Ex Parte Page et al

Board of Patent Appeals and Interferences

Nov 29, 2010

10312045 (B.P.A.I. Nov. 29, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/312,045 03/11/2003 Mark Page GRT/117-432 7198
23117 7590 11/30/2010
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON, VA 22203
EXAMINER
PENG, BO
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
11/30/2010 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARK PAGE, JIN-LI LI,
PAUL PUMPENS, and GALINA BORISOVA
__________

Appeal 2010-007720
Application 10/312,045
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and FRANCISCO C. PRATS,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
Appeal 2010-007720
Application 10/312,045

2
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 3-12, 16, 28-30, 32, and 33.2 We have
jurisdiction under 35 U.S.C. § 6(b).

STATEMENT OF THE CASE
Claims 16 and 32 are the independent claims on appeal, and read as
follows:
16. A pharmaceutical composition comprising a protein and a
pharmaceutically acceptable carrier, wherein the protein comprises the
following elements linked in an N- to C-terminal direction:
(i) a first part of hepatitis B core antigen (HBcAg) comprising
residues 1 to 67 of HBcAg,
(ii) an epitope from a protein other than HBcAg,
(iii) a second part of HBcAg comprising residues 91 to 144 of
HBcAg,
(iv) a further epitope from a protein other than HBcAg, and
(v) a third part of HBcAg comprising the C-terminal cysteine of
HBcAg;
wherein at least a part of the sequence of HBcAg from between
residue 145 and the C-terminal cysteine comprising one or more arginine
repeats is absent.

32. A pharmaceutical composition comprising a protein and a
pharmaceutically acceptable carrier, wherein the protein comprises the
following elements linked in an N- to C-terminal direction:
(i) an N-terminal part of hepatitis B core antigen (HBcAg) which
mediates the formation of particles,
(ii) a first epitope from a protein other than HBcAg, and
(iii) a C-terminal part of HBcAG comprising the C-terminal cysteine;

2 Claims 31 and 34 are also pending, but stand withdrawn from
consideration. (App. Br. 2.)
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wherein at least a part of the sequence of HBcAg between said N-
terminal part and said C-terminal part comprising one or more of first,
second, third, and fourth arginine repeats of HBcAg is absent.

The following ground of rejection is before us for review:
Claims 3-12, 16, 28-30, 32, and 33 stand rejected under 35 U.S.C.
§ 103(a) as being rendered obvious by the combination of Pumpens,3
Zlotnick,4 Nassal,5 and Ulrich.6
We affirm.
ISSUE
Does the combination of references as set forth by the Examiner
render obvious the use of a third part of HBcAg that comprises a C-terminal
cysteine?
FINDINGS OF FACT
FF1 The Specification teaches that “HBcAg is an unusual antigen which
can be used as a delivery vehicle for specific peptides to the immune
system.” (Spec. 1.)

3 Pumpens et al., Hepatitis B Virus Core Particles as Epitope Carriers, 38
INTERVIROLOGY 63-74 (1995).
4 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).
5 Michael Nassal, The Arginine-Rich Domain of the Hepatitis B Virus Core
Protein Is Required for Pregenome Encapsidation and Productive Viral
Positive-Strand DNA Synthesis but Not for Virus Assembly, 66 J. VIROLOGY
4107-4116 (1992).
6 Ulrich et al., Core Particles of Hepatitis B Virus as a Carrier for Foreign
Epitopes, 50 ADV. VIRUS RES. 141-182 (1998).
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FF2 According to the Specification, “HBcAG is an excellent vehicle for
the presentation of epitopes due to the molecular structure of the protein,
which self-assembles into particles.” (Id.)
FF3 The Specification teaches further:
HBcAg can be used to generate hybrid particles to be used as
prophylactic and therapeutic vaccines against infectious
diseases. However, initial work has identified a high nucleic
acid impurity profile due to the inherent nature of the core
protein to bind nucleic acid. The binding of nucleic acid is
known to be associated with four arginine repeats found at the
C-terminus of the protein. Removal of these repeats using
genetic tools has been shown to be feasible and results in the
production of particles which do not encapsidate nucleic acid.
However, removal of this region appears to reduce the inherent
stability of the particle structure.

(Id. at 2.)
FF4 The Examiner’s statement of the rejection may be found at pages 4-7
of the Answer. We adopt the Examiner’s findings of fact as our own. In
addition, as Appellants only argue claim 16 separately (App. Br. 14), we
focus our analysis on claim 32, and claims 3-12, 28-30, and 33 stand or fall
with that claim. 37 C.F.R. § 41.37(c)(1)(vii).
FF5 Birkett,7 cited by Appellants, teaches that a hepatitis B core chimeric
protein that contains a cysteine residue at or near the C-terminus confers
enhanced stability to the particles, and is sufficiently free of arginine so that
the particles are substantially free of nucleic acid binding. (Birkett, pp. 7-8.)

7 Birkett, WO 02/14478 A2, published Feb. 21, 2002.
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FF6 Chen,8 also cited by Appellants, teaches “that modification of the SH
group of cysteine-containing peptides has important positive and negative
effects on their antigenicity and immunogenicity in vitro and in vivo.”
(Chen, p. 1763, first column.) Chen was specifically looking at the two
cysteine containing influenza virus nuclear protein determinants. (Id. at
Abstract.)
FF7 Carrasco-Marín9 looked at the oxidative mechanisms involved in
antigen processing in vivo. (Carrasco-Marín, p. 314, second column.)
Carrasco-Marín found that “oxidation of protein antigens . . . allow protein
unfolding and enhance both processing and exposure of immunogenic
epitopes to specific T cells.” (Id. at Abstract.)
FF8 Collins,10 similarly to Carrasco-Marín, teaches that “[r]eduction of
disulfide bonds is a key step in antigen processing both to allow the
unfolding of protein antigens, increasing the access of proteolytic processing
enzymes, and to expose free Cys residues within linear peptide epitopes
recognized by T cells.” (Collins, Abstract.)

8 Chen et al., Modification of Cysteine Residues In Vitro and In Vivo Affects
the Immunogenicity and Antigenicity of Major Histocompatibility Complex
Class I-restricted Viral Determinants, 189 J. EXPER. MED. 1757-1764
(1999).
9 Carrasco-Marín et al., Oxidation of defined antigens allows protein
unfolding and increases both proteolytic processing and exposes peptide
epitopes which are recognized by specific T cells, 95 IMMUNOLOGY 314-321
(1998).
10 Collins et al., Reduction of Disulfide Bonds Within Lysosomes Is A Key
Step In Antigen Processing, 147 J. IMMNOLOGY 4054-4059 (1991).
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PRINCIPLES OF LAW
The Supreme Court has recently emphasized that “the [obviousness]
analysis need not seek out precise teachings directed to the specific subject
matter of the challenged claim, for a court can take account of the inferences
and creative steps that a person of ordinary skill in the art would employ.”
KSR Int’l v. Teleflex Inc., 550 U.S. 398, 418 (2007). “If a person of ordinary
skill can implement a predictable variation, § 103 likely bars its
patentability.” (Id. at 417.) Under the correct obviousness analysis, “any
need or problem known in the field of endeavor at the time of invention and
addressed by the patent can provide a reason for combining the elements in
the manner claimed.” Id. at 420.
Moreover, in determining whether a reference is non-analogous art,
the decision-maker must first decide whether the reference is in the
inventor’s field on endeavor, and if not, determine whether the reference is
reasonably pertinent to the particular problem with which the inventor was
involved. In re Wood, 599 F.2d 1032, 1036 (CCPA 1979).

ANALYSIS
Appellants argue, citing Birkett and De Filette,11 that the claimed
chimeric proteins, in comparison to proteins lacking the C-terminal cysteine,
“exhibit enhanced stability and reduced nucleic acid binding,” as well as
“higher immunogenicity and greater ease of production.” (App. Br. 6.)
According to Appellants, “the improvement was not at all predictable from

11 De Filette et al., Universal influenza A vaccine: Optimization of M2-based
constructs, 337 VIROLOGY 149-161 (2005).
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the use of the prior art elements with their established functions.” (Id. at 7.)
Specifically, according to Appellants:
[I]n native HBcAg particles containing full-length protein, the
C-terminal cysteine residues form disulfide bonds within
dimers of the protein. In contrast, the shortened protein
described in Zlotnick et al. forms disulfide bonds between
dimers (see Zlotnick et al., Figure 1(b) and page 9558, column
1, first paragraph of the Results and Discussion). This change
in disulfide bonding was not predicted by Zlotnick et al.

(Ans. 7.)
Appellants argue further that the Examiner’s assertion that “it would
have been obvious that retention of the C-terminal cysteine would enhance
the stability of particles and thereby produce increased immunogenicity” is
“not supported by any evidence.” (App. Br. 10-11.) Citing Chen,
Carrasco-Marín, and Collins, Appellants argue that in fact, the evidence of
record suggests that increased stability would reduce immunogenicity. (Id.
at 11-12.)
Appellants’ arguments have been carefully considered but are not
found to be convincing. First, to the extent that Appellants may be arguing
that the claimed composition has unexpected properties and thus
demonstrates unexpected results, it is well settled that results must be
established by factual evidence, and the results must be shown to be
unexpected compared with the closest prior art. In re Baxter Travenol Labs.,
952 F.2d 388, 392 (Fed. Cir. 1991). While Appellants cite Birkett and De
Filette to support that the proteins in the claimed composition have enhanced
stability and reduced nucleic acid binding, as well as higher immunogenicity
and greater ease of production, they do not point to data comparing the
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claimed composition to a composition representing the closest prior art.
Moreover, as discussed below, the properties of enhanced stability, reduced
nucleic acid binding, and higher immunogenicity would not have necessarily
been unexpected to the ordinary artisan.
Second, to the extent that Appellants are arguing that the Examiner
improperly combined the references as the Examiner has not provided a
reason as to why one would want an HBcAg particle with increased stability,
we agree with the Examiner’s conclusion that enhanced stability of the
HBcAg particle would be understood by the ordinary artisan to be a
desirable property.
As noted in the Specification, HBcAg is an unusual antigen that is
used as a delivery vehicle for specific peptides to the immune system, which
is due to the molecular structure of the protein, which assembles into
particles. (FFs 1 and 2.) As also noted by Pumpens, HBcAg is able to
correctly assemble into a core particle for the presentation of antigens.
(Pumpens, 63.) Thus, the reason why HBcAg is used as a carrier to present
foreign epitopes is its ability to assemble into the core particles. Thus, the
ordinary artisan would understand that increasing the stability of the core
particle would increase the ability of the HBcAg to be used as a carrier for
foreign epitopes, and thus, as found by the Examiner, increasing the
immunogenicity of the foreign epitopes carried by the particle, as compared
to those HBcAgs that are unable to form core particles or form unstable core
particles. (See Ans. 8.)
We have considered the Chen, Carrasco-Marín, and Collins
references, cited by Appellants, but agree with the Examiner that they are
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not relevant to the claimed invention. (Ans. 13-15.) Chen is drawn to the
immunogenicity of peptide epitopes themselves (FF6), while Carrasco-
Marín, and Collins are drawn to the oxidative mechanisms involved in
antigen processing in vivo (FFs7 and 8.) The claimed invention, however, is
not drawn to inducing an immunogenic response to the HBcAg itself, but to
the use of the HBcAg as a carrier for a foreign antigen. And as discussed
above, the ability of the HBcAg to act as a carrier for a foreign epitope is
dependent on its ability to form a core particle. As to the property of
reduced nucleic acid binding, as noted in the Specification, it was known
that the binding of nucleic acid was associated with four arginine repeats
found at the C-terminus of the protein (FF3), and thus an HBcAg having one
or more arginine repeats absent would be expected to have reduced nucleic
acid binding.
Finally, as to Appellants’ argument that in HBcAg particles
containing full-length protein, the C-terminal cysteine residues form
disulfide bonds within dimers of the protein, whereas the shortened protein
described in Zlotnick forms disulfide bonds between dimers, we agree with
the Examiner (Ans. 9) that Appellants are arguing limitations not in the
claims.
Appellants also argue that Zlotnick and Pumpens address different
problems, and thus are not relevant to the issue of “making an improvement
in chimeric proteins having advantageous properties.” (App. Br. 8.)
Specifically, Appellants assert that Pumpens addresses the problem of
heterologous epitopes for use in vaccines, while the purpose of retaining the
the C-terminal cysteine as taught by Zlotnick is unrelated to vaccination.
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(Id.) Appellants assert further that Pumpens “describes the C-terminus as
‘dispensable’ and thereby creates the impression that such particles as
known in the prior art were already adequately stable,” and thus provides
“no reason to explore ways of improving the stability of particles resulting
from C-terminally truncated forms of HBcAg.” (Id. at 9.) Appellants argue
further that “the core antigen of hepatitis B virus was a very extensively
studied protein and there were a vast number of publications relating to the
protein in the art,” and thus there was “no reason why one of ordinary skill
in the art would have selected the four specific references cited by the
Examiner.” (Id. at 10.)
Appellants’ arguments are again not convincing. Pumpens is drawn
to the use of the HBcAg as a display carrier for foreign epitopes, wherein the
ability of the HBcAg to act as a display carrier is dependent on its ability to
form core particles. Thus, Zlotnick, which teaches that the stability of the
core particle is increased by adding a C-terminal cysteine, is reasonably
pertinent to the problem of Pumpens.
As to claim 16, Appellants argue that the Examiner has not provided a
reason to combine the references, and that there was no reasonable
expectation of success of arriving at the claimed invention. (App. Br. 14.)
Appellants are essentially repeating the arguments made with respect
to claim 32, and thus are not found to be convincing for the reasons set forth
above.

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CONCLUSION OF LAW
We conclude that the combination of references as set forth by the
Examiner renders obvious the use of a third part of HBcAg that comprises a
C-terminal cysteine. We thus affirm the rejection of claims 3-12, 16, 28-30,
32, and 33 under 35 U.S.C. § 103(a) as being rendered obvious by the
combination of Pumpens, Zlotnick, Nassal, and Ulrich.

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)(1)(iv)(2006).

AFFIRMED

cdc

NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON, VA 22203