Etubics Corporation

Patent Trials and Appeals Board

Jul 29, 2020

13622263 - (D) (P.T.A.B. Jul. 29, 2020)

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.
13/622,263 09/18/2012 Joseph P. Balint 8774ETU-1-PCT-C1-CON 1028
157773 7590 07/29/2020
Sheridan Ross PC
1560 Broadway
Suite 1200
Denver, CO 80202
EXAMINER
ZEMAN, ROBERT A
ART UNIT PAPER NUMBER
1645
NOTIFICATION DATE DELIVERY MODE
07/29/2020 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
e-docket@sheridanross.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOSEPH P. BALINT, FRANK R. JONES,
and RICHARD B. GAYLE III1
Appeal 2020-001419
Application 13/622,263
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims relating
to an adenovirus vector, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
One aspect of the invention provides a method of
generating an immune response against one or more target

1 Appellant identifies the real party in interest as Etubics Corporation.
Appeal Br. 3. We use the word “Appellant” to refer to “applicant” as defined
in 37 C.F.R. § 1.42(a).
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Application 13/622,263

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antigens in an individual comprising administering to the
individual an adenovirus vector comprising: a) a replication
defective adenovirus vector, wherein the adenovirus vector has
a deletion in the E2b region, and b) a nucleic acid encoding the
one or more target antigens; and readministering the adenovirus
vector at least once to the individual; thereby generating an
immune response against the one or more target antigens.
Spec. 4:8–14.
“Target antigens of the present invention include but are not limited to
antigens derived from a variety of tumor proteins. Illustrative tumor proteins
useful in the present invention include . . . CEA.” Id. at 44:3–9.
Claims 37, 45–52, 57, 59, and 66–70 are on appeal. Claim 37,
reproduced below, is illustrative:
37. A composition comprising:
a replication defective adenovirus vector comprising:
(a) a deletion in an E2b region; and
(b) a nucleic acid sequence encoding a tumor associated
antigen, wherein the tumor associated antigen is a
carcinoembryonic antigen (CEA).

The claims stand rejected as follows:
Claims 37, 45–52, 57, 59, and 66–70 under 35 U.S.C. § 103(a) as
obvious based on Ojima2 and Amalfitano3 (Ans. 3);

2 Successful cancer vaccine therapy for carcinoembryonic antigen
(CEA)-expressing colon cancer using genetically modified dendritic cells
that express CEA and T helper-type 1 cytokines in CEA transgenic mice,
Int. J. Cancer 120:585–93 (2006).
3 Production and Characterization of Improved Adenovirus Vectors with the
E1, E2b, and E3 Genes Deleted, Journal of Virology 72(2):926–33 (1998).
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Claims 37, 45–52, 57, 59, and 66–70 under 35 U.S.C. § 103(a) as
obvious based on Huang4 and Amalfitano (Ans. 4);
Claims 37, 45–52, 57, 59, and 66–70 under 35 U.S.C. § 103(a) as
obvious based on Huang and Chamberlain5 (Ans. 6); and
Claims 37, 45–52, 57, 59, and 66–70 under 35 U.S.C. § 103(a) as
obvious based on Ojima and Chamberlain (Ans. 7).
OPINION
The Examiner has rejected all of the claims as obvious based on either
Ojima or Huang, combined with either Amalfitano or Chamberlain.
Appellant provides substantive arguments only with respect to the
combination of Ojima and Amalfitano, and relies on those arguments with
respect to all of the other rejections as well. See Appeal Br. 13–15. Because
the same issues are relevant to all of the rejections, and because Appellant
relies on the same arguments for all of the rejections, we will consider the
rejections together.
The Examiner finds that “Ojima et al. disclose the transfection of
dendritic cells with an adenovirus vector encoding CEA” but does not
disclose adenovirus vectors with a deletion in the E2b region. Ans. 3. The
Examiner finds that Huang similarly “disclose[s] that adenovirus vectors
encoding human CEA evoke a robust antibody response to CEA and are

4 A differential proteome in tumors suppressed by an adenovirus-based skin
patch vaccine encoding human carcinoembryonic antigen, Proteomics
5:1013–23 (2005).
5 US 6,083,750, issued July 4, 2000.
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capable of suppressing the growth of tumor cells,” but does not disclose
adenovirus vectors with a deletion in the E2b region. Id. at 4–5.
The Examiner finds that “Amalfitano et al. disclose adenovirus
vectors wherein the E1, E2b and E3 genes have been replaced with a
transgene” and that “their deletion vectors are superior standard adenovirus
vectors.” Id. at 3–4. The Examiner finds that, similarly, “Chamberlain et al
disclose the effective use of E2B deletion adenovirus mutants as viral
vectors. . . . Chamberlain et al. disclose that their deletion vectors are
superior standard adenovirus vectors since they can’t express all viral
proteins nor can they generate replication competent adenoviruses.” Id. at 6.
The Examiner concludes that it would have been obvious to use the
E2b-deleted adenoviral vector taught by either Amalfitano or Chamberlain
to express the CEA antigen taught by either Ojima or Huang, in order to gain
the advantages of the E2b-deleted vector that are taught by Amalfitano and
Chamberlain. Id. at 4–6, 8.
We agree with the Examiner’s fact-finding and conclusion. Ojima
discloses a study in which murine dendritic cells (DCs) were adenovirally
transduced with CEA, granulocyte macrophage colony-stimulating factor
(GM-CSF), and interleukin 12 (IL-12) and examined for whether these
vaccinations induced strong antitumoral immunity against tumor cells that
express CEA in CEA transgenic mice. Ojima 586, left col. Ojima discloses
recombinant adenoviral vectors comprising CEA cDNA. Id. Ojima reports
that “this vaccination therapy completely eliminated s.c. tumors in all mice.”
Id. at 590, right col.
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Huang describes “an anti-tumor vaccine . . . using adenovirus as a
vector which contains a cytomegalovirus early promoter-directed human
carcinoembryonic antigen gene (AdCMV-hCEA).” Huang 1013, abstract.
Huang reports that “vaccinated mice evoked a robust antibody titer to CEA
and demonstrated the capability of suppressing in vivo growth of implanted
murine mamma[r]y adenocar[c]i[n]oma cell line (JC-hCEA) tumor cells.”
Id. Huang states that its experiment used “adenovirus (E1/E3-defective non-
replicated adenovirus type 5) which contained a cytomegalovirus early
promoter-directed . . . human carcinoembryonic antigen gene (AdCMV-
hCEA).” Id. at 1014, right col.
Amalfitano discloses “an improved Ad vector that incorporated
deletions not only in the Ad E1 and E3 genes . . . but also the Ad polymerase
(E2b) gene.” Amalfitano 928, left col. Amalfitano discloses that “AdΔpol
vectors . . . have a theoretically decreased potential to generate replication-
competent Ad (RCA), since multiple recombination events are required to
regenerate a viable virus containing both the E1 and polymerase gene
functions.” Id. at 931, right col. Amalfitano also discloses that “the AdΔpol
vectors . . . have a significantly decreased potential to express viral late
genes such as the Ad fiber protein compared with first-generation Ad
vectors. Isolation of an Ad vector with a decreased potential to express viral
epitopes may improve gene transfer in vivo.” Id. at 932, left col.
Chamberlain states that “when genes critical to the viral life cycle are
deleted (e.g., the E2b genes), a further crippling of Ad to replicate and
express other viral gene proteins occurs. This decreases immune recognition
of virally infected cells, and allows for extended durations of foreign gene
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expression.” Id. at 13:61–66. Chamberlain also states that “[t]he most
important attribute of E1, polymerase and preterminal protein deleted
vectors[6] . . . is their inability to express the respective proteins, as well as a
predicted lack of expression of most of the viral structural proteins.” Id. at
13:66 to 14:2. “The polymerase and preterminal proteins are absolutely
required for Ad replication . . . and thus their deletion is extremely
detrimental to Ad vector late gene expression.” Id. at 14:13–17.
Based on the above teachings, it would have been obvious to combine
the CEA-encoding gene of Ojima or Huang with the adenoviral vector
disclosed by Chamberlain or Amalfitano because both Ojima and Huang
disclose using an adenoviral vector to express CEA to treat CEA-expressing
cancers, and both Chamberlain and Amalfitano disclose the advantages of
adenoviral vectors having a deletion in an E2b region. Specifically,
Chamberlain discloses that such vectors are defective in the expression of
viral proteins, resulting in decreased immune recognition and extended
duration of foreign gene expression, and Amalfitano discloses that they have
decreased potential to express viral late genes, and thus decreased potential
to express viral epitopes, which may improve in vivo gene transfer.
Appellant argues that “[e]xperimental results in the application as
filed, together with Dr. Amalfitano’s declaration,[7] establish that the
claimed composition can successfully elicit specific immunity by
homologous re-administration and that this result was unexpected to skilled

6 The “E2b region compris[es] the DNA polymerase and the adenovirus
preterminal protein gene.” Chamberlain 4:22–24.
7 Declaration under 37 C.F.R. § 1.132 of Andrea Amalfitano, filed January
28, 2019.
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persons at the time of invention.” Appeal Br. 7. “Homologous
readministration” refers to administering the same antigen-expressing vector
to a patient multiple times. See Spec. 2:26 to 3:2 (“[M]ost investigators
using First Generation Ad5 vector vaccines use the approach of a
heterologous prime-boost regimen. . . . This . . . results in a subsequent
immune response against Ad5 such that one cannot administer a further re-
immunization (boost) with the same (or a different) adenovirus vector
vaccine that utilizes the same viral backbone.”); 4:4–6 (“[T]here is no
homologous vaccine delivery vector that can be employed in a prime
reimmunization protocol for vaccination. The present invention provides this
and other advantages.”).
Appellant argues that the Specification’s “Example 6 demonstrates
that the claimed composition can successfully generate an effective immune
response in a homologous re-administration protocol.” Appeal Br. 7.
Appellant points to the Amalfitano Declaration as evidence that “this
property of the claimed composition was unexpected.” Id. Appellant argues
that “Dr. Amalfitano explains that she ‘did not believe that these replication
defective adenovirus vectors could be useful to generate immune responses
to target antigens where re-administered to a subject multiple times’” and
that “such understanding was the state of the art at the time of invention.”
Id., citing the Amalfitano Decl. ¶¶ 4, 5. Appellant argues that “Dr.
Amalfitano’s declaration—made under oath and citing to documented
evidence of ideas that were in circulation among workers in this field at the
time of invention—constitutes evidence of the unexpected nature of
Appellant’s discoveries.” Id. at 7–8.
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We have considered the evidence cited by Appellant—including the
Specification’s Example 6, the Amalfitano Declaration, and the Draper
reference8 cited therein—but find that a preponderance of the evidence
weighs in favor of a conclusion of obviousness. Appellant cites the
Specification’s Example 6 as evidence of unexpected results. That example
describes an experiment “show[ing] that the Ad5 [E1-, E2b-] vector platform
induces CMI [cell-mediated immune; Spec. 2:23] responses against the
tumor associated antigen (TAA) carcinoembryonic antigen (CEA) in the
presence of pre-existing Ad5 immunity in mice.” Spec. 75:4–6.
More specifically, the example compares “the immunization induction
potential of Ad5 [E1-]-CEA and Ad5 [E1-, E2b-]-CEA vaccines in Ad5
immune mice.” Id. at 76:2–4. Mice were immunized twice with “Ad5-null
VP” (Ad5 vector platform; id. at 75:16–17) and then immunized three times
with either “Ad5 [E1-]-CEA or Ad5 [E1-, E2b-]-CEA.” Id. at 76:4–7. “Two
weeks following the last immunization, mice were euthanized and their
spleens and sera harvested for analyses.” Id. at 76:7–9.
The Specification reports that “significantly elevated numbers of both
IFN-γ and IL-2 secreting cells were observed in spleens assayed from mice
immunized with Ad5 [E1-, E2b-]-CEA as compared to Ad5 [E1-]-CEA
immunized mice.” Id. at 76:14–17. These results are said to show that
“immunization of Ad5 immune mice with Ad5 [E1-, E2b-]-CEA induce [sic]
significantly higher CMI responses.” Id. at 76:20–21.

8 Draper et al., Viruses as vaccine vectors for infectious diseases and cancer,
Nature Reviews Microbiology 8:62–73 (2010).
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However, the Specification reports only the results observed after
three immunizations, with either Ad5 [E1-, E2b-]-CEA or Ad5 [E1-]-CEA.
The Specification does not provide evidence that multiple immunizations
with Ad5 [E1-, E2b-]-CEA result in a greater immunological response than a
single immunization with that vector, because samples were not analyzed
until after the third immunization. In addition, the Specification does not
characterize the results of Example 6 as surprising or unexpected. Spec. 75:1
to 78:7.
Dr. Amalfitano states that her “article (Amalfitano et al.) disclosed
new vectors that may be useful for gene therapy applications.” Amalfitano
Decl. ¶ 4 (referring to the same Amalfitano reference cited by the Examiner;
see id. ¶ 3). Dr. Amalfitano states that, based on her experience, she “did not
believe that these replication defective adenovirus vectors could be useful to
generate immune responses to target antigens when re-administered to a
subject multiple times.” Id.
Dr. Amalfitano does not identify the time at which she “did not
believe” that the vectors described in the Amalfitano reference would be
effective if re-administered to a subject. Based on the declaration, we
interpret Dr. Amalfitano’s statement to refer to the time at which the
Amalfitano reference was published, which was February 1998. The
effective filing date of the instant application, however, is July 2, 2007.
Spec. 1:4–9.
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Dr. Amalfitano states that, “[a]t the time of the claimed invention in
the instant application,[9] it was my opinion that because an immune
response is generated to immunogenic capsid proteins . . . , the effectiveness
of adenoviruses as vaccine vectors would have been limited to heterologous
immunization methods.” Amalfitano Decl. ¶ 5. This statement, however,
refers to “adenoviruses” generally, not adenoviruses with a deletion in an
E2b region, as recited in the claims on appeal.
Similarly, Dr. Amalfitano states that “[i]t is my opinion that the same
adenovirus vector generally may not be used for both the first and second
immunizations.” Id. This statement again does not specifically address
adenoviruses with a deletion in the E2b region, as claimed.
Dr. Amalfitano refers to Draper as evidence that “host responses to
the structural proteins of the viral vector itself were known to diminish
responses against the vaccine insert (target antigen) when the same vector
was used for multiple immunizations.” Amalfitano Decl. ¶ 5. Dr. Amalfitano
does not cite to any specific disclosure in Draper, which is a review of
“viruses as vaccine vectors.” Draper 62, abstract. Draper addresses
adenovirus vectors generally (see id. at 63, Table 1) and states that
heterologous prime-boost protocols with different viral vectors have been
tested (id. at 64, right col.), but does not appear to address adenoviral vectors
with a deletion in an E2b region, as claimed.

9 The Amalfitano Declaration was originally filed in a different application
(12/651,836, now US Patent 8,298,549 B2; Amalfitano Decl., page 1) but
that application and the instant application claim priority to the same
provisional patent application, so their effective filing dates are the same.
Spec. 1:4–9; ’549 patent, page 1.
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Dr. Amalfitano concludes that “it is [her] opinion that one would not
have expected to generate an effective immune response to one or more
target antigens using a homologous immunization protocol where the same
replication defective adenovirus vector used for the first administration is re-
administered to the subject in the second administration.” Amalfitano Decl.
¶ 5. Once again, however, Dr. Amalfitano refers generally to “replication
defective adenovirus vector[s],” rather than specifically addressing the
vector recited in the claims: an adenovirus vector comprising a deletion in an
E2b region.
In summary, the example in the Specification cited by Appellant does
not compare the effect of a single immunization to homologous re-
administration of the same vector, nor does it state that the results found
were unexpected or surprising, and neither the Amalfitano Declaration nor
the Draper reference address what would have been expected for an
adenoviral vector with a deletion in the E2b region, as of the effective filing
date of the instant application. We conclude that Appellant’s evidence is
entitled to little probative weight as a showing of unexpected results.
Weighing against Appellant’s evidence is Chamberlain’s disclosure
that a deletion in the E2b region of an adenoviral vector would be expected
to “crippl[e]” the ability of the adenovirus to express other genes, which
“decreases immune recognition of virally infected cells, and allows for
extended durations of foreign gene expression.” Chamberlain 13:61–66.
Chamberlain also states that E2b-deleted adenoviral vectors were expected
to be unable to express most viral structural proteins. Id. at 13:66 to 14:2.
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12
Similarly, the Amalfitano reference states that AdΔpol vectors (i.e.,
adenoviral vectors with a deletion in the E2b region) “have a significantly
decreased potential to express viral late genes” and “a decreased potential to
express viral epitopes,” which “may improve gene transfer in vivo.”
Amalfitano 932, left col.
The statements in Chamberlain and the Amalfitano reference
specifically address what would have been expected for adenoviral vectors
with a deletion in the E2b region, and indicate that such vectors were
expected to cause decreased immune recognition and decreased expression
of viral epitopes, as well as extended duration of foreign gene expression
and improved in vivo gene transfer. Based on these teachings, a skilled
artisan would reasonably expect that an E2b-deleted adenoviral vector would
be less likely to provoke an immune response to adenoviral gene products,
and therefore would be more likely to be useful for multiple administrations,
compared to a first generation (E1-deleted) adenoviral vector.
In summary, the evidence cited by the Examiner supports a prima
facie case of obviousness, and the evidence submitted by Appellant to show
nonobviousness is entitled to little probative weight because it does not
specifically address the claimed invention as of the effective filing date. We
conclude that a preponderance of the evidence supports the Examiner’s
rejections, which we therefore affirm.
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
37, 45–52,
57, 59, 66–
70
103(a) Ojima, Amalfitano 37, 45–52,
57, 59, 66–
70

37, 45–52,
57, 59, 66–
70
103(a) Huang, Amalfitano 37, 45–52,
57, 59, 66–
70

37, 45–52,
57, 59, 66–
70
103(a) Huang, Chamberlain 37, 45–52,
57, 59, 66–
70

37, 45–52,
57, 59, 66–
70
103(a) Ojima, Chamberlain 37, 45–52,
57, 59, 66–
70

Overall
Outcome
37, 45–52,
57, 59, 66–
70

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED