Ex Parte Medzhitov

Patent Trial and Appeal Board

Sep 24, 2013

11507387 (P.T.A.B. Sep. 24, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
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Ex parte RUSLAN MEDZHITOV
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Appeal 2011-004678
Application 11/507,387
Technology Center 1600
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Before RICHARD M. LEBOVITZ, MELANIE L. McCOLLUM, and
JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal under 35 U.S.C. § 134 by the Patent
Applicant (“Appellant”) from the Patent Examiner‟s rejections of claims 85
and 97-102 as obvious under 35 U.S.C § 103. The Board‟s jurisdiction for
this appeal is under 35 U.S.C. § 6(b). We affirm.

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STATEMENT OF THE CASE
This appeal involves Application Number 11/507,387 (“the „387
Application”). The claimed invention is directed to a fusion protein
comprising flagellin and Dengue viral protein. The fusion protein is
described as useful as a vaccine against Dengue virus. The fusion protein is
stated in the claim to activate the Toll-like Receptor 5 (“TLR5”). Activation
of the TLR5 signaling pathway induces an innate immune response, leading
to “the induction of the expression of cytokines, chemokines, adhesion
molecules, and co-stimulatory molecules by dendritic cells and macrophages
and, in some cases, B-cells.” („387 Application 12: 3-5.) Flagellin, which is
a structural protein of bacterial flagella (id. at 50:22), binds to TLR5 and
activates it (id. at 43: 1; 50: 24 to 51:1). The combination of flagellin and an
antigen of interest, such as Dengue viral protein, “provides [the] signals
necessary for the activation of the antigen-specific adaptive and innate
immune responses,” thus making the fusion protein effective as a vaccine
(id. at 74:21-22).
The Examiner rejected claims 85 and 97-102 as follows:
Rejection 1. Claims 85, 97, 98, 101 and 102 under 35 U.S.C. § 103(a)
as obvious in view of US 6,130,082 (“the „082 Patent” to Majarian), US
5,824,506 (“the „506 Patent” to Chan), US 6,541,011 (“the „011 Patent” to
Punnonen) and US Application 2005/0147627 A1 (“the „627 Application” to
Aderem); and
Rejection 2. Claims 99 and 100 under 35 U.S.C § 103(a) as obvious
in view of the „082 Patent, the „506 Patent, the „011 Patent, the „627
Application, and further in view of WO 95/34664 (“the „664 Application”).

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The only independent claim is claim 85 which reads as follows:
85. A fusion protein comprising a flagellin and a Dengue viral
antigen, wherein the fusion protein activates a Toll-like
Receptor 5.
FINDINGS OF FACT
The ‘082 Patent to Majarian
M1. The „082 Patent describes a recombinant fusion protein
comprising “an epitope encoded by a functional flagellin structural gene and
at least one epitope of a heterologous organism, which epitope is
immunogenic upon introduction of the fusion protein into a vertebrate host.”
(„082 Patent, col. 5, ll. 23-27).
M2. “The recombinant flagellin proteins of the invention are exported
to the cell surface, where, in a preferred embodiment, they assemble into
functional flagella containing the heterologous epitope.” („082 Patent, col.
5, ll. 35-39).
M3. “[T]he recombinant flagellin fusion proteins of the invention can
provoke a cellular, a mucosal, or a humoral response.” („082 Patent, col. 5,
ll. 39-41.)
M4. “Any DNA sequence which encodes an epitope of a
heterologous organism, which when expressed as a flagellin fusion protein,
produces protective immunity against such organism . . . can be isolated for
use in the vaccine formulations . . . [S]uch an organism is a pathogenic
microorganism. For example, such a heterologous epitope may be found on
bacteria, parasites, viruses or fungi which are the causative agents of
diseases or disorders.” („082 Patent, col. 9, ll. 56-65.)

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The ‘506 Patent to Chan
C1. The „506 patent describes dengue virus antigens “for immunizing
an individual against dengue hemorrhagic fever and/or dengue shock
syndrome” („506 Patent, col. 4, ll. 7-11).

The ‘627 Application to Aderem
A1. “The invention is directed to flagellin derived peptides that
exhibit immunomodulatory activity and to methods of inducing an immune
response through activation of toll-like receptor 5 (TLR5).” („627
Application, ¶ 21.)
A2. “[A] flagellin peptide functions to boost either or both humoral
and cell-mediated immune responses against the antigen.” („627
Application, ¶ 23.) “As described above, an immunomodulatory flagellin
peptide can be used to beneficially boost a general immune response in an
individual having a pathological condition by stimulating an innate immune
response.” (Id. at 88.)
A3. “A flagellin peptide of the invention induces an innate immune
response in an individual by binding to . . . TLR5.” („627 Application,
¶ 73.)
A4. The „627 Application describes flagellin peptides which have
TLR5 binding activity („627 Application, ¶ 25 & 27.) Example VII defines
a region of the flagellin monomer recognized by TLR5 (id. at 179 & 185)
A5. “The [flagellin] peptides can be used, for example, to effectively
stimulate an immune response . . . by administration of immunomodulatory
flagellin peptides and combinations of such peptides with antigens and other
immunomodulatory molecules.” („627 Application, ¶ 22.)
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A6. “[T]he invention provides a method of inducing an immune
response in an individual by administering a vaccine containing an
immunomodulatory flagellin peptide of the invention and an antigen.” („627
Application, ¶ 23.)
A7. “A chimeric flagellin peptide containing amino acid sequences of
an antigen or containing an antigenic molecule such as a carbohydrate,
nucleic acid, or lipid, can be used analogously to a vaccine, as described
above, as well as in a vaccine formulation, to induce an immune response in
an individual. As such, a chimeric flagellin peptide can be a vaccine that
induces both innate and adaptive immune system responses.” („627
Application, ¶ 71.) Viral antigens can also be used (id. at ¶ 79 & 81)

The Rejections
The Examiner found that the „082 Patent describes a recombinant
flagellin fusion protein comprising recombinant flagellin monomer and one
or more heterologous epitopes of various viral antigens, such as the rotavirus
antigen (Answer 4; M1, M3, & M4). The Examiner also found that the „627
Application teaches chimeric flagellin polypeptide comprising flagellin
peptide and amino acid sequence of an antigen to induce both innate and
adaptive immune responses (Answer 5; A7). The Examiner acknowledged
that neither the „082 Patent nor the „627 Application describes a fusion
protein comprising a Dengue viral antigen as claimed, but found that the
„506 and „011 Patents teach Dengue viral antigens for vaccines (Answer 4-5;
C1). Based on these teachings, the Examiner found that it would have been
obvious to one of ordinary skill in the art to have substituted Dengue viral
antigen for rotavirus antigen in the flagellin fusion protein described in the
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„082 Patent, where the flagellin peptide binds to the TLR5 receptor as taught
by the „627 Application (Answer 6; A1 & A3). The Examiner found it
obvious to have made such a fusion protein for the purpose of stimulating an
immune response again the Dengue virus (Answer 6).

1. REJECTION 1
It is well settled that the PTO “„bears the initial burden of presenting a
prima facie case of unpatentability . . . However, when a prima facie case is
made, the burden shifts to the applicant to come forward with evidence
and/or argument supporting patentability.‟ In re Glaug, 283 F.3d 1335, 1338
(Fed. Cir. 2002).” In re Sullivan, 498 F.3d 1345, 1351 (2007). In this case,
based on what the Examiner found and stated as discussed above, the
Examiner provided fact-based reasoning, supported by the evidence of
record, that it would have been obvious to one of ordinary skill in the art to
have made the claimed fusion protein of claim 85 (Answer 4-6). We thus
turn to Appellant‟s rebuttal arguments and evidence.
Appellant contends that the purpose of the „082 Patent is “to produce
flagellin fusion proteins that assemble into flagella, which do not bind to
Toll-like Receptor 5.” (Appeal Br. 5.) To support this position, Appellant
provides a declaration by Albert E. Price, Ph.D. (“the Price Decl.”). At the
time his declaration was executed, Dr. Price was an employee of the licensee
of the „387 Application and had responsibility for designing and testing
TLR5 fusion proteins (Price Decl. ¶ D). We therefore find Dr. Price
qualified to testify in the matters set forth in his declaration.
Dr. Price testified in his written declaration that “[n]one of the fusion
proteins described by the [„082] Patent, alone or in combination with the
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'506 Patent, would lead of [sic] one of ordinary skill in the art to predict that
a fusion protein comprising a flagellin and a Dengue viral antigen would
activate Toll-like Receptor 5.” (Price Decl. ¶ G3). Dr. Price also testified
that Smith et al., Nature Immunology 4:1247-1253 (2003) teaches that the
TLR5 is exquisitely sensitive to mutations (id. at ¶ G6). Thus, according to
Dr. Price, “Smith indicates that regions of flagellin that activate Toll-like
Receptor 5 could be disrupted, for example, by fusion to an antigen, which
could prevent activation of Toll-like Receptor 5 by the resulting fusion
protein.” (Id.)
Dr. Smith‟s testimony does not persuade us that the Examiner erred in
rejecting the claims as obvious based on the cited art at issue here.
First, Dr. Price did not list the „627 Application as prior art which he
considered in reaching his opinion that the claimed invention would not have
been obvious to one of ordinary skill in the art (Price Decl. ¶ F). Thus, Dr.
Price‟s opinion is not based on all of the prior art cited by the Examiner in
the rejection. The „627 Application, in particular, teaches a region of
flagellin which binds to TLR5 and that chimeric peptides comprising
flagellin and an antigen of interest can be made (A1, A3, A6, & A7). Dr.
Price‟s opinion that the skilled worker would not have been led to make a
fusion protein comprising flagellin that activates TLR5 is thus contrary to
the teachings in the „627 Application and were not considered by Dr. Price
in his written declaration.
Second, Dr. Price improperly relied on a post-published journal article
to establish the expectations of one ordinary skill in the art at the time of the
invention. Dr. Price testified that Smith indicates that a fusion protein with
flagellin could be prevented from activating TLR5 (Price Decl. ¶ G3).
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However, Smith was published in 2003, which is after the July 31, 2001
priority date of the „387 Application (Answer 12) and thus does not establish
what one of ordinary skill in the art would have expected on the date the
application was filed, the date on which it is assessed whether “the
differences between the claimed invention and the prior art are such that the
claimed invention as a whole would have been obvious.” 35 U.S.C. § 103.
To the contrary, the teachings in the „627 Application indicate an explicit
expectation at the time of filing that relevant fusion proteins would have
been capable of activating TLR5 (A7).
Dr. Price also opined that there would have been no reason to make a
fusion protein comprising Dengue virus and flagellin. Again, Dr. Price
neglected to consider the „627 Application. The „627 Application expressly
teaches that “a flagellin peptide functions to boost either or both humoral
and cell-mediated immune responses against the antigen” (A2), providing a
reason to have used flagellin and particularly a portion of it that was capable
of activating TLR5 (A1, A3-A5, & A7). The „082 Patent also teaches
“flagellin fusion proteins . . . can provoke a cellular, a mucosal, or a humoral
response” (M3). In sum, the reason to have made such a fusion protein
comprising a flagellin peptide and antigen would have been to obtain the
benefits of flagellin as taught by the „082 Patent (M3 and M4) and the „627
Application (A1, A2, A5, & A6).
Finally, Dr. Price reported experiments in which a fusion protein
comprising flagellin and Dengue viral antigen activated TLR5 and elicited
an immune response, which he stated “would not be expected in view of
common knowledge regarding flagellin structure and Dengue viral antigens,
and the teachings of the '513 Patent, alone or in combination with the '506
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Patent.” (Price Decl. ¶ G8.) However, Dr. Price again did not consider the
disclosure in the „627 Application, which explicitly discloses the benefits of
such a fusion proteins in eliciting an immune response (A7).
With respect to Appellant‟s argument that the „082 Patent‟s purpose is
to generate fusion proteins that assemble into functional flagella (Appeal Br.
6), we note that the claims do not exclude the recited fusion protein from
assembling into flagella. Thus, the teaching in the „082 Patent of a preferred
embodiment of assembling the fusion protein monomers into a flagella
provides a reason to have made the individual fusion protein monomers.
Nonetheless, as already discussed, the „627 Application provides an
independent reason to have made a fusion protein comprising a part of
flagellin capable of activating TLR5 and an antigen of interest (A6 & A7),
such as from Dengue virus as taught by the „506 Patent (C1), i.e., to induce
an immune response to the viral antigen (A7).
Appellant also states that a functional flagella would not activate
TLR5 (Appeal Br. 6). Even if it were true that a functional flagella does not
activate TLR5, the claim is drawn to an individual fusion protein, which
based on the teachings in the „627 Application, an ordinary artisan would
have expected to activate TLR5.
Appellant also states that the „627 Application has a priority date of
April 20, 2001, which is after the priority date of the „387 Application, and
is therefore not prior art (Appeal Br. 6). However, the Examiner determined
that the „387 Application is entitled to a priority date of July 31, 2001, which
is after the April 20, 2001 date of the „627 Application (Answer 12). The
Examiner had factual support for his determination, which Appellant did not
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persuasively rebut. Consequently, the „627 Application was properly cited
as prior art.
For the foregoing reasons, we affirm the rejection of claim 85 as
obvious. Claims 97, 98, 101 and 102 were not argued separately and
therefore fall with claim 85. 37 C.F.R. § 41.37(c)(1)(vii).

2. REJECTION 2
Appellant makes the same arguments for Rejection 2 of claims 99 and
100 as for Rejection 1. We thus affirm the rejection of these claims for the
same reasons.

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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