Ex Parte Agrawal et al

Board of Patent Appeals and Interferences

Dec 7, 2009

10167825 (B.P.A.I. Dec. 7, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte SUDHIR AGRAWAL and QIUYAN ZHAO
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Appeal 2009-010182
Application 10/167,825
Technology Center 1600
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Decided: December 8, 2009
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Before ERIC GRIMES, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving a claim to a method
of treating viral infection, which the Examiner has rejected as nonenabled.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

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Application 10/167,825

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STATEMENT OF THE CASE
The Specification states that it was known in the art that
the ex vivo induction of IL-6, IL-12 and IFN-gamma by
bacterial DNA is mediated by a structural motif of an
unmethylated CpG dinucleotide preceded by two purines and
followed by two pyrimidines and that this effect can be
duplicated by an oligonucleotide of at least eight nucleotides
containing such a structural motif.
(Spec. 2.)
Claim 6, the only claim on appeal,1 reads as follows:
6. A method for therapeutically treating a mammal which is
infected by a virus, the method comprising administering to the infected
animal an oligonucleotide having a structural motif which induces IL-12
expression in vivo in an amount and for a time sufficient to eliminate or
reduce symptoms of infection by the virus, wherein the oligonucleotide has
the nucleotide sequence N.sub.n1-Nn2-CpG-Nn3-N.sub.n4, wherein N
represents any nucleoside, n1 and n4 each independently represent a number
from 0 to 50, n2 represents a number from 0 to 50 and n3 represents a
number from 0 to 50 such that n2+n3 equals from about 6 to about 100,
wherein the underlined region[2] represents a nucleoside phosphodiester or
phosphorothioate region or a mixed backbone region having phosphodiester
and phosphorothioate nucleosides, wherein CpG represents a cytosine-
guanosine dinucleoside phosphorothioate or phosphodiester dinucleoside,
wherein the cytosine has a cytidine base having an unmethylated 5-position,
and wherein at least one of n1, n2, n3 and n4 comprises four contiguous
guanosine nucleosides.

1 Claims 1-3 are also pending but have been withdrawn from consideration
by the Examiner (Office action mailed Dec. 6, 2005, page 1).
2 Although no region of the sequence is underlined in claim 6, the
Specification (Spec. 4 & 8) and original claims (Spec. 13-14) show the
sequence of “Nn2-CpG-Nn3” as underlined.
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ENABLEMENT
Issue
The Examiner has rejected claim 6 under 35 U.S.C. § 112, first
paragraph, on the basis that the Specification, “while being enabling for
protecting mice against lethal murine cytomegalovirus (mCMV) infection by
using oligonucleotide HYB-0272 (SEQ ID NO. 2),” does not enable treating
infection by any virus in any mammalian host using the full scope of oligo-
nucleotides encompassed by the claim (Answer 4). The Examiner cites
Agrawal,3 Mutwiri,4 Dittmer,5 Verthelyi,6 and Sin7 as evidence of the state of
the art in support of the nonenablement rejection.
Appellants contend that “the specification provides adequate guidance
for one skilled in the invention to use the claimed invention without undue
experimentation, including a working example” (Appeal Br. 2). Appellants
argue that the Specification “clearly teaches how to make immuno-
stimulatory oligonucleotides and to test their ability to elevate IL-12 levels,”
and “[d]ozens of patents and published application[s] demonstrate that

3 Agrawal et al., Medicinal Chemistry and Therapeutic Potential of CpG
DNA, 8 Trends in Molecular Medicine 114-121 (2002).
4 Mutwiri et al., Biological Activity of Immunostimulatory CpG DNA motifs
in Domestic Animals, 91 Veterinary Immunology and Immunopathology,
89-103 (2003)
5 Dittmer et al., Treatment of Infectious Diseases with Immunostimulatory
Oligodeoxynucleotides Containing CpG motifs, 6 Current Opinion in
Microbiology 472-477 (2003)
6 Verthelyi et al., CpG Oligodeoxynucleotides as Vaccine Adjuvants in
Primates, 168 Journal of Immunology 1659-1663 (2002)
7 Sin et al., Improving DNA Vaccines Targeting Viral Infection, 43
Intervirology 233-246 (2000).
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screening of potentially immunostimulatory oligonucleotides is typical in
this art” (id. at 4).
The issue presented is: Does the evidence of record support the
Examiner’s conclusion that practicing the full scope of the claimed method
would require undue experimentation?
Findings of Fact
1. The Examiner finds that “the protective effects of . . . CpG
containing nucleic acid are due to the stimulation of immune response in a
host, for example, increased expression of IL-12, IL-10, and MIP-2”
(Answer 5).
2. The Specification discloses “a method for therapeutically treating a
mammal, including a human, which is infected by a pathogen. . . . [A]n
oligonucleotide having a structural motif which induces IL-12 expression in
vivo is administered to a mammal which is infected by the pathogen.”
(Spec. 7.)
3. The Specification states that the
methods according to the invention are useful for preventing or
treating pathogenic infections in animals. . . . Such pathogens
include numerous pathogenic viruses. Preferred viruses include
without limitation human immunodeficiency virus (type 1 or 2),
influenza virus, herpes simplex virus (type 1 or 2), Epstein-Barr
virus, human and murine cytomegalovirus, respiratory syncytial
virus, hepatitis B virus, hepatitis C virus and papilloma virus.
(Spec. 9.)
4. The Examiner finds that “infections caused by various viral species
. . . differ from each other pathologically and physiologically” (Answer 5).
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5. Agrawal discloses that the “recognition of CpG DNA by innate
immune system cells, macrophages and DCs [dendritic cells] results in:
(1) the secretion of cytokines such as IL-12, IL-6, tumor necrosis factor α
(TNF-α) and IFN-γ. . . . The secreted cytokines are known to provide
nonspecific protection against infections and cancers.” (Agrawal 116, left
col.).
6. Mutwiri discloses that “[s]ince the innate immune system
recognizes conserved microbial components (PAMP), present in a wide
variety of pathogens, it is conceivable that a single potent PAMP (e.g. CpG
ODN [oligonucleotides]) could sufficiently stimulate innate immunity to
provide a universal treatment for multiple infectious agents” (Mutwiri 93,
paragraph bridging the columns).
7. Dittmer discloses that “[a]s viruses are intracellular pathogens, the
resolution of most viral infections is associated with Th1-type responses
characterized by cytotoxic T-cell (CTL) activity and production of IFNγ.
Such immune responses have been shown to be promoted by CpG-ODN.”
(Dittmer 473-474).
8. Dittmer discloses that “results from different models of viral
infections demonstrate that CpG-ODN therapy significantly enhances virus-
specific Th1-type immune responses and prevents virus-induced diseases”
(Dittmer 474, right col.).
9. Mutwiri discloses that “clinical studies are in various stages in
humans to evaluate CpG ODN therapy against infectious disease, cancer,
asthma and allergy” (Mutwiri 90, left col.).
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10. Agrawal discloses that “[s]everal CpG DNA candidates are under
preclinical and clinical evaluation against a broad range of infectious
dieseases [sic] and cancers” (Agrawal 116, left col.).
11. The Examiner finds that the “stimulation of immune response by
CpG varies among different animals” (Answer 5) and “ODNs containing
different CpG motifs can have different immunostimulatory effects in
different animals” (id. at 6).
12. Mutwiri discloses that “[e]vidence is accumulating from both in
vitro and in vivo studies which confirms that CpG ODN can also activate the
immune system in a variety of domestic species including cattle, sheep, pigs,
horses, dogs, cats and chickens” (Mutwiri 90, left col.).
13. Mutwiri discloses that the “basic formula for a CpG motif has
been described as 5'-X1X2CGY1Y2-3', where X1 is a purine, X2 is a purine or
a T, while Y1 and Y2 are pyrimidines. However, it appears that the specific
purines and pyrimidines surrounding the CpG motifs may influence both the
level and the type of immune stimulation.” (Mutwiri 90, left col. (reference
citation omitted)).
14. Agrawal discloses that the “optimal motif for recognition by
human immune cells is GTCGTT or TTCGTT. However, the optimal CpG
sequence requirement for many other animal species is not known.”
(Agrawal 115, left col.)
15. Mutwiri discloses that “the GTCGTT motif is optimal for
stimulation of lymphocyte proliferation in several species, including cattle,
goats, horses, pigs, dogs, cats and chickens, while the GACGTT motif was
optimal only for inbred rabbits and mice” (Mutwiri 90, right col.).
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16. Agrawal discloses that “change of the nucleotide sequence two
bases away from the CpG dinucleotide on either side does not have
significant influence on immunostimulatory activity” (Agrawal 117, right
col.).
17. Mutwiri discloses that,
[w]ith the exception of avian colibacillosis, there is no direct
evidence that CpG ODN can stimulate protective innate
immunity in veterinary species. Thus, the potential for using
CpG ODN as immunoprophylactic or immunotherapeutic
agents in domestic animals has yet to be clearly demonstrated.
However, we are optimistic that if we can develop appropriate
delivery vehicles this will become a reality.
(Mutwiri 98, paragraph bridging the columns.)
18. The Examiner finds that Dittmer “points out that CpG-ODN can
have negative effects that accelerate disease progression in some viral
infection[s]” (Answer 7).
19. Dittmer discloses that,
[i]n stark contrast to the success of post-exposure treatment,
CpG treatment of susceptible mice before FV [Friend virus]
infection accelerated the development of virus-induced
erythroleukemia. . . . The CpG pre-treatment of these mice
stimulated the main target cell populations of FV, erythroid
precursor cells and B cells, and thus provided an enlarged
target-cell population for viral infection.
(Dittmer 474, right col.).
20. Dittmer concludes that “the timing of CpG-ODN administration
was a critical factor in treatment efficacy against FV” (Dittmer 474, right
col.). Dittmer suggests that “[s]uch a phenomenon might be important for
other viruses that infect cells of the haematopoetic system (e.g. human
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immunodeficiency virus, human T-cell leukemia virus, measles virus,
hepatitis B and hepatitis C virus” (id. at 474-475).
21. The Specification provides a working example in which mice
infected with cytomegalovirus were administered a CpG-containing
oligonucleotide at doses of 5, 10, or 25 mg/kg/day (Spec. 11). The example
concludes that the oligonucleotide “had a significant inhibitory effect on
mCMV infection as shown by a significant number of survivors among
infected mice treated with the lowest dose, increase in mean day to death in
the mid- and low-dosage groups, and reduction in spleen and salivary titers.
This compound actually hastened death in infected animals in the high
dosage group.” (Id. at 12.)
22. The Examiner finds that the Specification “fails to provide
adequate guidance and evidence for whether administration of the claimed
oligonucleotides via various administration routes would be able to treat any
mammal with any viral infection” (Answer 8).
23. The Specification states that the “oligonucleotide is administered
in an amount and for a time sufficient to eliminate or reduce symptoms of
infection by the pathogen. Preferably, such administration should be
parenteral, oral, sublingual, transdermal, topical, intranasal or intrarectal.”
(Spec. 7.)
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
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reasons for doubting any assertions in the specification as to the
scope of enablement.
In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).
Enablement is a legal determination of whether a patent enables
one skilled in the art to make and use the claimed invention, is
not precluded even if some experimentation is necessary,
although the amount of experimentation needed must not be
unduly extensive, and is determined as of the filing date of the
patent application. . . . . Furthermore, a patent need not teach,
and preferably omits, what is well known in the art.
Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed.
Cir. 1986) (citations omitted).
Analysis
The Examiner has asserted three main sources of unpredictability to
support the conclusion that the Specification is not enabling: treatment of
different virus infections, treatment of different animals, and treatment with
CpG oligonucleotides having different sequences. We conclude that the
Examiner has not shown that these sources of unpredictability, even taken
collectively, would result in an undue amount of experimentation.
The claim reads on treating infection by any virus, and the Examiner
finds that infections by different viruses “differ from each other
pathologically and physiologically” (FF 4). The evidence shows, however,
that CpG-containing oligonucleotides stimulate the immune system
generally. Agrawal discloses that CpG DNA causes secretion of cytokines,
which “provide nonspecific protection against infections” (FF 5). Mutwiri
discloses that stimulating the innate immune system, for example by CpG
ODN, could provide “a universal treatment for multiple infectious agents”
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(FF 6). And Dittmer discloses that “results from different models of viral
infections” show the efficacy of CpG-ODN therapy (FF 8).
The evidence shows, therefore, that the claimed method would be
expected to provide a therapeutic response to infection by any of a variety of
viruses. Claim 6 requires only a reduction in the symptoms of viral
infection, not complete elimination of virus from the patient. The Examiner
has not provided evidence that the general, nonspecific immune stimulation
caused by CpG oligonucleotide therapy would not have been expected to
produce a reduction in symptoms caused by various viral infections.
The Examiner also points out that claim 6 reads on treating any
mammal with any of a variety of CpG-containing oligonucleotides, and finds
that different CpG-containing sequences can have different effects in
different animals (FF 11). The evidence shows, however, that CpG-
containing sequences and their effects in different mammals have been well-
studied.
Mutwiri describes the “basic formula for a CpG motif” (FF 13).
Mutwiri also discloses that GTCGTT is the optimal CpG sequence for
“several species, including cattle, goats, horses, pigs, dogs, cats and
chickens” (FF 15) and Agrawal teaches that the same sequence is one of two
optimal sequences for humans (FF 14). Agrawal discloses that changes in
the sequence of a CpG-containing oligonucleotide outside the 6-nucleotide
core sequence do not have a “significant influence on immunostimulatory
activity” (FF 16). The evidence therefore does not support a conclusion that
testing CpG-containing oligonucleotides with different sequences would be
a source of more than routine experimentation.
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The Examiner finds that Dittmer discloses that CpG-containing
oligonucleotides can, under some conditions, make viral infections worse
(FF 18). The Specification, as well, states that high doses of a CpG-
containing oligonucleotide hastened death in mice caused by CMV infection
(FF 21). And Mutwiri states that “the potential for using CpG ODN as
immunoprophylactic or immunotherapeutic agents in domestic animals has
yet to be clearly demonstrated” (FF 17).
While these disclosures show that some experimentation would be
required to practice the claimed method, the evidence does not show that the
amount of experimentation would be undue. Dittmer explained the basis of
its negative results when the CpG oligonucleotide was administered before
infection by Friend virus: the CpG motif stimulated expansion of erythroid
precursor cells and B cells, thus providing more cells for the virus to infect
(FF 19). Dittmer thus provides guidance to those skilled in the art seeking to
practice the claimed method to treat viruses that infect hematopoietic cells:
treat the patient after infection, not before.
The Specification’s dose-dependent results indicate a need to
determine what doses are safe and effective in different patient populations,
a line of experimentation that has not been shown to be more than routine.
And although Mutwiri states that CpG treatment has not been clearly
demonstrated in domestic animals, both Mutwiri and Agrawal summarize
clinical trials underway using CpG oligonucleotides to treat a variety of
infectious diseases (FFs 9, 10). Thus, the evidence shows that those skilled
in the art considered CpG oligonucleotide therapy to be established well
enough to merit application to human patients.
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Finally, the Examiner finds that the Specification does not provide
evidence that administering a CpG oligonucleotide “via various
administration routes would be able to treat any mammal with any viral
infection” (FF 22). The Specification, however, states that any of a variety
of administration routes can be used (FF 23) and the burden is on the
Examiner to show that the Specification’s statements are not accurate. The
Examiner has provided no evidence or science-based reasoning to doubt the
accuracy of the Specification.
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that practicing the full scope of the claimed method would require undue
experimentation.
SUMMARY
We reverse the rejection of claim 6 under 35 U.S.C. § 112, first
paragraph.

REVERSED

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