Ex Parte Chatfield

Board of Patent Appeals and Interferences

Aug 3, 2010

10892018 (B.P.A.I. Aug. 3, 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.
10/892,018 07/15/2004 Steven Neville Chatfield KCO1002USC1 2051
9561 7590 08/03/2010
POPOVICH, WILES & O'CONNELL, PA
8519 EAGLE POINT BLVD
Suite 180
LAKE ELMO, MN 55042
EXAMINER
LI, BAO Q
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
08/03/2010 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 STEVEN NEVILLE CHATFIELD
__________

Appeal 2010-001184
Application 10/892,018
Technology Center 1600
__________

Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a fusion
protein. The Examiner has rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

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 2010-001184
Application 10/892,018

2
Statement of the Case
The Claims
Claims 15, 17, 18, and 25-28 are on appeal. Claim 15 is
representative. The claims are not argued separately and therefore stand or
fall together. 37 C.F.R. § 41.37(c)(1)(vii). Claim 15 reads as follows:
15. A fusion polypeptide comprising
(i) tetanus toxin fragment C, fused to
(ii) a polypeptide consisting of at least 20
contiguous amino acids of sequence of pre-S1 of
hepatitis B virus (HBV),
wherein the fusion polypeptide induces
antibody that recognizes pre-S1 of HBV.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Khan et al. WO 94/03615 Feb. 17, 1994

Neurath et al., Antibodies to synthetic peptides from the preS1 region
of the hepatitis B virus (HBV) envelope (env) protein are virus-neutralizing
and protective, 7 VACCINE 234-236 (1989).

The issue
The Examiner rejected claims 15, 17, 18, and 25-28 under 35 U.S.C. §
103(a) as obvious over Khan and Neurath (Ans. 3-4).
The Examiner finds it would have been obvious to the skilled artisan,
based on the teachings of Khan and Neurath “to make a HBV vaccine
composition with improved immunogen[i]city using recombinant peptide
antigen of HBV pre-S1 fused with tetC, especially including the neutralizing
epitope 21-47 of HBV pre-S1. The said composition would have been
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expected to be able to induce a more efficient and enhanced immune
response in vivo” (Ans. 4).
Appellant contends that a “person of ordinary skill, working before
the date of the invention, would have had no reason to mix and match these
two specific references and to combine their teaching in such a way as to
reach a fusion polypeptide as now claimed” (App. Br. 7). “Appellant
believes that the Examiner's reason is improperly tainted by hindsight”
(App. Br. 7). Appellant contends that
there is no evidence in Khan et al. to suggest that it might
actually be possible to induce such a response using a fusion
protein of TetC with any of these numerous antigens. As
discussed further below, the skilled reader of Khan et al.
would appreciate that significant further experimentation
would be needed to try to identify suitable antigenic
sequences, combine them in a suitable way with a TetC
sequence, and then test them to determine whether the
required effect could be achieved.

(App. Br. 10). Appellant also contends that it “was not predictable that
tetanus toxin fragment C and a polypeptide consisting of at least 20 amino
acids of HBV pre-S1 could be combined in a fusion polypeptide in such a
way as to effectively present the pre-S1 sequence to the immune system and
thereby enhance the antibody response against the pre-S 1 sequences” (App.
Br. 13).
The issues with respect to this rejection are: Does the evidence of
record support the Examiner’s conclusion that the claims are obvious over
the teachings of Khan and Neurath?

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Findings of Fact
1. Khan teaches that the “potent immunogenicity of TetC in
Salmonella suggested to us that it may be possible to exploit this character to
promote the immune response of the guest peptides or proteins. However,
fusing two proteins together often leads to an incorrectly folded chimaeric
protein” (Khan 3).
2. Khan teaches that “[w]e have now found that efficient
expression of recombinant antigens, and in particular fusion proteins, can be
achieved in bacteria such as salmonellae, by the use of an inducible
promoter such as nirB and by incorporating a flexible hinge region between
two antigenic components of the fusion protein” (Khan 3-4).
3. Khan teaches that the “resulting recombinant antigens have
been shown to have good immunogenicity” (Khan 4).
4. Khan teaches that “it is preferred that the first said protein is an
antigenic sequence comprising tetanus toxin fragment C or epitopes thereof”
(Khan 5).
5. Khan teaches that the “second protein is preferably an antigenic
determinant of a pathogenic organism. For example, the antigenic
determinant may be an antigenic sequence derived from a virus, bacterium,
fungus, yeast or parasite” (Khan 5).
6. Khan teaches that “[e]xamples of viral antigenic sequences for
the first and/or second heterologous proteins are sequences derived from . . .
hepatitis A or B virus” (Khan 5).
7. Neurath teaches that “studies with synthetic peptides indicated
the involvement of the preS1 region in HBV-cell receptor interactions,
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suggesting that anti-preS1-specific antibodies may be virus-neutralizing and
protective by blocking virus attachment to cells” (Neurath 234, col. 1).
8. Neurath teaches that to “assess directly the protective efficacy
of a synthetic peptide derived from the N-terminal portion of the preS1
sequence, two chimpanzees were immunized with a myristylated peptide
preS(12-47)” (Neurath 234, col. 2).
9. Neurath teaches that the “myristylated peptide in combination
with incomplete Freund’s adjuvant was immunogenic in rabbits” (Neurath
236, col. 1). Neurath teaches that the chimpanzee results “indicate the
presence of protective epitopes on the preS1 sequence encompassing
residues 12-47” (Neurath 236, col. 1).
10. Neurath teaches that “these results suggest that the preS1
domain of the HBV env protein or portions of it should be considered for
inclusion into hepatitis B vaccines” (Neurath 236, col. 1).
11. Neurath teaches that inclusion of the preS1 domain in vaccines
“is expected to result in: (a) elicitation of a broader repertoire of protective
antibodies resembling or surpassing the repertoire of protective antibodies
acquired during natural infection; (b) an enhanced antibody response to S-
protein; and (c) a decrease in the proportion of non-responders to hepatitis B
vaccines” (Neurath 236, col. 1-2).
Principles of Law
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
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nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
The Supreme Court has 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). As noted by the Court in KSR, “[a]
person of ordinary skill is also a person of ordinary creativity, not an
automaton.” 550 U.S. at 421.
Analysis
Khan teaches preparation of a protein vaccine which preferably
comprises a tetanus toxin fragment C portion, a hinge portion, and an
antigenic determinant of a pathogenic organism (FF 1-5). Khan specifically
suggests that hepatitis B antigenic sequences would be of interest (FF 6).
Khan teaches that the “resulting recombinant antigens have been shown to
have good immunogenicity” (Khan 4; FF 3).
Neurath teaches that the preS1 domain of HBV functions as an
immunogen (FF 7-9). Neurath specifically teaches that “the preS1 domain
of the HBV env protein or portions of it should be considered for inclusion
into hepatitis B vaccines” (Neurath 236, col. 1; FF 10). Neurath teaches that
inclusion of the preS1 domain in vaccines “is expected to result in: (a)
elicitation of a broader repertoire of protective antibodies resembling or
surpassing the repertoire of protective antibodies acquired during natural
infection; (b) an enhanced antibody response to S-protein; and (c) a decrease
in the proportion of non-responders to hepatitis B vaccines” (Neurath 236,
col. 1-2; FF 11).
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We conclude that both Khan and Neurath satisfy not only the
requirements of obviousness under KSR, but reasonably provide specific
motivations as well. Khan teaches vaccines, including HBV vaccines, and
directly suggests that inclusion of the TetC portion functions to “promote the
immune response of the guest peptides or proteins” (Khan 3; FF 1-6).
Neurath directly suggests and provides specific reasons to select the preS1
domain of the HBV env protein for inclusion into hepatitis B vaccines,
including elicitation of a broad repertoire of protective antibodies, enhanced
antibody response and a decrease in the proportion of non-responders to the
hepatitis B vaccine (FF 11).
We agree with the Examiner that the ordinary practitioner would,
when constructing an HBV vaccine as suggested by Khan, select the preS1
domain for the specific reasons provided by Neurath (FF 1-11).
Appellant contends that a “person of ordinary skill, working before
the date of the invention, would have had no reason to mix and match these
two specific references and to combine their teaching in such a way as to
reach a fusion polypeptide as now claimed” (App. Br. 7). Appellant also
refers the Page Declaration (App. Br. 10), where Dr. Page states that “a very
large number of carrier[] proteins were known to scientists working in the
field” (Page Dec. 2 ¶ 4). Dr. Page states that the “number of antigenic
sequences which could potentially be linked to each of these carriers was
even greater than the number of potential carriers” (Page Dec. 2 ¶ 5).
We are not persuaded. It is well settled that it is a matter of
obviousness for one of ordinary skill in the art to select a particular
component from among many disclosed by the prior art as long as it is
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taught that the selection will result in the disclosed effect, even when the
possible selections number 1200 or in the thousands. Merck & Co., Inc. v.
Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771
F.2d 1496, 1500 (Fed. Cir. 1985). In the instant situation, Neurath provides
specific reasons to select the preS1 HBV sequence as an antigen and Khan
teaches that HBV is a desirable vaccine target (FF 6, 10-11). Further, Khan
teaches that TetC is a desirable carrier protein (FF 1-4).
Appellant also contends that “the Examiner's reason is improperly
tainted by hindsight” (App. Br. 7).
We are not persuaded. The Federal Circuit has recognized that
an implicit motivation to combine exists not only when a
suggestion may be gleaned from the prior art as a whole, but
when the “improvement” is technology-independent and the
combination of references results in a product or process that
is more desirable, for example because it is stronger,
cheaper, cleaner, faster, lighter, smaller, more durable, or
more efficient.

DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464
F.3d 1356, 1368 (Fed. Cir. 2006). Khan expressly suggests the use of TetC
along with antigens from a number of different known pathogens, including
HBV, in formulating vaccines (FF 1-6). Thus, Khan teaches that TetC
produces vaccines that increase immune response of many different antigens
(FF 1). Neurath specifically suggests that the preS1 sequence is superior for
use in HBV vaccines (FF 7-11). Khan’s improved immune response and
Neurath’s improved immune repertoire, immune response, and decrease of
non-responders to HBV are motivations to select TetC and the preS1 HBV
sequence (FF 1-11). These are specific and credible reasons why the person
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of ordinary skill would have incorporated the preS1 sequence of Neurath
into the TetC based vaccine of Khan. Khan and Neurath together provided a
problem solving strategy to be applied in vaccine development, and it was
reasonable for the Examiner to rely on their disclosures as motivating the
person of ordinary skill in the art. See Dystar, 464 F.3d at 1366 (“the
‘evidence’ of motive will likely consist of an explanation of the well-known
principle or problem-solving strategy to be applied”).
Appellant contends that
there is no evidence in Khan et al. to suggest that it might
actually be possible to induce such a response using a fusion
protein of TetC with any of these numerous antigens. As
discussed further below, the skilled reader of Khan et al.
would appreciate that significant further experimentation
would be needed to try to identify suitable antigenic
sequences, combine them in a suitable way with a TetC
sequence, and then test them to determine whether the
required effect could be achieved.

(App. Br. 10). Appellant also contends that it “was not predictable that
tetanus toxin fragment C and a polypeptide consisting of at least 20 amino
acids of HBV pre-S1 could be combined in a fusion polypeptide in such a
way as to effectively present the pre-S1 sequence to the immune system and
thereby enhance the antibody response against the pre-S1 sequences” (App.
Br. 13). Appellant cites the Page Declaration, which states that the “design
of immunogens is an empirical art. It is difficult or impossible to predict in
advance whether a particular polypeptide will induce a good immune
response such as an antibody response” (Page Dec. 3 ¶ 7).
We are not persuaded. In this case, no such empirical testing was
necessary since Neurath teaches that the preS1 polypeptide of HBV induces
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10
a protective immune response (FF 9). Thus, given the teachings of Neurath,
it is entirely predictable that the preS1 sequence of HBV will induce an
immune response (FF 8-11). Kubin stated that “[r]esponding to concerns
about uncertainty in the prior art influencing the purported success of the
claimed combination, this court [in O’Farrell] stated: ‘[o]bviousness does
not require absolute predictability of success … all that is required is a
reasonable expectation of success.”’ In re Kubin, 561 F.3d 1351, 1360 (Fed.
Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988)).
We conclude that given the direct suggestion in the Khan that fusion
proteins with the required hinge would be expected to function, and the
direct teaching in Neurath that the preS1 HBV sequence induces a protective
immune response, there would have been a reasonable expectation of
success in modifying the fusion protein of Khan to incorporate the preS1
HBV sequence of Neurath (FF 1-11).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
claims would have been obvious over the teachings of Khan and Neurath.
SUMMARY
In summary, we affirm the rejection of claim 15 under 35 U.S.C. §
103(a) as obvious over Khan and Neurath. Pursuant to 37 C.F.R. §
41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 17, 18, and 25-
28 as these claims were not argued separately.

Appeal 2010-001184
Application 10/892,018

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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

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POPOVICH, WILES & O'CONNELL, PA
8519 EAGLE POINT BLVD
SUITE 180
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