Ex Parte Braun

Board of Patent Appeals and Interferences

May 18, 2012

10508143 (B.P.A.I. May. 18, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RALPH PATRICK BRAUN
__________

Appeal 2010-012184
Application 10/508,143
Technology Center 1600
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Before DEMETRA J. MILLS, LORA M. GREEN, and
STEPHEN WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the rejection of
claims directed to a method of enhancing cell-mediated immune response.
The Patent Examiner rejected the claims for obviousness. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.
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STATEMENT OF THE CASE
Claims 1-5, 7-11, and 14-20 are on appeal. Claim 1 is representative
and reads as follows:
1. A method of enhancing or stimulating in an individual a cell-mediated
immune response to an antigen, said method comprising the steps of
administering to the individual an isolated recombinant polynucleotide
capable of expressing the antigen and, only 12 to 36 hours subsequent to the
administration of the polynucleotide, topically or transdermally
administering to the individual a single dose of a compound which is
selected from the group consisting of an imidazoquinoline amine,
imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2-
bridged imidazoquinoline amine, thiazolo- and oxazolo-quinolinamines,
thiazolo- and oxazolo-pyridinamines, imidazonaphthyridine and
tetrahydroimidazonaphthyridine amine.

The Examiner rejected claims 1-5, 7-11, and 14-20 under 35 U.S.C.
§ 103(a) as unpatentable over Miller,1 Suter,2 and Steele.3

OBVIOUSNESS
As a preliminary matter, the Examiner states that examination has
been limited to these elected species of practicing the invention:
The route of administration is transdermal administration of a
polynucleotide capable of expressing an antigen, and topical
administration of the compound of imidazoquinoline amine; wherein

1 Richard L. Miller et al., US 6,083,505, issued July 4, 2000.
2 Mark Suter et al., BAC-VAC, a novel generation of (DNA) vaccines: A
bacterial artificial chromosome (BAC) containing a replication-competent,
packaging-defective virus genome induces protective immunity against
herpes simplex virus 1, 96 PROC. NAT’L ACAD. SCI. 12697-12702 (1999).
3 K. E. Steele et al., Cutaneous DNA Vaccination Against Ebola Virus by
Particle Bombardment: Histopathology and Alteration of CD3-positive
Dendritic Epidermal Cells, 38 VET. PATHOL. 203-215 (2001).
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the polynucleotide capable of expressing the antigen of herpes
simplex virus (HSV).

(Ans. 4.)

The Issue
The Examiner’s position is that Miller taught a method of enhancing
an immune response to an antigen by administering an immunogen and the
adjuvant imidazoquinoline amine. (Ans. 5.) The Examiner found that
Miller disclosed that imidazoquinoline amine enhanced both cell mediated
and antibody immune responses, and that immunization with HSV
glycoprotein and imidazoquinoline resulted in reduced total lesion score and
recurrent HSV-2 disease. (Id.) According to the Examiner, Miller
“exemplifies that administering imidazoquinoline amine either
simultaneously with HSV glycoprotein administration, or after a delay of 48
hours after HSV glycoprotein administration, results in reduced total lesion
score.” (Id.) Miller did not teach HSV DNA-coated gold particles as an
immunogen, nor administering imidazoquinoline amine 12-36 hours after
administering the vaccine. (Id. at 6.) Suter disclosed HSV immunization
with HSV DNA applied intradermally by gold particle bombardment. (Id.)
The Examiner concluded it would have been obvious to use HSV DNA
vaccine and imidazoquinoline amine to enhance an immune response to
HSV. (Id.) Suter also disclosed that expression of the HSV antigen coded
by the administered DNA increased between 4 and 8 hours post-vaccination,
then decreased to near zero by 48 hours. (Id. at 7.) Steele taught that
antigen expression of DNA-coated gold particles in skin cells peaks about 8
hours post-vaccination. (Id.) The Examiner reasoned:
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Based upon the teachings and successful examples in Miller and
Steele, one of ordinary skill in the art would know to administer
imidazoquinoline amine in a time window of about 8 to 48 hours after
the DNA vaccine is administered (when HSV glycoprotein is
expressed by the HSV DNA vaccine) to enhance an immune response
to HSV protein. One of ordinary skill in the art would expect that the
time period of 12 to 36 hours post-vaccination for administering
imidazoquinoline amine of the claimed method would work because it
is well within the workable time window taught by the prior art,
absence any evidence to the contrary. Also, it is within the capability
of one of ordinary skill in the art to determine and optimize the timing
of administering imidazoquinoline amine adjuvant based on the HSV
expression in different systems by routine testing.
(Id. at 7-8.)
Appellant contends:
A skilled artisan declared on the written record in this case that
it was known in the art that adjuvants that are effective with protein or
whole-organism vaccines, exactly like those listed in Miller, were
generally ineffective when utilized with isolated recombinant nucleic
acid vaccines, such as those of the claimed invention (see Declaration
under 37 CFR § 1.132 of Dr. Deborah Lynch; Exhibit 4). Thus, there
could not have been any reasonable expectation that an adjuvant
known to be effective with a protein or whole-organism vaccine
would be effective with an isolated recombinant polynucleotide
vaccine.

(App. Br. 6-7.) Appellant also contends that
the overwhelming teaching of the prior art was that numerous doses of
the imidazoquinoline amine should be used over an extended period
of time, so it was particularly non-obvious to give a single dose of the
imidazoquinoline amine in a specific time window of 12-36 hours
after administration of an isolated recombinant polynucleotide
vaccine.

(Id. at 10.)
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The Examiner responds that the evidence does not support Dr.
Lynch’s Declaration statements. (Ans. 8-9.) In particular, the Examiner
notes that references the Declaration cited involved administering
recombinant interferon, not imidazoquinoline amine. (Id. at 9-11.) Further,
the Examiner contends that the claim term “isolated recombinant
polynucleotide” should be read to include compositions containing whole,
killed, attenuated or inactivated bacteria, viruses, parasites, or other
microbes. (Id. at 12, citing Spec. at ¶ [0343].) The Examiner argues that the
polynucleotide capable of expressing an antigen would in fact express the
protein antigen, and “the immunogenic polypeptide encoded by DNA is the
real immunogen/antigen for stimulating an immune response.” (Id. at 13.)
Thus, the Examiner reasons that the real antigen “is not fundamentally
different from viral proteins expressed by a live viral vaccine used in the
method of Miller.” (Id.) The Examiner disputes Appellant’s arguments and
Declarant Lynch’s statements concerning “surprising” results produced by
the 12 to 36 hour post-vaccination administration of adjuvant. (Id. at 14-22.)
Appellant replies to the Examiner’s arguments. (Reply Br. 2-10.)

Findings of Fact
1. The record contains a “Declaration” by Deborah T. Lynch, Ph.D.
2. Dr. Lynch stated:
Before the time the patent application was filed, adjuvants
known to be effective with protein-based vaccines had been tried with
DNA-based vaccines, but had met with little success. For example,
alum, Freund’s Complete Adjuvant (FCA), Freund’s Incomplete
Advjuvant (FIA), and interferon-γ were known to be effective as
adjuvants in combination with protein-based vaccines but were found
not to be effective in DNA vaccination.
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. . .
However, interferon-γ was ineffective when used in
combination with a DNAvaccine (Ref. 5 listed in Appendix I). Indeed,
it was found that, when a plasmid expressing IFN-γ was co-inoculated
with a plasmid expressing a vaccine antigen (the glycoprotein of
rabies virus), there was a decrease in the immune response to the
antigen (see the abstract of Ref. 5).

(Decl. ¶ 5, citing references.)
3. Dr. Lynch stated:
It is notable that Miller et al suggests that imidazoquinoline
amine adjuvants work through a mechanism that involves stimulation
of the biosynthesis of cytokines such as interferons (see Miller et al,
column 2, lines 54-57 and column 3, lines 13-25). Thus, Miller et al
suggests that imidazoquinoline amines have their adjuvant effect on
protein-based vaccines through the same kind of mechanisms that had
been shown be deleterious for DNA-based vaccines in Ref. 5.

(Id. at ¶ 6.)
4. Dr. Lynch opined:
Thus, Examiner's position does not have sound scientific
foundation. For the reasons explained above, it would not have been
expected that the imidazoquinoline amines described in Miller et al as
adjuvants for protein-based vaccines would also work with nucleic
acid-based vaccines.

(Id. at ¶ 7.)
5. Dr. Lynch stated that the superiority of the 12 to 36 hour time window
“was surprising when considering the literature available at the time
and the data generated by the inventors” (id. at ¶ 8, citing evidence),
and stated that “[i]t was particularly surprising that administration on
day 1 only was superior to three administrations on days 0, 1 and 2
(see Figure 1)” (id. at ¶ 9).
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6. Dr. Lynch discussed results disclosed in several articles from the
medical literature and stated that the results reported in those articles
suggested that frequent administrations of adjuvant were needed. (Id.
at ¶¶ 11-15.)

Principles of Law
“Obviousness does not require absolute predictability. Only a
reasonable expectation that the beneficial result will be achieved is
necessary to show obviousness.” In re Merck & Co., Inc., 800 F.2d 1091,
1097 (Fed. Cir. 1986) (citations omitted). The presence of a reasonable
expectation of success is measured from the perspective of a person of
ordinary skill in the art at the time the invention was made. Life Techs., Inc.
v. Clontech Labs., Inc., 224 F.3d 1320, 1326 (Fed. Cir. 2000).

Analysis
The method claimed requires the administration of an isolated
recombinant polynucleotide, not a polynucleotide in a live, attenuated, or
other form of bacterium or virus. We disagree that Spec. ¶ [0343] defined
“isolated” as broadly as the Examiner urges, and therefore also disagree that
the claim reads on Miller’s vaccinations with a bacterium or virus.
The Briefs and the Answer provide thorough presentations of the two
sides in this dispute. After consideration of all the evidence, we are
persuaded by Declarant Lynch’s analysis that (1) there would not have been
a reasonable expectation of success in enhancing an immune response by
administering an isolated polynucleotide, followed by a single dose of
imidazoquinoline 12 – 36 hours later; and (2) the result Appellant obtained
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with only one dose of adjuvant was surprising in view of the literature
reports available. The rejection is therefore reversed.

SUMMARY
We reverse the rejection of claims 1-5, 7-11, and 14-20 under
35 U.S.C. § 103(a) as unpatentable over Miller, Suter, and Steele.

REVERSED

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