Ex Parte Nagaoka

Board of Patent Appeals and Interferences

Sep 2, 2008

10644221 (B.P.A.I. Sep. 2, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HITOSHI NAGAOKA
__________

Appeal 2008-3448
Application 10/644,221
Technology Center 1600
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Decided: September 2, 2008
__________

Before DEMETRA MILLS, RICHARD M. LEBOVITZ, 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 a method
for treating HIV using a mycelium extract which the Examiner has rejected
as indefinite and failing to enable the claims. We have jurisdiction under
35 U.S.C. § 6(b). We reverse.

Appeal 2008-3448
Application 10/644,221

Background
“It was reported that the first deceased [person] by HIV-infection in
the world was found in Africa in 1950, and . . . HIV-infected persons spread
all over the world” (Spec. 1). The Specification discloses that “therapeutic
agents for the HIV-infected persons include AZT, ddI, ddC, interleukin-II,
GL0223, DHCA, γ-beta-ser Interferon, alpha interferon, gamma interferon”
(Spec. 1). The Specification also describes prior art which reported that the
“lentinan obtained from Lentinus edodes inhibits proliferation of HIV by the
use thereof in combination with the HIV therapeutic agent AZT” (Spec. 2).
Appellant teaches that the “HIV activity inhibitor comprising the
Lentinus edodes mycelium extract obtained by the [Specification’s] process
inhibits viral activity of Hepatitis B virus and HIV, is able to restrain
proliferation of said virus and is excellent in the safety by virtue of less
anxiety of side effects” (Spec. 3).
Statement of the Case
The Claims
Claims 1 and 2 are on appeal. Claims 1 and 2 read as follows:

1. A method for treating a human infected with human
immunodeficiency virus (HIV), comprising:
(a) inoculating Lentinus edodes fungus in a solid
culture medium comprising 90 parts by weight of bagasse
and 10 parts by weight of rice bran to yield proliferated
mycelium;
(b) disentangling the solid culture medium containing
the proliferated mycelium so that the amount of the bagasse
of 12-in mesh is not more than 30% by weight and adding
thereto 1 to 10 kg of water and 0.5 to 5 g of at least one
enzyme selected from the group consisting of cellulase,
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protease and glucosidase based on 1 kg of the disentangled
solid culture medium, while keeping the solid culture
medium at 30 to 50°C, to give a bagasse-containing mixture;
(c) grinding and milling the bagasse-containing
mixture so that the amount of the bagasse of 12-in mesh is
not less than 70% by weight;
(d) heating the ground and milled bagasse-containing
mixture to a temperature of 75 to 95°C to inactivate the
enzyme;
(e) filtering the resultant mixture through a filter cloth
of 50 to 120-in mesh to thereby obtain a purified,
concentrated pharmaceutical Lentinus edodes mycelium
extract; and
(f) administering orally at least one effective dose of
said purified, concentrated extract to said human, wherein
said extract weakens HIV activity and inhibits HIV
proliferation in said human.

2. The method according to claim 1 wherein the enzyme
is cellulase.

The rejections as presented by the Examiner are as follows:
A. Claims 1 and 2 stand rejected under 35 U.S.C. § 112, second
paragraph, as failing to comply with the definiteness requirement (Ans. 3).
B. Claims 1 and 2 stand rejected under 35 U.S.C. § 112, first paragraph,
as being nonenabled (Ans. 3).
A. 35 U.S.C. § 112, second paragraph indefiniteness rejection
Appellant argues that to “those skilled in the art of the prior art of
Lentinus edodes infusion, the effective dose is apparent from the present
specification. The present specification gives very particular direction as to
how to prepare the Lentinus edodes infusion” (App. Br. 5). Appellant
further contends that the claimed composition “is administered in beverage
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amounts, which, as a practical matter, involve a few to several ounces per
administration, and such administration is described, for example at
specification paragraphs 28-30” (App. Br. 5).
The Examiner responds that “Appellant has not proffered prior art
disclosing or discussing the administration of particular infusions or
protocols for this purpose. Thus, there is no clear definition of the record of
what constitutes ‘at least one effective dose’ in the context of the claimed
invention” (Ans. 6). The Examiner also argues that the “the issue is whether
one of ordinary skill in the art can readily determine what constitutes an ‘at
least one effective dose’ . . . i.e., frequency of administration and length of
treatment” (Ans. 7).
In view of these conflicting positions, we frame the indefiniteness
issue before us as follows:
Is the claimed phrase “effective dose” indefinite in the context of
claim 1?
Discussion of the 35 U.S.C. § 112, second paragraph rejection
We agree with Appellant that the phrase “effective dose” is definite in
the context of the instant Specification. See Geneva Pharmaceuticals, Inc. v.
GlaxoSmithKline PLC, 349 F.3d 1373, 1383 (Fed. Cir. 2003)(“Our
predecessor court has stated that ‘effective amount’ is a common and
generally acceptable term for pharmaceutical claims and is not ambiguous or
indefinite”). In our opinion, the Examiner is essentially arguing the
enablement rejection guised in terms of definiteness (see Ans. 7). When the
Examiner contends that “the issue is whether one of ordinary skill in the art
can readily determine what constitutes an ‘at least one effective dose’” (Ans.
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7), the Examiner is framing the issue in enablement terms, not definiteness
terms. To establish indefiniteness, the Federal Circuit noted that “[i]f the
meaning of the claim is discernible, even though the task may be formidable
and the conclusion may be one over which reasonable persons will disagree,
we have held the claim sufficiently clear to avoid invalidity on indefiniteness
grounds.” Exxon Research and Engineering Co. v. U.S., 265 F.3d 1371,
1375 (Fed. Cir. 2001). In the instant context, we conclude that the amount
of an “effective dose” is reasonably construed as a discernable feature that
can be determined using routine experimentation, in the absence of evidence
to the contrary.
We reverse the rejection of claims 1 and 2 under 35 U.S.C. § 112,
second paragraph.
B. 35 U.S.C. § 112, first paragraph Enablement rejection
Claims 1 and 2 stand rejected under 35 U.S.C. § 112, first paragraph,
on the basis that the Specification does not enable the claimed invention
(Ans. 3).
The Examiner reasons that the ordinary artisan
would not have a reasonable expectation of success of
treating a human infected with HIV by administering orally
at least one effective dose of a purified, concentrated extract
of Lentinus edodes of unknown composition, in the absence
of a clear definition of what constitutes an "effective dose"
and of an indication of how often and for how long such an
oral dose is to be administered in order to achieve the stated
purpose of weakening HIV activity.

(Ans. 6.) The Examiner argues that the “issue is whether or not it would
require undue experimentation for one of ordinary skill in the art to
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determine what constitutes ‘at least one effective dose’ in the instant context
specifically and particularly to treat HIV in the manner claimed” (Ans. 10).
The Examiner further contends that the “issue of the treatment of HIV
cannot readily and dismissively equated with any treatment in herbal
medicine” (Ans. 10).
Appellant argues that the
essence of the present invention is not primarily in the
preparation and general administration of the Lentinus
edodes infusion, therefore, but emphasizes the infusion's
new and unexpected effectiveness against HIV, such that
administration of the Lentinus edodes infusion has an
indication-specific medicinal effect even when given
according to prior art dosages and routes of administration.

(App. Br. 7.) Appellant further contends that “[w]hen Appellant submitted
the MT-4 results in the specification and urged such results as supportive of
the asserted enablement, Appellant identified an effectiveness correlation
with their enabled effective dose. The in vitro results in the Sawadaishi
Declaration dated June 9, 1997 give further confirmation.” (App. Br. 10.)
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Would it have required undue experimentation to treat HIV with an
“effective dose” of the Lentinus edodes extract?
Findings of Fact (FF)
Breadth of the Claims
1. “The claims are broadly drawn to a method of treating a human
infected with HIV by orally administering at least one effective dose,
without amounts and concentrations.” (Ans. 3.)
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Presence of Working Examples
2. The Specification discloses “a single working embodiment the
treatment of MT-4 cells infected with one particular strain of HIV. The data
of Table 1, for example, show only inhibition of the HIV virus in MT-4 cells
and not in living organisms.” (Ans. 4; see Spec. 8.)
Amount of Direction or Guidance Presented
3. The Specification teaches a specific method to prepare the
Lentinus edodes extract (Spec. 3-5). The Specification teaches that the
“extract of Lentinus edodes mycelium as obtained above can be used as its
concentrate, or can be used in the form of a powder obtained by freeze-
drying the extract” (Spec. 5 ¶ 0028).
4. The Examiner states that “[i]t is noted that the at least one
effective dose is never defined or identified in the instant written disclosure”
(Ans. 3-4).
5. The Specification discloses that maximum viability of MT-4
cells infected with HIV was obtained with a dosage of 125 µg/ml of extract,
with both lower and higher dosages having less effect (see Spec. 8, Table I).
6. The Specification discloses that the assay procedure followed
was that described in “Antiviral Research”1 (Spec. 7 ¶ 0042) which

1 This article was cited on the 3/13/2006 IDS and the full citation is
Yoshio Inouye et al. In vitro antiviral activity of
polyoxomolybdates. Mechanism of inhibitory effect of PM-104
(NH4)12H2(Eu4(MoO4)(H2O)16(Mo7O24)4)·13H2O on human
immunodeficiency virus type 1, 20 ANTIVIRAL RESEARCH 317-331
(1993).
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reference teaches a six day incubation with the virus to proceed prior to
testing (Inouye 321).
State of the Prior Art and Unpredictability of the Art
7. The Examiner cites Pauwels2 to show that while some HIV
drugs are successful “a number of important therapeutic challenges remain”
(Pauwels 79).
8. However, Pauwels also teaches that the “human T
lymphoblastoid cell line MT-4 . . . is one of the cell types that has been
extensively used in anti-HIV drug discovery efforts” (Pauwels 81).
9. Pauwels teaches that “[i]n the course of two decades, this
methodology led to the first description of a number of important new anti-
HIV agents and/or classes” (Pauwels 81).
10. The Examiner cites Suzuki3, which notes that “[i]t should be
stressed, however, that the activity of an agent against HIV in vitro does not
ensure that the agent will be clinically applicable in the setting of HIV-
infection. Bioavailability, metabolic features, toxicities, and other factors
may negate the usefulness of a given agent” (Suzuki 372).
11. The final section of Suzuki quoted by the Examiner notes
“[n]evertheless, our findings described here and previous observations that

2 Rudi Pauwels, Aspects of successful drug discovery and
development, 71 Antiviral Research 77-89 (2006).
3 Harumi Suzuki et al., Inhibition of the infectivity and cytopathic
effect of Human Immunodeficiency Virus by water-soluble lignin in
an extract of the culture medium of Lentinus Edodes Mycelia
(LEM), 160 Biochemical and Biophysical Research
Communications 367-373 (1989).
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EPS4 appears to have multiple biological activities including apparent
immunopotentiating capability together with an activity against HIV in vitro
warrant for further investigation” (Suzuki 372).
12. The Examiner states that “[a]nother issue to be considered is the
degradation and loss of antiviral effects in the complex physiological
environment of the human or animal body” (Ans. 5).
13. The Sawadaishi Declaration teaches that a “highly significant
percentage of patients infected with hepatitis B, after daily treatment with
the Lentinus edodes mycelium extract of the present invention, showed a
remarkable improvement in their serum liver enzymes” (Sawadaishi
Declaration 2/28/03, 3).
14. The Sawadaishi Declaration teaches that treatment using the
mycelium extract showed “a complete lack of adverse side effects”
(Sawadaishi Declaration 2/28/03, 3).
Quantity of Experimentation necessary and Level of Ordinary Skill
15. The Examiner made no factual findings regarding the quantity
of experimentation necessary to carry out the invention or the level of
ordinary skill.
Discussion of 35 U.S.C. § 112, first paragraph Enablement rejection
“The essential question here is whether the scope of enablement … is
as broad as the scope of the claim[s].” Amgen, Inc. v. Chugai
Pharmaceutical Co., 927 F.2d 1200, 1212 (Fed. Cir. 1991). We agree with
the Appellant that the Examiner has not provided sufficient evidence to
show that it would have required undue experimentation to practice of the
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claimed invention. In our opinion, analysis of the Wands factors favors
Appellant. In re Wands, 858 F.2d 731, 736 (Fed. Cir. 1988).
We specifically find that the factor of “working examples” favors
Appellant since the Appellant has shown that the mycelium extract is active
against HIV (FF 2) in the same in vitro assay used in the prior art to identify
other anti-HIV agents (FF 8,9).
We also find that “state of the art” and “the predictability or
unpredictability of the art” factors weighs in favor of Appellant, since the
prior art routinely uses the same methods to identify HIV inhibitors (FF 8,
9), the prior art teaches that the mycelium extract warrants investigation (FF
11), and the Sawadaishi Declaration shows safety of the mycelium extract in
patients (FF 14) as well as bioavailability and efficacy of the mycelium
extract against HBV, a different type of viral infection (FF 13). While the
Examiner has shown that there is some level of unpredictability (FF 7), the
Examiner’s issues regarding bioavailability, toxicity, and degradation in the
body (FF 10, 12) are rebutted by the Sawadaishi Declaration, which shows
that an “effective dose” of the mycelium compound is sufficiently
bioavailable and resistant to degradation to inhibit HBV (FF 13) as well as
showing that the compound is nontoxic (FF 14).
We also find that the “amount of guidance” in the Specification is
more than minimal, with the Specification showing the method of preparing
the compound (FF 3) as well as effective amounts in vitro using a standard
assay (FF 5, 6). We recognize that the Specification does not have extensive
guidance either, with no specific dosing information (FF 4).
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In our opinion, the breadth of the claims is also relatively narrow,
since the claims require the use of a particular extract obtained in a particular
way, for treatment of a particular disease (see FF 1, 3).
As we balance these factors, “[t]he question is, with regard to
pharmaceutical inventions, what must the applicant prove regarding the
practical utility or usefulness of the invention for which patent protection is
sought.” In re Brana, 51 F.3d 1560, 1564 (Fed. Cir. 1995). In Brana, the
court determined that “[o]nly after the PTO provides evidence showing that
one of ordinary skill in the art would reasonably doubt the asserted utility
does the burden shift to the applicant to provide rebuttal evidence sufficient
to convince such a person of the invention's asserted utility.” Id. at 1566.
We conclude that the Examiner has not met her burden to show that one
would doubt that the mycelium compound, shown to be effective in vitro
against HIV and bioavailable in vivo against HBV (FF 5, 11, 13, 14), is not
useful and enabled.
We are not persuaded by the Examiner’s argument that the “issues
such as bioavailability, metabolic features, and toxicities as well as other
factors may negate the usefulness of a given agent” (Ans. 4). While this
statement is true generically, the Examiner must provide evidence that these
issues are problematic in the instant case, not simply point to generic issues
in drug design. See In re Cortright, 165 F.3d 1353, 1357 (Fed. Cir.
1999)(“The PTO cannot make this type of rejection, however, unless it has
reason to doubt the objective truth of the statements contained in the written
description”). In the instant case, the evidence does not support this
argument since the Sawadaishi Declaration demonstrates that the Lentinus
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edodes extract is bioavailable and non toxic (FF 13, 14) and the
Specification demonstrates that the compounds have some anti-HIV efficacy
(FF 5).
We also do not find persuasive the Examiner’s argument regarding the
“challenges and difficulties of producing anti-HIV drugs that are effective”
(Ans. 5) and that “[n]o protocol is identified for oral administration of the
extract to treat a human infected with the human immunodeficiency virus
(HIV) such that the extract weakens HIV activity. . . . A protocol of
administration to MT-4 cannot be extrapolated to humans” (Ans. 11).
While we recognize that drug development is fraught with
difficulties, Pauwels also teaches that the “human T lymphoblastoid cell line
MT-4 . . . is one of the cell types that has been extensively used in anti-HIV
drug discovery efforts” (FF 8). This is the same drug line used by Appellant
to show anti-HIV efficacy of the extract (FF 5). Further, Pauwels teaches
that “[i]n the course of two decades, this methodology led to the first
description of a number of important new anti-HIV agents and/or classes”
(FF 9). Thus, rather than representing something outside the mainstream,
Appellant’s approach to identification of an HIV inhibitor falls squarely
within the standard modes of the prior art (FF 8, 9). The Examiner has not
provided a preponderance of specific evidence to show that the Lentinus
edodes extract, which functions in vitro against HIV and in vivo against
HBV (FF 5, 8, 9, 13, 14) would be expected not to function in vivo against
HIV.
We reverse the rejection of claims 1 and 2 under 35 U.S.C. § 112, first
paragraph, enablement.
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CONCLUSION
In summary, we reverse the rejection of claims 1 and 2
under 35 U.S.C. § 112, second paragraph and under 35 U.S.C. §
112, first paragraph, enablement.
REVERSED

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