Ex Parte Chada

Board of Patent Appeals and Interferences

Sep 16, 2010

11001702 (B.P.A.I. Sep. 16, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte SUNIL CHADA
__________

Appeal 2009-015169
Application 11/001,702
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of suppressing or preventing an infection. The Examiner has rejected the

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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claims for lack of enablement. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
The Specification discloses that “[m]elanoma differentiation
associated gene 7 (mda7) is a tumor suppressor gene. . . . The inventors
have discovered that MDA-7 functions in a manner that involves certain
pathways in cancer cells that are involved in pathogen infection and
pathogen replication.” (Spec. 5: 11-17.)
Claims 1, 2, 15, 16, 20-27, 30-35, 37-44, and 47 are on appeal.
Claims 1 and 32 are representative and read as follows:
1. A method of suppressing or preventing an infection of a subject
by a pathogen, comprising administering to the subject a composition
comprising: (a) a therapeutically effective amount of an MDA-7 polypeptide
or a nucleic acid encoding the MDA-7 polypeptide; and (b) a
pharmaceutically acceptable preparation suitable for delivery to said subject,
wherein the MDA-7 suppresses or prevents the infection.

32. A method of suppressing or preventing a viral infection of a
cell, comprising: (a) obtaining an MDA-7 polypeptide or a nucleic acid
encoding the MDA-7 polypeptide; and (b) contacting the cell with the
MDA-7 polypeptide or the nucleic acid encoding the MDA-7 polypeptide;
wherein the MDA-7 suppresses or prevents infection of the cell.

The Examiner states that, as a result of a restriction requirement,
“examination has been limited to the elected nucleic acid encoding MDA-7,
administered intravenously” (Answer 3).
Issue
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 112, first paragraph, on the basis that the “specification is not enabling for
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a method of suppressing or preventing a Hepatitis C viral infection of a
subject or a cell, comprising intravenous administration to said subject of a
therapeutically effective amount of an adenoviral or non-viral vector
encoding the MDA-7 polypeptide, or contacting a cell with said nucleic
acid” (Answer 3).
The Examiner finds that the Specification does not provide an
adequate basis for “correlating the anti-cancer apoptotic action of MDA-7 to
suppressing or preventing viral infection” (id. at 4). The Examiner also
finds that practicing the claimed method using “adenoviral or non-viral
vectors encoding mda-7, delivered by intravenous administration” (id. at 5)
would require undue experimentation because “adenoviral mediated gene
delivery is associated with a number of significant problems . . . [and]
intravenous delivery of mda-7 nucleic acid via a non-viral vector would not
likely result in the cell targeting and expression of MDA-7 to any significant
degree” (id. at 6).
Appellant contends that “one of ordinary skill in the art, in view of the
teachings of the instant specification, would understand that MDA-7 induces
PKR expression, that this PKR expression exerts antiviral and anticellular
function, and that MDA-7 can thus be applied in the prevention or
suppression of viral infection in a subject” (Appeal Br. 4). Appellant also
contends that declaratory evidence and the prior art show that undue
experimentation would not be required to practice the claimed method using
adenoviral or non-viral vectors (id. at 9-11).
The issue presented in this appeal is: Does a preponderance of the
evidence of record support the Examiner’s conclusion that practicing the
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claimed method to treat infection with hepatitis C virus, by administering
MDA-7-encoding DNA via an adenoviral or non-viral vector, would require
undue experimentation?
Findings of Fact
1. The Examiner finds that Bottaro2 provides evidence that MDA-7
would not be useful for suppressing or preventing viral infection, because
Bottaro “discloses methods of protecting cells from HIV-1 pathogenesis
using inhibitors of PKR” (Answer 4).
2. Bottaro discloses “antagonists of double-stranded RNA dependent
protein kinase (PKR). . . . [T]he PCR [sic, PKR] antagonists are
administered to provide protection from the excessive cell death caused by
human immunodeficiency virus type 1 (HIV-1).” (Bottaro, col. 5, ll. 35-45.)
3. The Examiner finds that the “specification is silent on providing
any evidence of suppression or prevention for hepatitis C infection or any
other type of viral infection in a subject. Therefore, no connection is evident
between the described apoptotic effects of MDA-7 and the claimed
suppression or prevention of viral infection.” (Answer 5.)
4. The Specification discloses that one “mechanism whereby viruses
ensure translational efficiency involves the cellular kinase known as
interferon-induced, double stranded (ds) RNA-activated serine/threonine
protein kinase (PKR)” (Spec. 3: 7-9).
5. The Specification discloses that PKR “mediates the antiviral
actions of interferon” (id. at 3: 19).

2 Bottaro et al., US 6,326,466 B1, Dec. 4, 2001
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6. The Specification discloses that “[m]any viruses inhibit PKR
activity. One such example is Hepatitis C virus (HCV). . . . Other examples
of viruses that inhibit PKR activity include adenovirus, EBV, poxvirus,
influena [sic] virus, reovirus, HIV, polio, HSV, and SV40.” (Id. at 3: 25-
31.)
7. The Specification discloses that “Ad [adenovirus]-mda-7 has been
shown to induce and activate PKR in cancer cells, which leads to . . .
induction of apoptosis” (id. at 15: 11-12).
8. The Specification discloses that “Ad-mda7 apoptosis is dependent
on a functional PKR pathway. These characteristics indicate that MDA-7
has broad therapeutic, prognostic and diagnostic potential as an inducer of
PKR and, consequently, an enhancer of an induced immune response.” (Id.
at 34: 27-30.)
9. The Specification discloses that “[a]nother mediator of ER
[endoplasmic reticulum] stress is the Unfolded Protein Response (UPR). . . .
Prolonged UPR activation leads to activation of death-related signaling
pathways and ultimately, to apoptotic death.” (Id. at 4: 9-15.)
10. The Specification discloses that the “UPR is used by many
endoplasmic reticulum-tropic viruses . . . to facilitate their life cycle and
pathogenesis” (id. at 4: 15-17).
11. The Specification discloses that “pathogens other than viruses can
activate the PKR and UPR defense systems” (id. at 4: 21-22).
12. The Specification discloses that “Ad-mda7 transduction of lung
cancer cells results in activation of the UPR. . . . In view of the fact that the
UPR is exploited by viruses, these findings further support the inventors’
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discovery that MDA-7 can be applied in the prevention and treatment of
infections of subjects by pathogens.” (Id. at 5: 19-25.)
13. The Specification discloses that “expression of . . . UPR-
associated proteins is up-regulated after Ad-mda7 transduction, suggesting
that UPR activation was the mechanism by which MDA-7 was killing cancer
cells” (id. at 62: 13-15).
14. The Examiner finds that Wilson3 discloses that when adenovirus
is infused directly into the blood, it targets essentially only hepatocytes, or
liver cells (Answer 5).
15. Appellant has provided two declarations under 37 C.F.R. § 1.132
(dated March 16, 2007 (“First Chada Declaration”) and Nov. 30, 2007
(“Second Chada Declaration”)).
16. Appellant declared that Tolcher4 “contradicts the Examiner’s
belief that intravenous or systemic delivery of adenoviral vectors may be
dangerous,” and provides evidence that systemically administered
adenoviral vectors can transduce cells that are distant from the site of
administration (First Chada Declaration, ¶ 5).
17. Tolcher discloses that “Ad5CMV-p53 can be feasibly
administered at doses up to 3 x 1012 vp IV daily for 3 days every 28 days to
patients with advanced solid tumors. . . . The safe, prolonged circulation of

3 Wilson, Adenovirus-Mediated Gene Transfer to Liver, 46 Advanced Drug
Delivery Reviews 205-209 (2001)

4 Tolcher et al., Phase I, Pharmacokinetic, and Pharmacodynamic Study of
Intravenously Administered Ad5CMV-p53, an Adenoviral Vector Containing
the Wild-Type p53 Gene, in Patients with Advanced Cancer, 24 J. Clin.
Oncol. 2052-2058 (2006)
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the intact vector, and successful transduction of p53 into tumor cells at sites
distant from Ad5CMV-p53 IV administration represents an important proof
of concept.” (Tolcher 2057.)
18. Appellant declared that Mhashilkar5 discloses that “MDA-7 is
actively secreted from cells. . . . Therefore, if one hepatic cell were to be
transduced with an adenoviral vector with a nucleic acid encoding MDA-7,
the subsequent MDA-7 polypeptide would be secreted and interact with
other hepatic cells.” (Second Chada Declaration, ¶ 6.)
19. The Second Chada Declaration provides data “demonstrat[ing]
that increasing dosages of MDA-7 result in a linear dose-dependent decrease
in the production of hepatitis C viral RNA. . . . [B]oth interferon [a positive
control] and MDA-7 suppress hepatitis C infection by preventing hepatitis C
replication.” (Second Chada Declaration, ¶ 5.)
20. The Examiner finds that “expression of any gene of interest
encoded by a simple nucleic acid, such as a plasmid . . . , would be transient
and would not allow sustained suppression of a viral infection in a subject”
(Answer 6).
21. The Specification discloses that methods of administering genetic
material, including MDA-7-encoding DNA, to host cells via lipid-mediated
transformation were known in the art (Spec. 49-51).

5 Mhashilkar et al., Melanoma Differentiation Associated Gene-7 (mda-7): A
Novel Anti-Tumor Gene for Cancer Gene Therapy, 7(4) Molecular Medicine
271-282 (2001)
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Principles of Law
When rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of
protection provided by that claim is not adequately enabled by
the description of the invention provided in the specification of
the application; this includes, of course, providing sufficient
reasons for doubting any assertions in the specification as to the
scope of enablement. If the PTO meets this burden, the burden
then shifts to the applicant to provide suitable proofs indicating
that the specification is indeed enabling.
In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).
Analysis
We agree with Appellant that the Examiner has not provided evidence
or sound scientific or logical reasoning sufficient to support a conclusion
that practicing the claimed method would require undue experimentation.
The Examiner asserts that the Specification does not adequately correlate the
tumor-suppressing apoptotic activity of MDA-7 with its use in suppressing
or preventing viral infection (Answer 5). However, the Specification
discloses that MDA-7 induces and activates PKR (FF 7), which is inhibited
by many viruses (FF 6), and which mediates the antiviral activity of
interferon (FF 5). The Specification also discloses that MDA-7 activates the
Unfolded Protein Response (UPR) (FF 12), which leads ultimately to
apoptotic cell death (FF 9). In addition, Appellant has provided declaratory
evidence showing that expression of MDA-7 causes a dose-dependent
reduction in transcription of hepatitis C virus RNA (FF 19).
As evidence showing that MDA-7 is not useful for suppressing or
preventing viral infection, the Examiner cites Bottaro’s disclosure that PKR
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antagonists can be used to protect cells from HIV-1 pathogenesis (FF 1).
Considered in context, however, Bottaro’s statement does not contradict the
Specification’s disclosure. Bottaro discloses the use of PKR antagonists to
protect cells from being killed by HIV-1 (FF 2), while the Specification
discloses that MDA-7 causes apoptosis (cell death) by activating PKR and
UPR in cancer cells (FFs 7, 9, 12); causing apoptosis in virus-infected cells
would suppress or prevent further infection by limiting the number of
infectious viral particles. Bottaro therefore does not support the Examiner’s
rejection.
The Examiner has asserted that “cell death is not a desired outcome in
any therapeutic approach and should be avoided, as taught by Bottaro”
(Answer 8). This broad assertion, however, is not supported by Bottaro, or
by the state of the art: a skilled worker would recognize that killing cancer
cells or virus-infected cells before they can further spread the cancer or virus
infection would be therapeutically effective, and in fact is the objective of
most anti-cancer and anti-viral therapies.
The Examiner also asserts that practicing the claimed method using
either adenoviral vectors or non-viral vectors, administered intravenously,
would require undue experimentation because intravenously administered
adenoviruses target essentially only hepatocytes (FF 14), and a non-viral
vector would lead only to transient expression of MDA-7, which would not
allow sustained suppression of viral infection (FF 20).
The Examiner has not adequately shown that these considerations
would result in a need for undue experimentation. Appellant has provided
evidence that MDA-7 is secreted from cells in which it expressed (FF 18)
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and therefore would affect cells other than those into which an MDA-7-
encoding vector was introduced. Appellant also argues that hepatitis C virus
infects hepatocytes (liver cells) (Appeal Br. 11), the cells targeted by
adenoviral vectors according to Wilson (FF 14). While the Examiner argues
that HCV infects cells of tissues other than the liver (Answer 11), Appellant
has provided evidence that adenoviral vectors are not limited to infecting
hepatocytes (FF 17).
With regard to non-viral vectors, the Examiner has not provided
evidence to support the assertion that only transient expression can be
attained using non-viral vectors, or to show that transient expression would
be inadequate to practice the claimed method. The Examiner therefore has
not provided an adequate basis for disputing the Specification’s disclosure
that the claimed method can be practiced routinely using non-viral vectors
(e.g., administered via lipid-mediated transformation).
In sum, the Examiner has not provided sufficient evidence to support
a conclusion that practicing the claimed method would require undue
experimentation.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that practicing the claimed method to treat infection
with hepatitis C virus, by administering MDA-7-encoding DNA via an
adenoviral or non-viral vector, would require undue experimentation.
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SUMMARY
We reverse the rejection of claims 1, 2, 15, 16, 20-27, 30-35, 37-44,
and 47 for lack of enablement.

REVERSED

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