov 30, 2012

09930915 (P.T.A.B. Nov. 30, 2012)

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.
09/930,915 08/15/2001 Ashley J. Birkett LOR-102.2 (81175) 2278
24628 7590 12/03/2012
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
12/03/2012 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 ASHLEY J. BIRKETT
__________

Appeal 2011-000331
Application 09/930,915
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 a decision on appeal under 35 U.S.C. § 134 from the
Examiner‟s rejection of claims directed to a recombinant chimer hepatitis B
core protein molecule having enhanced stability due to insertions of cysteine
residues toward the C-terminus of the core molecule. 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 “a chimeric hepatitis B virus (HBV)
nucleocapsid protein that is engineered for both enhanced stability of self-
assembled particles and the display of an immunogenic epitope.” (Spec. 1.)
The “hepatitis B core (HBc) chimeric protein [or chimer hepatitis B core
protein molecule or HBc chimer molecule or just chimer] [] self-assembles
into particles after expression in a host cell.” (Spec. 7.) “The[se] particles
are substantially free of nucleic acid binding and exhibit enhanced stability
relative to particles comprised of otherwise identical proteins that are free of
the cysteine residue.” (Spec. 8.)

Claims 1-9, 12-33, 35-38, and 42-78 are on appeal, and can be found
in the Appendix of the Appeal Brief (App. Br. 51-69). Claims 1, 18, 42, 51,
and 63 are independent claims. Claim 1 is representative of the claims on
appeal, and reads as follows:
1. A recombinant chimer hepatitis B core (HBc) protein
molecule up to about 515 amino acid residues in length that
(a) contains an HBc sequence of at least about 130 of the N-
terminal 150 amino acid residues of the HBc molecule that include a
peptide-bonded heterologous epitope or a heterologous linker residue
for a conjugated epitope present in the HBc immunodominant loop,
(b) contains one to ten cysteine residues toward the C-terminus
of the molecule from the C-terminal residue of the HBc sequence and
within about 30 residues from the C-terminus of the chimer molecule
[C-terminal cysteine residue(s)],
(c) contains a sequence of at least 5 amino acid residues from
HBc position 135 through position 140 toward the HBc C-terminus,
said chimer molecules (i) containing no more than about 5
percent substituted amino acid residues in the HBc sequence
corresponding to a sequence of SEQ ID NO:246-251 from position 1
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through 149, (ii) self-assembling into particles that are substantially
free of binding to nucleic acids on expression in a host cell, and said
particles are more stable than are particles formed from otherwise
identical HBc chimer molecules that lack said C-terminal cysteine
residue(s) or in which a C-terminal cysteine residue present in the
chimer molecules is replaced by another residue, wherein said particle
stability is assayed as a measurement of the percentage of full length
chimer molecules determined by Coomassie Blue stain of reducing
buffer 15%SDS-PAGE results obtained after dilution of purified
particles to a concentration of 1 mg/mL in aqueous 50 mM NaPO4,
pH 6.8, with sodium azide added to a final concentration of 0.02%
and incubation at 37° C for about 14 days.

The following grounds
1
of rejection are before us for review:
Ground 1. The Examiner has rejected claims 1-9, 12-33, 35-38, and
42-78 under 35 U.S.C. § 112 first paragraph, as failing to comply with the
enablement requirement.
Ground 2. The Examiner has rejected claims 1-9, 12-33, 35-38, and
42-78 under 35 U.S.C. § 112 first paragraph, as failing to comply with the
written description requirement.
Ground 3. The Examiner has rejected claims 1-9, 15, 16, 18-26, 30-
33, 35, 38, 42-58, 63-75, 77, and 78 under 35 U.S.C. § 103(a) as
unpatentable over Pumpens
2
in view of Zlotnick.
3

1
We note that the Examiner has withdrawn the rejection of claims 12-14,
17, 27-29, 36, 37, 59-62, and 76 under 35 U.S.C. § 103(a) as unpatentable
over Pumpens in view of Zlotnick further in view of Birkett, US 6,231,864
B1, issued May 15, 2001, because Birkett does not constitute prior art under
35 U.S.C. § 102(e) as being “by another.” (Ans. 3.)
2
Pumpens et al., Hepatitis B Virus Core Particles as Epitope Carriers, 38
INTERVIROLOGY 63-74 (1995).
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Ground 4. The Examiner has rejected claims 12-14, 17, 27-29, 36,
37, 59-62, and 76 under 35 U.S.C. § 103(a) as unpatentable over Pumpens in
view of Zlotnick further in view of Thornton.
4

Ground 5. The Examiner has rejected claims 1-9, 12-33, 35-38, and
42-78 as unpatentable under obviousness-type double patenting, as being
obvious over (1) claims 1-46 of co-pending application 10/732,862; (2)
claims 1-53 of 10/787,734; (3) claims 98-109 of 10/805,913; (4) claims 79-
115 of 10/806,006; (5) claims 47-85 of 11/508,655; (6) claims 1-22, 25, 26
of 11/507,083. The filing of a terminal disclaimer is held in abeyance by
Appellant until allowable subject matter is indicted. (App. Br. 29; Ans. 15.)
Ground 6. The Examiner has rejected claims 1-9, 12-33, 35-38, and
42-78 are unpatentable under obviousness-type double patenting, as being
obvious over (1) claims 1-19 of U.S. Patent No. 6,213,864 in view of
Zlotnick. The filing of a terminal disclaimer is held in abeyance by
Appellant until allowable subject matter is indicted. (App. Br. 30; Ans. 15.)

ANALYSIS
Ground 1. 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. 4.) Specifically, the

3
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).
4
Thornton et al., US 5,143,726, issued Sep. 1, 1992.
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Examiner finds that “the scope of the claims encompasses a large number of
HBc chimers comprising up to about 5% unspecified mutations variously
arranged along the amino acids 1-149 of a native HBc, but having enhanced
particle stability.” (Id. at 5.) The Examiner finds that there are no examples
of mutations with “up to 5 percent random mutations in HBc sequences of
SEQ ID Nos: 246-251” (id.), thus, the Specification provides no guidance to
arrive at the claimed genus. The Examiner concludes that “there is no
correlation between the stability of HBc particles and an arbitrary percentage
of random change of amino acids along positions 1-149 of HBc.” (Id.)
Even single amino acids changes can prevent HBc protein self-assembly
(FF1; Ans. 5).
Appellant asserts that “ample data has been provided to show that the
Applicant was indeed in possession of the claimed invention.” (App. Br.
19.) Additionally, “the specification recites that substitutions, other than in
the immunodominant loop or at the termini, are preferably in the non-helical
portions, between residues 1-15 and 24-50, approximately, to help assure
particle formation, citing Koschel et al. (see page 48, first paragraph).”
(Reply Br. 7-8.)
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
FF1. Metzger disclosed that a single amino acid change, Pro-138 to
Gly, prevents the HBc protein self-assembling into particles (Metzger
5
Fig.
2; Ans. 5). While the Pro→Gly amino acid changes at positions 134/135
and 144 did not affect particle assembly. (Metzger Fig. 2.)
FF2. The Specification disclosed
Chimeric hepatitis B core particles bearing internal
insertions often appear to have a less ordered structure, when
analyzed by electron microscopy, compared to particles that
lack heterologous epitopes. [Schodel et al. (1994) J.Exp.Med.,
180:1037-1046]. In some cases, the insertion of heterologous
epitopes into C-terminally truncated HBc particles has such a
dramatic destabilizing affect that hybrid particles cannot be
recovered following heterologous expression.
(Spec. 6; Ans. 18.)
FF3. Example 16 of the Specification provides “HBc particles with
inserted lysine residues at every position in the immunodominant, surface-
exposed loop region (amino acids 75-85).” (Spec. 145.) “Three of the
linker group-containing HBc chimer particles prepared from constructs
[HBc150 (K75), HBc150(K77), and HBc150(K79)] were produced at levels
of between 50 and 100 mg/L, which is comparable with typical yields for
wild-type, unmodified HBc particles, e.g. HBc149 particles.” (Spec. 147.)
Table 16 of the Specification shows that 11 constructs were prepared out of
which 3 produced particles at levels comparable to wild-type. (Spec. 148.)

5
Karin Metzger and Ricardo Bringas, Proline-138 is essential for the
assembly of hepatitis B virus core protein, 79 J. GEN. VIROL. 587-590
(1998).
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FF4. Example 6 of the Specification provides “chimer HBc molecule
that contained the (NANP)4 malarial B cell epitope inserted between
residues 78 and 79 . . . The thermal stability (at 37° C) of this chimer particle
(V2.Pfl+C; []) as compared to a similar chimer particle lacking the inserted
cysteine (V2.Pfl) was found to be dramatically increased, as is seen in Fig.
3.” (Spec. 126.)
FF5. Example 22 of the Specification provides “particles with a
single cysteine after V149 of the HBc gene, followed by a T cell epitope.”
(Spec. 161.) “The stability of this particle (V12.Pf1(C17A)C150) was
compared to V12.Pf1, with the only difference between the two particles
being the position of the cysteine residue.” (Spec. 162.)
“V12.Pf1(C17A)C150 was significantly more stable than V12.Pf1(C17A)
following incubation at 37°C. After 14 days at 37°C, V12.Pf1(C17A)
monomers are totally degraded (Figure 4), whereas V12.Pf1(C17A)C150
monomers are only partially degraded (Figure 8).” (Spec. 163.)
FF6. Example 23 of the Specification provides particle formation for
C-terminal cysteine residue chimers. Table 17 reproduced below describes 6
cysteine stabilized particles immediately after production the table shows the
percentage of the core particles as a particle vs. non-particle form.
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(Spec. 165.) The particles disclosed in Table 17 were further assessed for
stability during storage at 37ºC. This data is disclosed in Table 18,
reproduced below:

(Spec. 166.) Table 18 shows particle stability of C-terminal chimers.
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FF7. 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 1 to about 15 and residues 24 to about 50 to help assure particle
formation.” (Spec. 48.)

ANALYSIS
Appellant asserts that not all permutations of the generic claim need to
be operable in order to meet the enablement requirement citing In re
Angstadt and Griffin, 190 USPQ 214 (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. 15.) Appellant further asserts “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,
Appellant points to Fig. 3 of the Specification, that shows particles with an
inserted cysteine residue at the C-terminus are more stable. (Id. at 13.)
“[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
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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
Appellant 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
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 (FFs 1-2), we find that Appellant has disclosed several cysteine
substituted HBc chimer molecules that have shown increased stability after
incubation at “37ºC for about 14 days” as recited in claim 1 (FF4). Even
though the Specification did not produce a chimer molecule with 5 percent
of the amino acid sequence substituted in SEQ ID NO: 246-251 from
positions 1-149, we find that the totality of the evidence, however, still
weighs in Appellant‟s favor (FFs 3-7). The Specification also recognizes
that not all C-terminal cysteine substituted chimer particles will be stable for
14 days, and this claim limitation can easily be assessed by the ordinary
artisan (FF6). Additionally, the Specification provides guidance to where in
the chimer molecule substitutions may be made and what areas should be
avoided for substitutions (FF7).
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
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arrive at the claimed invention is undue. We find that it would not be undue
to make the mutations as claimed, given the guidance in the Specification
(FFs 2-7) 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. Background Section 1-7).
Accordingly, we reverse the non-enablement rejection.

Ground 2. Written Description
The Examiner takes the position that even single amino acid changes
in native HBc are not predictable for their ability to form stable particles
(Ans. 22). “Support for a genus is generally found where the applicant 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 7.)
Examiner takes the position that the Specification does not provide sufficient
written description for the claimed stabilized HBc particles, citing MPEP
2163 (id. at 6). To support the Examiner‟s position that there is uncertainty
in the art, the Examiner cites to Example 14
6
from a co-pending application
where only 7 out of 24 chimers yielded particles, and 14 chimers lost their
ability to form particles altogether (id. at 7-8).
Appellant asserts that the Specification provides direction with regard
to the substitutions within the HBc sequence. (App. Br. 18.) Appellant
contends that the Specification teaches that the “substitutions are to be

6
The Examiner cites to co-pending Application 10/732,862 as evidence that
a single amino acid substitution in the HBc sequence can be unpredictable.
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conservative, that guidance as to proper conservative substitutions can be
obtained with LASERGENE software and the like, and that the region of
substitution is in the non-helical portion of the molecule, within residues 2-
15 or 24-50, to assure particle formation.” (App. Br. 18.)
The issue with respect to this rejection is: Does the Specification
describe HBc particles that have up to 5% mutations in the amino acid
sequence and show increased stability?
“[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 (2010).
After considering all the evidence and arguments, we agree with
Appellant‟s position that the disclosure in the Specification sufficiently
describes the chimeric particles. Here, Appellant relies 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. 46-47), and the description of regions in the HBc that
can accommodate conservative substitutions (App. Br. 18; Spec. 2-7, 46-47).
We find that the Specification guides the artisan to make conservative
substitutions to the non-helical portion of the HBc molecule 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 (FFs 5-6).
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The Examiner cites to experimental evidence found in a co-pending
application that shows only 7 out of 24 HBc chimer molecules are able to
form particles (Ans. 7-8), to support the position that there is unpredictably
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 the claimed invention. This
evidence further supports the Appellant‟s position that the Specification
provides sufficient descriptive support to meet the written description
requirement.
Accordingly, we reverse the Examiner‟s rejection.

Ground 3. Obviousness over Pumpens in view of Zlotnick.
The Examiner takes the position that it would have been obvious to
add cysteine residues to the HBc molecule “because Zlotnick teaches that
the addition of a cysteine to the C-terminus of an HBc molecule with a C-
terminal truncation results in enhanced stability.” (Ans. 12.) The Examiner
finds that Pumpens disclosed “recombinant HBc chimers [that] contain an
HBC sequence of at least about 130 of the N-terminal 150 amino acid
residues of the HBc molecule.” (Id. at 10.) The Examiner concludes that the
two important points disclosed in Pumpens are “that HBcΔ chimers are
capable of self-assembly, and do not bind or 'pack' nucleic acid. [] . . . that
„capsids formed by C-terminally truncated HBc monomers are less stable
than the corresponding full-length protein particles.‟” (Id. at 11.) Based on
the combination of Pumpens and Zlotnick, the Examiner concludes, that at
the time of the claimed invention it would have been prima facie obvious to
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“modify the HBcΔ chimer particles of Pumpens by adding a C-terminal
cystine to HBcΔ as taught by Zlotnick in order to make more sable [sic]
HBcΔ chimer particles.” (Ans. 12.)
Appellant contends that “Pumpens does not teach adding 1-10 C-
terminal cysteines to stabilize the chimeric molecule. Zlotnick does not
teach a conjugated epitope present in the HBc immunodominant loop in
conjunction with 1-10 cysteine residues at the C-terminus.” (App. Br. 20.)
The issue with respect to this rejection is: Has the Examiner
established by a preponderance of the evidence that the combination of
Pumpens and Zlotnick renders obvious the composition of claim 1 directed
to a stabilized C-terminal cysteine substituted HBc chimer particle?

FINDINGS OF FACT
FF8. Pumpens disclosed regions for insertion in the HBc core
protein. Figure 1 is reproduced below:
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(Pumpens Fig. 1.) 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.
(Pumpens Fig. 1; Ans. 10.)
FF9. Pumpens disclosed that “[t]hese 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. 10.)
FF10. Pumpens disclosed that “[a]lthough capsids formed by C-
terminally truncated HBc monomers are less stable than the corresponding
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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. 10.)
FF11. Pumpens disclosed examples of “HBV core particles as carriers
of epitopes inserted at N-terminus of HBc protein (full length)” (Pumpens
Table 1), “HBV core particles as carries of internally inserted epitopes.”
(Pumpens Table 2.), and “HBV core particles as carriers of epitopes inserted
at C-terminus of full-length and C-terminally truncated HBc protein”
(Pumpens. Table 3),
FF12. Zlotnick disclosed the addition of a C-terminal cysteine residue.
Figure 1 is depicted below:

(Zlotnick 9557; Ans. 11.)
FF13. Zlotnick disclosed
Using Cp constructs progressively truncated from the C
terminus, we found that residues 138-149 play an influential
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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.)
FF14. 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*149capsids or reduced Cp*150 capsids-are resistant to dissociation by
3.5 M urea (Fig. 2b).” (Zlotnick 9558; Ans. 11, 12, 16, 27.)

ANALYSIS
Appellant contends that reliance on “Zlotnick is misplaced. Zlotnick
teaches substitution of Cys48, Cys61, Cys107, and Arg150. The present
invention does not require these substitutions.” (App. Br. 20.) Appellant
asserts that in “Cp*150, there are 4 amino acid substitutions and no control
molecule of 150 amino acids with no amino acid substitutions with which to
compare. Therefore it is impossible to accurately state what the effects of
those 4 amino acid substitutions are on the molecule.” (Id. at 21.) Appellant
asserts that deletions and substitutions are unpredictable and need to be
tested with controls. (Id.)
We are not persuaded. We agree with the Examiner‟s finding that
Pumpens disclosed the production of HBc chimers as epitope carriers. (Ans.
10-11; FFs 8-10.) Pumpens disclosed HBc chimers and teaches where in the
molecule insertions are permissible (FF8). In addition, Pumpens provides
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examples of epitope insertions at the N-terminus, C-terminus as well as
internal insertions (FF11).
“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.”
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).
We are not persuaded by Appellant‟s contention that reliance on
Zlotnick is misplaced. Appellant asserts that “if there were some stability
enhancement due to the presence of the C-terminal Cys, there would also
most likely be some difference in the conditions of particle assembly.”
(App. Br. 22.) As acknowledged by the Examiner Zlotnick disclosed the
addition of C-terminal cysteine residues in HBc molecules and assessed their
ability to form stable particles (Ans. 11-12, 24-27; FFs 12-13). We agree
with the Examiner that
Just because Zlotnick suggests that other forces are at work
besides cysteine binding in terms of capsid assembly, it does
not mean that the knowledge that C-terminal cysteines
responsible for capsid stabilization is not important to one of
ordinary skill in the art. Zlotnick explicitly teaches that C-
terminal cysteines are responsible for capsid stabilization.

(Ans. 27.)
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Appellant contends that “Zlotnick teaches away from the inclusion of
a C-terminal cysteine, because Zlotnick teaches that there is no advantage in
having a C-terminal cysteine in his gold-labeled molecule.” (Reply Br. 19.)
We are also 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). Here Zlotnick disclosed that the cysteine
bonds stabilize the capsid structure (FF14), thus, the ordinary artisan would
not be discouraged from adding cysteine residues to an HBc chimer
molecule.
Appellant asserts that “[i]t is heavily emphasized in Zlotnick that the
molecules with no freely available C-terminal cysteines s[t]ill form
particles.” (Reply Br. 21.) We find that Zlotnick does not teach away from
the addition of cysteine residues. The argument that the cysteine residues
form particles just like molecules without cysteine residues is not convincing
because the claims are not directed to the formation of particles, rather they
are directed to the stability of the particle once formed. Zlotnick disclosed
that the cysteine containing particles are stable under high stringency
condition (FF14). We find nothing in Zlotnick that would suggest to the
ordinary artisan that the addition of epitopes to the Cp*150 molecule would
not result in stable particles as claimed.
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that the combination of Pumpens and
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Zlotnick renders obvious the chimeric cycteine stabilized HBc molecules of
claim 1. We thus affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as
being obvious, as claims 2-9, 15, 16, 18-26, 30-33, 35, 38, 42-58, 63-75, 77,
and 78 were not separately argued, and therefore stand with claim 1, we
affirm the rejection as to those claims as well.

Ground 4. Obviousness over Pumpens in view of Zlotnick further in view
of Thornton.
Based on the combination of Pumpens, Zlotnick, and Thornton, the
Examiner concludes that it would have been prima facie obvious at the time
of the claimed invention to “to make a HBcΔ molecule that could
present an epitope via a side-chain.” (Ans. 14.) The Examiner takes the
position that the combination of Pumpens and Zlotnick disclosed a C-
terminal cysteine stabilized HBc core molecule. (Id. at 13.) Thornton
discloses “the use of HBc as an immunogenic carrier molecule where a
polypeptide is linked to the carrier/core molecule through an amino acid side
chain on the core molecule.” (Id. at 13-14.) “Thornton teaches that
operatively linking a polypeptide immunogen to HBcAg particles increases
the immunogenicity of the linked immunogen to an unexpected degree
through the operation of HBcAg's previously unknown T cell-dependent and
T cell-independent determinants.” (Id. at 14.)
Appellant contends that the combination of Pumpens and Zlotnick
would not allow the ordinary artisan to arrive at a cysteine stabilized
chimeric HBc molecule. (Reply Br 24.) The addition of Thornton “likewise,
does not teach the placement of C-terminal cysteines that stabilize a
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polypeptide molecule relative to a molecule without those cysteines.”
(Reply Br. 25.)
The issue is: Has the Examiner established by a preponderance of the
evidence that the combination of Pumpens, Zlotnick and Thornton renders
obvious the claims directed to a C-terminal cysteine stabilized chimeric HBc
particle as claimed?

FINDINGS OF FACT
FF15. Thornton disclosed “immunogenic polypeptide conjugate[s]
comprising a HBcAg protein operatively linked through an amino acid
residue side chain to a polypeptide immunogen.” (Thornton, col. 9, ll. 59-
63; Ans. 14.) “A sulfhydryl group may also be incorporated into either
polypeptide by reaction of amino functions with 2-iminothiolane or N-
hydroxysuccinimide ester of 3-(3-dithiopyridyl) propionate.” (Thornton, col.
10, ll. 38-42; Ans. 14.)
FF16. Thornton disclosed the use of heterobifunctional agents that
generate “a disulfide link at one functional group end and a peptide link at
the other.” (Thornton, col. 14, l. 66 to col. 15, l. 2; Ans. 14.) “Many of
these thioether forming agents are commercially available and include
reactive esters of 6-maleimidocaproic acid, 2 bromoacetic acid, 2-iodoacetic
acid, 4-(N-maleimido-methyl) cyclohexane-l-carboxylic acid and the like.”
(Thornton, col. 15, ll. 10-14.)
FF17. The Specification provides that “a chimer particle containing a
heterologous linker residue such as a lysine, glutamic or aspartic acid,
cysteine or tyrosine in the loop region of Domain II and an added cysteine
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residue in Domain IV [can be linked to a hapten] to form a HBc chimer
conjugate.” (Spec. 77.) The Specification provides that it is well known
that “both the HBc protein and a polypeptide hapten can be used in their
native form or their functional group content can be modified by
succinylation of lysine residues or reaction with cysteine-thiolactone.”
(Spec. 78.) Conjugation between proteins can be achieved for example with
2-iminothiolane (Spec. 78), the N-hydroxysuccinimide ester of 3-(3-
dithiopyridyl)propionate (Spec. 79), 6-maleimidocaproic acid (Spec. 80), 2-
bromoacetic acid (Spec. 80), 2-iodoacetic acid (Spec. 80), 4-(N-
maleimidomethyl) cyclohexane- 1-carboxylic acid (Spec. 80) and others.

ANALYSIS
Appellant asserts that “[o]ne of skill in the art would recognize that a
chemically modified amino acid residue is structurally and functionally not
the same as a residue in its native state.” (Reply Br. 25.) “[T]he present
invention does not utilize an endogenous amino acid side chain for linking.
The present invention utilizes a heterologous linker residue (see claim 12).
Therefore, that which Thorton [sic] is teaching is different from that which is
being used in the present invention.” (App. Br. 26.)
“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. at 416. It is proper to “take account
of the inferences and creative steps that a person of ordinary skill in the art
would employ.” Id. at 418.
We find that the preponderance of the evidence of record supports the
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Examiner‟s conclusion that the combination of Pumpens and Zlotnick meet
all the limitations set out in claim 12. We are not persuaded by Appellant‟s
contention that the combination with Thornton does not use a heterologous
linker residue (App. Br. 26), and that “chemical modification[s] of a peptide
would [not] produce a reasonable expectation of success” (id. at 27). A
heterologous linker residue can be both an epitope and a linker amino acid at
the same time. Thus, the combination of Pumpens and Zlotnick as discussed
above would result in HBc core molecules with epitope insertions in the
immunodominant loop (FFs 8, 11) that are stabilized by the C-terminal
cysteine insertion (FFs 12-14). These inserted epitopes are made up of
amino acids that can function as heterologous linker amino acids. The
reference of Thornton discloses linking immunogens to proteins, specifically
to HBcAg (FF15), resulting an HBc particles with attached epitopes. “A
person of ordinary skill is also a person of ordinary creativity, not an
automaton.” KSR. at 421.
Furthermore, Thornton disclosed that linking of immunogens can be
achieved using a variety of chemical agents (FFs 15-16). The Specification
provides that the linking of peptide immunogens using a heterologous linker
residue is achieved using the same chemical entities (FF17) as those
disclosed by Thornton. Thus, Appellant‟s arguments directed to
“heterobifunctional agents” (Ans. 27) for attaching epitopes to the HBc core
are not persuasive.
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that the combination of Pumpens,
Zlotnick and Thornton renders obvious “a heterologous linker residue for a
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conjugated epitope” of claim 12. We thus affirm the rejection of claim 12
under 35 U.S.C. § 103(a) as being obvious, as claims 13, 14, 17, 27-29, 36,
37, 59-62, and 76 were not separately argued and therefore stand with claim
12, we affirm the rejection as to those claims as well.

Ground 5. Obviousness-type double patenting over pending applications
The rejection of claims 1-9, 12-33, 35-38, and 42-78 under the
doctrine of obviousness-type double patenting as unpatentable over claims
(1) claims 1-46 of 10/732,862; (2) claims 1-53 of 10/787,734; (3) claims 98-
109 of 10/805,913; (4) claims 79-115 of 10/806,006; (5) claims 47-85 of
11/508,655; (6) claims 1-22, 25, 26 of 11/507,083.
Appellant does not traverse the merits of these rejections in their
Appeal Brief, and have indicated that “[i]n the event that any of the current
claims are ultimately allowed [and any of the claims of the above-noted
application are allowed,] the filing of a terminal disclaimer will be examined
in view of the allowed claims and those of the patent.” (App. Br. 29-30;
Reply Br. 26-27.)
We summarily affirm these rejections, as Appellant does not provide
any arguments on the merits of these rejections. Moreover, in this case the
provisional obviousness-type double patenting rejections are not the only
rejections remaining at this time.

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Ground 6. Obviousness-type double patenting over U.S. Patent
No. 6,213,864 in view of Zlotnick.
The rejection of claims 1-9, 12-33, 35-38, and 42-78 under the
doctrine of obviousness-type double patenting as unpatentable over claims
1-19 of U.S. Patent No. 6,231,864 in view of Zlotnick.
Appellant does not traverse the merits of this rejection in their Appeal
Brief, and have indicated that “[i]n the event that any of the current claims
are ultimately allowed, the filing of a terminal disclaimer will be examined
in view of the allowed claims and those of the patent.” (App. Br. 30; Reply
Br. 27-28.)
We summarily affirm this rejection, as Appellant does not provide any
arguments on the merits of the rejection. Moreover, in this case the
provisional obviousness-type double patenting rejection is not the only
rejection remaining at this time.

SUMMARY
Ground 1. We reverse the rejection of claims 1-9, 12-33, 35-38, and
42-78 under 35 U.S.C. § 112 first paragraph, as failing to comply with the
enablement requirement.
Ground 2. We reverse the rejection of claims 1-9, 12-33, 35-38, and
42-78 under 35 U.S.C. § 112 first paragraph, as failing to comply with the
written description requirement.
Ground 3. We affirm the rejection of claims 1-9, 15,16, 18-26, 30-
33, 35, 38, 42-58, 63-75, 77, and 78 under 35 U.S.C. § 103(a) as
unpatentable over Pumpens in view of Zlotnick.
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Ground 4. We affirm the rejection of claims 12-14, 17, 27-29, 36,
37, 59-62, and 76 under 35 U.S.C. § 103(a) as unpatentable over Pumpens in
view of Zlotnick further in view of Thornton.
Ground 5. We affirm the rejection of claims 1-9, 12-33, 35-38 and
42-78 as unpatentable under obviousness-type double patenting, as being
obvious over (1) claims 1-46 of co-pending application 10/732,862; (2)
claims 1-53 of 10/787,734; (3) claims 98-109 of 10/805,913; (4) claims 79-
115 of 10/806,006; (5) claims 47-85 of 11/508,655; (6) claims 1-22, 25, 26
of 11/507,083.
Ground 6. We affirm the rejection of claims 1-9, 12-33, 35-38, and
42-78 as unpatentable under obviousness-type double patenting, as being
obvious over (1) claims 1-19 of U.S. Patent No. 6,213,864 in view of
Zlotnick.

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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