Ex Parte Laurent et al

Board of Patent Appeals and Interferences

Sep 11, 2012

10842922 (B.P.A.I. Sep. 11, 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.
10/842,922 05/10/2004 Philippe E. Laurent 035510/319518 3199
47656 7590 09/11/2012
David W. Highet, VP & Chief IP Counsel
Becton, Dickinson and Company
(Alston & Bird LLP)
1 Becton Drive, MC 110
Franklin Lakes, NJ 07417-1880
EXAMINER
ARCHIE, NINA
ART UNIT PAPER NUMBER
1645
MAIL DATE DELIVERY MODE
09/11/2012 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte PHILIPPE E. LAURENT, ROBERT L. CAMPBELL,
GE JIANG, VINCE J. SULLIVAN,
KEVIN D. MAR, and KEVIN G. DOLAN
__________

Appeal 2011-012131
Application 10/842,922
Technology Center 1600
__________

Before ERIC GRIMES, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
influenza vaccine formulation. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

Appeal 2011-012131
Application 10/842,922

2
Statement of the Case
Background
According to the Specification, the invention “is based, in part, on the
surprising discovery by the inventors of a dermal and particularly an
intradermal vaccine delivery formulation which enhances the therapeutic
efficacy and protective immune response of the vaccine by specifically
targeting the intradermal compartment of a subject’s skin” (Spec. 4 ¶ 0012).
The Claims
Claims 1, 4, 19, and 24-26 are on appeal. Claim 1 is representative
and read as follows:
1. A vaccine formulation comprising a split influenza
viral antigen, a gelling agent, and a bioadhesive molecule,
wherein the gelling agent is a polyoxyalkylene block
copolymer selected from the group consisting of poloxamer
407, poloxamer 188, poloxamer 338, poloxamer 237,
poloxamer 231, poloxamer 282, poloxamer 331, poloxamer
401, poloxamer 402, and poloxamer 461, and the
bioadhesive molecule is a carboxymethylcellulose; and
wherein the formulation enhances the immune
response against the split influenza viral antigen upon
intradermal administration of the formulation to a subject.

The Issue

The Examiner rejected claims 1, 4, 19, and 24-26 under 35 U.S.C. §
103(a) as obvious over Cates,
1
Blonder,
2
and Singh
3
(Ans. 4-6).

1
Cates et al., WO 00/35481 A2, published Jun. 22, 2000.
2
Blonder et al., US 2002/0025326 A1, published Feb. 28, 2002.
3
Singh et al., WO 00/50078 A1, published Aug. 31, 2000.
Appeal 2011-012131
Application 10/842,922

3
The Examiner finds that Blonder teaches “a biocompatible polymer
incorporated in an immunogenic composition comprising an antigen from
influenza virus useful for delivering said antigen as a vaccine (see abstract
and paragraph [0059]), wherein the biocompatible polymer is a bioadhesive
and use in a liquid used as vehicle to form a gel and become gelatinous”
(Ans. 5). The Examiner finds that Blonder teaches that “any biocompatible
polymer, such as polyoxyethylene-polyoxypropylene block copolymers . . .
also known as Poloxamer 407(see paragraph [0070]), can be formulated in
an immunogenic composition” (Ans. 5).
The Examiner finds that Cates teaches an “immunoeffective non-
virulent split influenza antigen in an immunogenic composition formulated
as a protective vaccine in vivo” (Ans. 5). The Examiner finds that Cates
teaches “pluronic polymers which are immunomodulators that may act by
retaining the antigen locally near the site of administration to produce a
depot effect facilitating a slow, sustained release of antigen to cells of the
immune system” (Ans. 5).
The Examiner finds that Singh teaches “vaccine compositions
comprising a bioadhesive such as carboxymethylcellulose for mucosal
delivery” (Ans. 5). The Examiner finds that Singh teaches a “greater
enhancement in immunogenicity when a bioadhesive and antigen is
administered to elicit an immune response than an immune response elicited
without a bioadhesive” (Ans. 6).
The Examiner finds that the split influenza virus of Cates is an
obvious variation of the vaccine formulation of Blonder, and it would have
been obvious to “to incorporate said carboxymethylcellulose of Singh et al.
Appeal 2011-012131
Application 10/842,922

4
into the vaccine formulation of Blonder et al.[ ] in order to take advantage of
the increased efficacy in antigen delivery associated with
carboxymethylcellulose” (Ans. 6).
Appellants contend that the “the Examiner has merely pieced together
the claimed invention by citing to the elements in separate references. The
Examiner has not articulated a reason with some rational underpinning to
support the legal conclusion of obviousness” (App. Br. 11).
Appellants “submit herewith as Exhibit A, Figure 3 of the present
application. It illustrates the unexpected and enhanced antibody serum
response when the FLUZONE® vaccine was supplemented with
PLURONIC® F127 and carboxymethylcellulose as compared to
FLUZONE® alone” (App. Br. 15-16). Appellants “submit herewith Exhibit
B, Figure 1 of the present application. It demonstrates that the addition of
PLURONIC® F127 (poloxamer 407) alone to an influenza vaccine produces
only a marginal increase in the resultant serum antibody response when
compared to the antibody titers obtained with the influenza vaccine lacking
PLURONIC® F127” (App. Br. 16).
The issues with respect to the rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Cates, Blonder and Singh render claim 1 obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations that, when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Appeal 2011-012131
Application 10/842,922

5
Findings of Fact
1. Cates teaches “that combining a mixture of RSV proteins with
non-virulent influenza virus in a vaccine formulation provides an immune
response which is substantially the same as the response obtained by
administration of the components individually” (Cates 5, ll. 4-7).
2. Cates teaches that the
influenza virus vaccine utilized herein is a sterile suspension
prepared from influenza virus propagated in chicken
embryos. The virus-containing allantoic fluids are harvested
and inactivated with formaldehyde. The virus is then
concentrated and purified in a linear sucrose density gradient
solution, using a continuous flow centrifuge. The virus is
then chemically disrupted using Triton® X-100 producing a
split-antigen. The split-antigen is then further purified by
chemical means and suspended in sodium phosphate-
buffered isotonic sodium chloride solution.

(Cates 11, ll. 12-19).
3. Cates teaches that “[i]mmunogenicity can be significantly
improved if the antigens are coadministered with adjuvants. Adjuvants
enhance the immunogenicity of an antigen . . . Adjuvants may act by
retaining the antigen locally near the site of administration to produce a
depot effect facilitating a slow, sustained release of antigen” (Cates 13, ll.
27-31).
4. Blonder teaches that the “immunogen composition of the
present invention is useful for delivering an antigen to a host to treat or
prevent an infectious disease . . . Other useful antigens include . . . influenza
and tumor-specific antigens” (Blonder 6 ¶ 0059).
Appeal 2011-012131
Application 10/842,922

6
5. Blonder teaches that in “the immunogen composition, the
biocompatible polymer helps to protect the antigen from possible
degradation and to promote prolonged release of the antigen into the host
following administration” (Blonder 3 ¶ 0020).
6. Figure 5 of Blonder is reproduced below:

“FIG. 5 is a graph of the IgG anti-TT antibody response over time in sera of
inbred mice immunized i.p. at day 0 with 1.5 LfTT in PBS and subsequently
boosted i.n. four weeks later with 1.5 LfTT in either F127/chitosan or
chitosan alone” (Blonder 5 ¶ 0035).
7. Blonder teaches “preferred polyoxyalkylene block copolymers
including polyoxyethylene-polyoxypropylene block copolymers referred to
Appeal 2011-012131
Application 10/842,922

7
herein as POE-POP block copolymers, such as Pluronic™ F68, Pluronic™
F127, Pluronic™ L121, and Pluronic™ L101, and Tetronic™ T1501”
(Blonder 7 ¶ 0064).
8. Blonder teaches that “Pluronic™ F-127, also known as
Poloxamer 407, is such a material” (Blonder 8 ¶ 0070).
9. Singh teaches that “the mucosal delivery of bioadhesives,
including mucoadhesives and mucoadhesive derivatives, and an adjuvant, in
combination with an antigen of interest, acts to enhance the immunogenicity
of the antigen coadministered therewith” (Singh 2, ll. 33-36).
10. Singh teaches that in “preferred embodiments, the bioadhesive
is a mucoadhesive wherein the mucoadhesive is selected from the group
consisting of . . . carboxymethylcellulose” (Singh 3, ll. 17-21).
11. Singh teaches that “[a]ntigens derived from other viruses will
also find use in the claimed methods, such as without limitation, proteins
from members of the families . . . Orthomyxoviridae (e.g., influenza virus
types A, B and C, etc.)” (Singh 14, ll. 9-18).
12. Singh teaches that “groups of rabbits that were administered
[influenza virus] antigen and adjuvant with carbopol or HPMC had higher
titers than rabbits that were administered [influenza virus] antigen and
adjuvant alone” (Singh 27, ll. 11-14).
13. The Specification teaches that the “present invention is based,
in part, on the surprising discovery by the inventors of a dermal and
particularly an intradermal vaccine delivery formulation which enhances the
therapeutic efficacy and protective immune response of the vaccine by
Appeal 2011-012131
Application 10/842,922

8
specifically targeting the intradermal compartment of a subject’s skin”
(Spec. 4 ¶ 0012; FF 13).
14. Figure 1 of the Specification is reproduced below:

Figure 1 shows the “[s]erum antibody response following vaccination of
Balb/c mice with a FLUZONE preparation containing Pluronic F127 is
compared to FLUZONE preparation alone (w/o F127)” (Spec. 10 ¶ 0030).
15. Figure 3 of the Specification is reproduced below:

Appeal 2011-012131
Application 10/842,922

9
Figure 3 shows the “[s]erum antibody response following vaccination of
Balb/c mice with FLUZONE preparation containing Pluronic F127 and
carboxymethylcellulose is compared to FLUZONE preparation alone (w/o
[c]arboxymethylcellulose )” (Spec. 10 ¶ 0030).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). “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).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472-
1473 (Fed. Cir. 1984). Secondary considerations include: long-felt but
unsolved needs, failure of others, unexpected results, commercial success,
copying, licensing, and praise. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir.
1998); U.S. Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1565 (Fed. Cir.
1997).
Analysis
Prima facie obviousness
Cates teaches a vaccine formulation composed of a split influenza
viral antigen (FF 2) and an adjuvant which “may act by retaining the antigen
locally near the site of administration to produce a depot effect facilitating a
slow, sustained release of antigen” (Cates 13, ll. 27-31; FF 3). Blonder
suggests influenza virus vaccines combined with poloxamer 407 (FF 4-8),
Appeal 2011-012131
Application 10/842,922

10
where poloxamer 407 functions “to protect the antigen from possible
degradation and to promote prolonged release of the antigen into the host
following administration” (Blonder 3 ¶ 0020; FF 5). Singh teaches that
carboxymethylcellulose (FF 9) and “an adjuvant, in combination with an
antigen of interest, acts to enhance the immunogenicity of the antigen
coadministered therewith” (Singh 2, ll. 33-36; FF 10)).
We conclude that the combination of Cates, Blonder, and Singh
reasonably suggests combining the split flu viral antigen of Cates with the
poloxamer 407 adjuvant of Blonder and the carboxymethylcellulose
bioadhesive of Singh in order to prolong release of antigen and enhance the
immunogenicity of the antigen as suggested by Blonder and Singh (FF 4-
12).
Appellants contend that the “the Examiner has merely pieced together
the claimed invention by citing to the elements in separate references. The
Examiner has not articulated a reason with some rational underpinning to
support the legal conclusion of obviousness” (App. Br. 11).
We are not persuaded. Blonder’s teaching that poloxamer 407
protects an antigen and promotes prolonged release into host (FF 5)
dovetails closely with Cates’ teaching that “[i]mmunogenicity can be
significantly improved if the antigens are coadministered with adjuvants.
Adjuvants enhance the immunogenicity of an antigen . . . Adjuvants may act
by retaining the antigen locally near the site of administration to produce a
depot effect facilitating a slow, sustained release of antigen” (Cates 13, ll.
27-31; FF 3). The poloxamer 407 of Blonder satisfies the adjuvant
requirements of Cates and the ordinary artisan would have incorporated
Appeal 2011-012131
Application 10/842,922

11
poloxamer 407 to facilitate the slow, sustained release of influenza antigen
desired by Cates (FF 3, 5).
Further, Singh teaches that bioadhesives such as
carboxymethylcellulose “enhance the immunogenicity of the antigen
coadministered therewith” (Singh 2, ll. 33-36; FF 9). The ordinary artisan
reasonably is motivated to maximize immunogenicity of vaccines, and
would therefore have been motivated to incorporate the bioadhesive of
Singh into the poloxamer 407/split influenza antigen vaccine of Cates and
Blonder, consistent with DyStar, where the court 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). Here the improvement resulting from
combining Singh and Blonder with Cates results in an influenza vaccine
product with the expected advantages of improved immunogenicity and
prolonged release (FF 3, 9).
Unexpected Results
However, having found a prima facie case of obviousness, we must
now consider Appellants’ evidence of secondary considerations. See In re
Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“[T]he PTO must consider
comparative data in the specification in determining whether the claimed
invention provides unexpected results.”)
Appeal 2011-012131
Application 10/842,922

12
The Specification teaches that the “present invention is based, in part,
on the surprising discovery by the inventors of a dermal and particularly an
intradermal vaccine delivery formulation which enhances the therapeutic
efficacy and protective immune response of the vaccine by specifically
targeting the intradermal compartment of a subject’s skin” (Spec. 4 ¶ 0012;
FF 13).
Appellants identify two figures in the Specification, Figures 1 and 3,
which are argued to demonstrate these unexpected results (see App. Br. 15-
16; FF 14-15). These figures show that the addition of the poloxamer 407 or
poloxamer 407 and carboxymethylcellulose improve the serum response. In
Figure 1, the data shows an improvement from an OD of slightly over 0.6
for flu vaccine alone to slightly over 0.8 for flu vaccine and poloxamer 407,
yielding an approximate 33% improvement over flu vaccine alone. In
Figure 3, the combination of flu vaccine, poloxamer 407, and
carboxymethycellulose resulted in an OD of nearly 1, while the flu vaccine
alone was nearly 0.8, yielding an approximate 25% improvement of the
combination over flu vaccine alone.
However, as the Examiner points out, Blonder teaches “that the use of
bioadhesives results in the stimulation of strong immune response” (Ans. 9).
Figure 5 of Blonder shows that at weeks 6 and 8 (which represent 2 and 4
weeks after boost with either poloxamer 407/chitosan or chitosan alone), the
inclusion of the poloxamer 407 increased the titers by at least two fold, if not
greater than the chitosan adjuvant alone (please note that the y-axis scale in
Blonder is logarithmic, not linear) (FF 6). This two-fold or greater
Appeal 2011-012131
Application 10/842,922

13
improvement shown by Blonder is substantially greater than the result
shown in Appellants’ Specification (FF 6, 14, 15).
Therefore, based upon the disclosure of Blonder, the expected result
of including poloxamer 407 in an influenza vaccine composition of Cates
and Singh would be to substantially increase the antibody titers relative to
the influenza vaccine without poloxamer 407. Moreover, Singh discloses
that the mucosal delivery of bioadhesives, such as carboxymethylcellulose,
“acts to enhance the immunogenicity of the antigen coadministered
therewith” (FF 9-10). Appellants’ results are therefore not unexpected
relative to the teachings of Blonder and Singh. See In re Skoner, 517 F.2d
947, 950 (CCPA 1975) (“Expected beneficial results are evidence of
obviousness of a claimed invention. Just as unexpected beneficial results are
evidence of unobviousness.”)
As explained in Soni, 54 F.3d at 751, “[m]ere improvement in
properties does not always suffice to show unexpected results.” While we
can agree that Figures 1 and 3 show improved properties using poloxamer
407/vaccine and poloxamer 407/carboxymethylcellulose/vaccine relative to
vaccine alone, this improvement is not unexpected relative to the
improvement shown by Blonder (FF 6). We therefore do not find that the
results are sufficient to overcome the prima facie case of obviousness
presented by the Examiner.
Conclusions of Law
(i) The evidence of record supports the Examiner’s conclusion that
Cates, Blonder and Singh render claim 1 obvious.
Appeal 2011-012131
Application 10/842,922

14
(ii) Appellants have not presented evidence of secondary
considerations that, when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Cates, Blonder, and Singh. Pursuant to 37 C.F.R. §
41.37(c)(1), we also affirm the rejection of claims 4, 19, and 24-26 as these
claims were not argued separately.

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
alw