Ex Parte Mizel et al

Patent Trial and Appeal Board

Nov 15, 2017

13375417 (P.T.A.B. Nov. 15, 2017)

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.
13/375,417 02/13/2012 Steven B. Mizel 9151-126 7617
20792 7590
MYERS BIGEL, P.A.
PO BOX 37428
RALEIGH, NC 27627
11/15/2017 EXAMINER
LYONS, MARY M
ART UNIT PAPER NUMBER
1645
MAIL DATE DELIVERY MODE
11/15/2017 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 STEVEN B. MIZEL and SEAN REID
Appeal 2017-003240
Application 13/375,417
Technology Center 1600
Before DONALD E. ADAMS, DEMETRA J. MILLS, and
DAVID COTTA, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
Appeal 2017-003240
Application 13/375,417
STATEMENT OF CASE
Claims 1—7, 9, 13, 31, 40, and 47 are on appeal. The following claim
is representative.
1. A fusion protein comprising:
a flagellin adjuvant comprising a TLR5 recognition site; and
a Streptococcus pneumoniae PspA antigen,
wherein the PspA antigen is an amino terminal extension
of the flagellin adjuvant, and
wherein the fusion protein is able to activate the TLR5
pathway and generate PspA-specific IgG that reacts with native
PspA.
Cited References
Thoma US 2002/0015706 A1 Feb. 7, 2002
Aderem US 2009/0297552 A1 Dec. 3, 2009
Rhee WO 2005/070455 A1 Aug. 4,2005
M. Darrieux et al., Fusion Proteins Containing Family 1 and Family 2
PspA Fragments Elicit Protection against Streptococcus pneumoniae
That Correlates with Antibody-Mediated Enhancement of
Complement Deposition, Infection and Immunity, Vol. 75, No. 12,
5930-38 (Dec. 2007) (“Darrieux”).
Camilo Cuadros et al., Flagellin Fusion Proteins as Adjuvants or
Vaccines Induce Specific Immune Responses, Infection and
Immunity, Vol. 72, No. 5, 2810-16 (May 2004) (“Cuadros”).
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Application 13/375,417
Grounds of Rejection
1. Claims 1, 9, 13, 31, and 47 are rejected under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Rhee in view of Cuadros and
Aderem.
2. Claims 2—7 are rejected under pre-AIA 35 U.S.C. § 103(a) as being
unpatentable over Rhee in view of Cuadros, Aderem, and
Darrieux.
3. Claim 40 is rejected under pre-AIA 35 U.S.C. § 103(a) as being
unpatentable over Rhee in view of Cuadros, Aderem, and Thoma.
FINDINGS OF FACT
The Examiner’s findings of fact are set forth in the Non-Final Action
dated March 17, 2017, at pages 4—22 and Answer at pages 2—27.
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
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Appeal 2017-003240
Application 13/375,417
Obviousness Rejection 1
Rhee, Cuadros, Aderem
According to the Examiner,
Rhee et al. teach vaccine adjuvants containing flagellin as
an active component and methods of manufacturing
recombinant immunogens (i.e. antigens) having the
adjuvanticity induced by flagellin, by substituting genes
encoding for the various immunogenic epitopes for a part of the
genes between the N-terminal and C-terminal regions of the
structural genes of bacterial flagellin (i.e. resulting in constructs
that produce fusion proteins), including protein antigen epitopes
from pneumococcus (i.e. Streptococcus pneumoniae), including
PspA antigens ([0001, 0034-0038]; meeting limitations of claim
1 and 9). Rhee et al. teach making fusion proteins by
substituting the genes for recombinant immunogens for the
genes for making flagellin [0036] ....
Ans. 2—3. The Examiner finds that
the difference between the prior art and the invention is the
physical location of the PspA antigen portion of the fusion
protein, relative to the flagellin adjuvant portion of the fusion
protein. In other words, the prior art teaches the PspA antigen is
inserted into the flagellin adjuvant sequence, i.e. between the N-
terminal and C-terminal ends, whereas the claimed invention
re-positions the same PspA antigen at the N-terminal end of the
same flagellin adjuvant sequence.
Ans. 4. Thus, the Examiner relies on Cuadros as teaching
that a major limitation in the use of flagellin as an adjuvant is
that sequences inserted into the flagellin sequence (i.e. between
the N- and C-terminal ends) may interfere with the folding,
transport, and/or assembly of the flagellin proteins and
therefore recombinant fusion proteins in which an antigen of
interest is bound to an end of flagellin would be advantageous
(page 2811, left column). Cuadros et al. teach recognition of
flagellin is via Toll-Like Receptor 5 (i.e. flagellin comprises a
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Application 13/375,417
TLR5 recognition site; page 2810, right column; also meeting
limitations of instant claim 1).
Ans. 5. The Examiner relies on Aderem as disclosing
that non-flagellin polypeptides (e.g. antigens) can be fused to
either the C-terminus or the N-terminus of flagellin (e.g.
[0048]). Aderem et al. teach the flagellin portion of the fusion
protein contains the relevant sequences to maintain the TLR5
recognition site (e.g. the D1 domain; see [0011, 0048]; also
meeting limitations of claim 1). Aderem et al. teach that
flagellin fusion proteins are used for generating an immune
response in mammals and include flagellin polypeptides linked
to non-flagellin polypeptides derived from the same or different
organisms (e.g. [0048]). Aderem et al. teach the use of flagellin,
with or without linker moieties, selected to facilitate protein
folding and stability (e.g. [0048-0049]). Aderem et al. teach the
heterologous amino acid sequence fused to the flagellin
includes one or more antigens for which an adaptive immune
response is desired, including bacterial antigens (e.g. [0052]),
derived from, inter alia, Streptococcus pneumoniae (e.g.
[0095]).
Ans. 6. The Examiner concludes that:
it would have been prima facie obvious to a person of
ordinary skill in the art, at the time the invention was made, to
modify a fusion protein comprising a flagellin adjuvant and a
Streptococcus pneumoniae PspA antigen, as taught by Rhee et
al., by moving the PspA antigen from the hyper-variable central
region of flagellin to a terminal end of flagellin, including the
N-terminal end of the flagellin, thereby arriving at the claimed
invention, in order to reduce the interference with folding,
transport, and/or assembly of the flagellin fusion protein as
taught by Cuadros et al. and to facilitate both stability and
folding of the flagellin fusion protein as taught by Aderem et al.
Therefore, each and every stmctural element is taught in the
prior art and the combination is beneficial and desirable (see
MPEP 2144(H)).
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Application 13/375,417
The person of ordinary skill in the art would have been
motivated to make the modification because constructing a
fusion protein with the antigen of interest bound to a terminal
end of the flagellin, instead of one inserted within the flagellin
sequence, was an art-recognized solution to reduce miss-folding
of flagellin fusion proteins, as taught by Cuadros et al., and
because flagellin fusion proteins were constructed to facilitate
protein folding and stability, as taught by Aderem et al.
Ans. 6—7.
Appellants contend, among other things, that:
1. Rhee teaches away from the claimed invention. Appeal Br. 3^4.
2. The cited references do not direct one of ordinary skill in the art to
select Streptococcus pneumoniae PspA antigen as the desired
antigen in a flagellin fusion protein. Appeal Br. 4—5.
3. The cited references do not provide one of ordinary skill in the art
with a reasonable expectation of success of achieving the claimed
fusion protein. Appeal Br. 7.
4. The Examiner has not given appropriate weight to the Declaration
of Steven B. Mizel, Ph.D. Reply Br. 5—6.
ANALYSIS
We agree with the Examiner’s fact finding, statement of the rejection,
and responses to Appellants’ arguments as set forth in the Answer. We find
that the Examiner has provided evidence to support a prima facie case of
obviousness. We provide the following additional comment to the
Examiner’s position set forth in the Non-Final Rejection and Answer.
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Aderem discloses a fusion protein in the configuration claimed,
having the bacterial antigen at the N or amino terminus of the flagellin
protein. Aderem || 48, 52, 95. While Aderem does not provide a specific
example using PspA antigen as the bacterial antigen, Aderem suggests that
the, “fused to the immunomodulatory flagellin polypeptide will be one or
more antigens for which an adaptive immune response is desired” {id. 1 52)
for example, including bacteria such as S. pneumoniae {id. H 81, 95).
Furthermore, Rhee specifically discloses the desire of those of ordinary skill
in the art to use a PspA in a flagellin fusion protein, albeit having a different
configuration than that claimed. Rhee 138.
We agree that the Examiner has established that the claimed fusion
protein would have been obviousness on the evidence before us. In
particular, one of ordinary skill in the art at the time of the invention would
have modified the flagellin fusion protein having an antigen fused to the
amino terminal end of the immunomodulatory flagellin polypeptide selected
from one or more antigens for which an adaptive immune response is
desired, as described in Aderem, to include a bacterial component from S.
pneumoniae, as described in Aderem. It would have been further obvious to
include PspA as the bacterial component from S. pneumoniae, in view of
Rhee’s disclosure of a flagellin fusion protein including PspA antigen.
We are not persuaded that Rhee teaches away from the claimed
invention. Rhee teaches the desirability of using flagellar components as a
vaccine adjuvant (Rhee 11), and discloses an example of a flagellar fusion
protein {id. H 34—39) for use as a vaccine that may incorporate PspA.
Aderem discloses the claimed flagellin fusion protein configuration with the
antigen at the amino or N terminus of the flagellin protein. Cuadros
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Application 13/375,417
provides further motivation to those of ordinary skill in the art to prepare
flagellin fusion proteins in order to avoid antigen interference with the
folding, transport, or assembly of the flagella protein (Cuadros 2811, col. 1).
Appellants err in attacking the references individually, as the rejection is
based on a combination of references. See In re Merck & Co., Inc., 800 F.2d
1091, 1097 (Fed. Cir. 1986). The references cannot be read in isolation, but
must be read for what they teach in combination with the prior art as a
whole. See id.
We are not persuaded by Appellants argument that the cited
references do not direct one of ordinary skill in the art to specifically select
Streptococcus pneumoniae PspA antigen as the desired antigen to
incorporate into a flagellin fusion protein. Appeal Br. 4—5. Rhee directs one
of ordinary skill in the art to use PspA in a flagellin fusion protein (Rhee
Tflf34—39). Aderem also discloses the use of bacterial component from S.
pneumoniae, in flagellar fusion proteins (Aderem H 81, 95).
Appellants put forth the Declaration of Steven B. Mizel, PhD. in
support of patentability of the pending claims, arguing that the Declaration
shows that one of ordinary skill in the art at the time of the invention would
not have had a reasonable expectation of success of achieving the claimed
fusion protein. App. Br. 7-8.
However, we agree with the Examiner, for the reasons outlined in the
Answer that the Declaration is insufficient to overcome obviousness
rejection 1. In particular, we agree with the Examiner that the Declaration
paragraph 7 exemplification
is not sufficiently similar to the arguments set forth by the
Office because the antigen of interest was not moved to the N-
terminal end (i.e. the antigen remained in the central region)
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and adding 9 unrelated amino acids to the N-terminal end is not
analogous to the combination set forth by the Office. The
essential comparison would be to move the OVA antigen from
between the N-terminal and C-terminal ends of the flaqellin to
the N-terminal end of flaqellin and then determine if (A) TLR5
activity was “destroyed” and/or (B) if anti-0VA antibodies
were not indeed produced. Therefore, in view of the teachings
provided by all three prior art references, it is the Office’s
position that one of ordinary skill in the art would have
sufficient motivation to move the antigen from the
hypervariable region to either end, with a reasonable
expectation of success in doing so.
Ans. 25—26. Appellants did not clearly respond to this argument of the
Examiner in the Reply Brief.
Furthermore, while Appellants argue that there is no reasonable
expectation of success in achieving the claimed fusion protein that is able to
activate the TLR5 pathway (Reply Br. 5), again we are not persuaded. Rhee
discloses that, “the flagellin from V. vulnificus, which is an agonist of TLR-
5, stimulates production of interleukin-8 (IL-8) from epithelial cells.” Rhee,
p. 2; Rhee, Figs. 5-8. Cuadros discloses that
Purified or recombinant flagellin causes inflammatory
responses on treated cells in vitro (22) or when systemically
administered in vivo (46). This effect is mediated by the
activation of TFR-5 (14) present on target APCs. It has been
reported that ftagellin is an effective adjuvant capable of
enhancing T-cell responses in vivo (9, 27).
Cuadros, p. 2811, left col. Aderem discloses that, “As is understood
in the art, these polypeptides are portions of flagellin monomer or defined
variants thereof that effect an innate immune response that comprises a
TFR5-mediated immune response, an Ipaf-mediated immune response or
both.” |38. A preponderance of the evidence of record provides a
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reasonable expectation of success of preparing a fusion protein that activates
the TLR-5 pathway. Some experimentation, even a considerable amount, is
not “undue” if, e.g., it is merely routine, or if the specification provides a
reasonable amount of guidance as to the direction in which the
experimentation should proceed. See In re Wands, 858 F.2d 731, 737 (Fed.
Cir. 1988). In the present case, there is a clear understanding on the part of
those of ordinary skill in the art that flagellin activates the TLR-5 pathway,
and that the skilled artisan needs to be mindful of proper fusion protein
folding. All that is required is a reasonable expectation of success, not
absolute predictability of success. See In re O’Farrell, 853 F.2d 894, 903
(Fed. Cir. 1988). A preponderance of the evidence or record does not
support Appellants argument that one of ordinary skill would lack of a
reasonable expectation of success or that one of ordinary skill in the art
would have to engage in an unreasonable amount of experimentation (undue
experimentation) which was not routine in the art, to arrive at the claimed
invention in view of the disclosures of the cited references in combination.
The remaining of Appellants’ arguments in the Brief have been fully
addressed in the Answer, and we adopt the Examiner’s responses to
Appellants’ other arguments as our own.
The preponderance of the evidence in this case supports the
Examiner’s obviousness rejection.
For rejections 2 and 3 set forth in the grounds of rejection above,
Appellants rely on their arguments for rejection 1. Appeal Br. 11—13.
Appellants argue that neither Darrieux nor Thoma overcomes the
deficiencies of Rhee, Cuadros, and Aderem, in combination. Having found
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no deficiencies in the combination of Rhee, Cuadros, and Aderem, in
combination, we also affirm rejections 2 and 3.
CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejections,
which are affirmed for the reasons of record. All pending, rejected claims
fall.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv). See
37 C.F.R. § 41.50(f).
AFFIRMED
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