Ex Parte Flack et al

Board of Patent Appeals and Interferences

Feb 20, 2009

10806088 (B.P.A.I. Feb. 20, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARY R. FLACK, RICHARD KNAZEK,
and MARCUS REIDENBERG
__________

Appeal 2009-1290
Application 10/806,088
Technology Center 1600
__________

Decided:1 February 20, 2009
__________

Before ERIC GRIMES, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating cancer with gossypol. The Examiner has rejected the claims

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).
Appeal 2009-1290
Application 10/806,088

as obvious over the prior art. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
This appeal arises out of an application for reissue of U.S. Patent
6,114,397, originally issued Sept. 5, 2000. The ‘397 patent discloses that
“[g]ossypol is a double biphenolic compound derived from crude cottonseed
oil . . . which has been used extensively as a male contraceptive in China”
(‘397 patent, col. 1, ll. 18-21). The ‘397 patent describes administration of
gossypol to human patients for treatment of cancer (id. at col. 6, l. 17 to col.
7, l. 21).
Claims 8-14, 16, and 38-43 are pending and on appeal. The claims
subject to each rejection have not been argued separately and therefore stand
or fall together. 37 C.F.R. § 41.37(c)(1)(vii). Claims 8 and 13 are
representative and read as follows (additions and deletions to original claim
8 indicated by underlining and brackets, respectively):
8. A method for treating a cancer in a human, wherein the cancer is
susceptible to treatment with gossypol, a [pharmaceutically] physiologically
acceptable salt of gossypol, or a combination thereof, which method
comprises:

administering to said human a composition comprising an anti-cancer
effective amount of at least one compound selected from the group
consisting of gossypol and a physiologically acceptable salt thereof, [and]
wherein the at least one compound is administered with a pharmaceutically
acceptable carrier, and wherein the at least one compound exhibits an overall
effect of rotating the plane of polarized light in the (-) direction.

13. The method of claim 8, wherein said compound is administered
orally at a dose of 20-100 mg/d.

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The Examiner relies on the following evidence:
Zhang et al. (Zhang), “Comparison of the Killing Effect of Levorotatory,
Dextrorotatory and Racemic Gossypol on HeLa Cells,” 7 Acta Academiae
Medicinae Sinicae 384-387 (1985).
Band et al. (Band ‘86), “Cytocidal Effects of Gossypol and its Optical
Isomers on Reproductive Cancer Cell Lines,” 23 Gynecologic Oncology 261
(1986).
Wu et al. (Wu ‘86), “Pharmacokinetics of (±)-, (+)-, and (–)-gossypol in
humans and dogs,” 39 Clin. Pharmacol. Ther. 613-618 (1986).
Wu et al. (Wu ‘89), “An in Vitro and in Vivo Study of Antitumor Effects of
Gossypol on Human SW-13 Adrenocortical Carcinoma,” 49 Cancer
Research 3754-3758 (1989).

Appellants rely on the following evidence:
Band et al. (Band ‘89), “Antiproliferative Effect of Gossypol and Its Optical
Isomers on Human Reproductive Cancer Cell Lines,” 32 Gynecologic
Oncology 273-277 (1989).
Declaration under 37 C.F.R. § 1.132 of Marcus Reidenberg, filed May 12,
2005.
Declaration under 37 C.F.R. § 1.132 of Jon Theodore Holmlund, filed Oct.
20, 2006.

The claims stand rejected under 35 U.S.C. § 103(a) as follows:
• Claims 8-10, 16, and 38-43 based on Wu ‘89, Band ‘86, and Zhang;
and
• Claims 11-14 based on Wu ‘89, Band ‘86, Zhang, and Wu ‘86.
OBVIOUSNESS
The Issue
The Examiner has rejected claims 8-10, 16, and 38-43 as obvious in
view of Wu ‘89, Band ‘86, and Zhang. The Examiner’s position is that the
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prior art would have suggested administering (–)-gossypol to human patients
to treat cancer, and would have provided those skilled in the art with a
reasonable expectation that the treatment would be successful.
Appellants contend that those of ordinary skill in the art would not
have had a reasonable expectation that gossypol could be used successfully
to treat cancer in human patients.
The issue is: Did the Examiner err in concluding that the prior art
would have provided a reasonable expectation of success in administering (–)-
gossypol to treat cancer in human patients?
Findings of Fact
1. Claim 8 is directed to a method of treating cancer in humans by
administering gossypol (or a physiologically acceptable salt of it) that
“exhibits an overall effect of rotating the plane of polarized light in the (–)
direction” (claim 8).
2. The gossypol enantiomer recited in claim 8 is also known in the art
as (–)-gossypol and levorotatory gossypol (see Zhang 384).
3. The complementary gossypol enantiomer is known in the art as
(+)-gossypol or dextrorotatory gossypol (see id.).
4. A mixture of (–)-gossypol and (+)-gossypol is known in the art as
(±)-gossypol or racemic gossypol (see id.).
5. Wu ‘89 discloses injection of nude mice with SW-13 cells (Wu ‘89
3755, left-hand col.).
6. SW-13 cells are human adrenocortical carcinoma cells (id. at 3754,
right-hand col.).
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7. Wu ‘89 discloses that the mice injected with SW-13 cells were
treated with gossypol (id. at 3755, left-hand col.).
8. Wu ‘89 discloses that “[g]ossypol was shown to suppress the
proliferation of SW-13 human adrenocortical carcinoma cells” and that
“[e]stablished tumors were also shown to respond to gossypol treatment” (id.
at 3757, right-hand col.).
9. Wu ‘89 concludes that “gossypol appeared to be safe and effective
in delaying growth of SW-13 cells in nude mice” (id.).
10. Wu ‘89 states that “[t]hese data suggest that gossypol may
provide a beneficial effect in patients with adrenocortical carcinoma by
decreasing the overall tumor burden and prolonging their duration of
survival” (id. at 3758, left-hand col.).
11. Wu ‘89 does not state that the gossypol used had been resolved
into (+)- and (–)-enantiomers.
12. Band ‘86 discloses that “gossypol at micromolar concentrations
. . . inhibits the growth and has cytocidal effects on a variety of reproductive
cancer cell lines of male and female origin” (Band ‘86 261).
13. Band ‘86 discloses that seven cancer cell lines “were significantly
. . . more sensitive to gossypol (0.90-1.78 µg/ml) than normal human cells of
high mitotic activity . . . and low mitotic activity” (id.).
14. Band ‘86 discloses that the “tumor growth inhibitory activity of
gossypol, which is a racemic mixture of its optical isomers[,] is primarily
attributable to the (–)-isomer which is 3.6–9.3 times more potent than the
(+)-isomer” (id.).
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15. Band ‘86 concludes that, “[c]onsidering the established absence
of side effect in the administration of low doses of gossypol to humans,
these data suggest that (–)-gossypol, alone or in combination with other
drugs, may be useful clinically in the treatment of cancer of reproductive
tract origin” (id.).
16. Zhang states that “[s]ince 1960’s, it has been reported both in
China and the rest of the world that gossypol can be used as an antitumor
drug” (Zhang 384).
17. Zhang discloses that gossypol “has the function of inhibiting
DNA synthesis of the cells” (id.).
18. Zhang discloses that “(+) gossypol has no effect on the growth of
HeLA [sic] cells at all; (±) and (–) gossypols can significantly inhibit the
growth of HeLa cells; 5 µg/ml of (–)gossypol has the similar effect as 10
µg/ml of (±)gossypol, indicating that the functional part of the (±) gossypol
is probably the (–) portion” (id. at 385).
19. Zhang discloses that “5 µg/ml or 10 µg/ml of (–) gossypol or 10
µg/ml of (±) gossypol . . . all can inhibit cell division, DNA synthesis and
the function of re-proliferation of HeLa cells” (id. at 385-386).
20. Wu ‘86 discloses administration of (–)-gossypol to healthy men at
a dose of 20 mg orally (Wu ‘86 614, left-hand col.).
21. Band ‘89 discloses a comparison of “the effects of racemic
gossypol and the (–) and (+) isomers of gossypol on the proliferation of
different human cell lines (both untransformed and cancer cell lines) of
different tissue origins and mitogen-activated peripheral blood mononuclear
cells” (Band ‘89 273, right-hand col.).
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22. Band ‘89 reports that the “antiproliferative action of gossypol was
not restricted to reproductive cancers, as non-reproductive cancer cell lines
were also equally sensitive” (id., abstract).
23. Band ‘89 states that “actively proliferating untransformed cells
such as fibroblasts and PHA-activated lymphocytes were also sensitive”
(id.).
24. Band ‘89 concludes that the “results demonstrate that gossypol in
vitro acts as a general and nonselective antiproliferative agent and that the
antiproliferative and other related activities of gossypol are primarily
attributable to its content of (–) isomer” (id. at 276-277).
25. Band ‘89 states that, “[i]n view of a general antiproliferative
activity of gossypol . . . , the lack of any reported in vivo side effects
attributable to such an activity is surprising” (id. at 276, right-hand col.).
26. Dr. Reidenberg declares that “[s]uccessful anticancer drugs
selectively kill tumor cells; if anticancer drugs killed cells indiscriminately,
the cure would be worse than the disease” (Reidenberg declaration, ¶ 5).
27. Dr. Reidenberg declares that “[g]iven the general toxicity of
gossypol to both normal and cancerous human cells in vitro as disclosed by
Band [‘89], one of ordinary skill in the art, upon reading that reference,
would reasonably conclude that gossypol would be toxic to cancerous and
noncancerous cells in vivo” (id. at ¶ 6).
28. Dr. Reidenberg declares that Rao2 reported that “gossypol could
be safely and effectively administered [to treat cancer in mice] within only a
very narrow dosage range,” because “although a dosage of 0.5 mg/mouse

2 Rao et al., 15 Cancer Chemother. Pharmacol. 20-25 (1985), of record.
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was reportedly effective, . . . at 0.6 mg/mouse, nearly two-thirds of the mice
died due to gossypol toxicity” (id. at ¶ 7).
29. Dr. Reidenberg declares that Tso3 reported that “gossypol could
be safely and effectively administered [to treat cancer in mice] within only a
very narrow dosage range” because “[a]lthough a daily dosage of 25-100 µg
of gossypol was found to be relatively safe and effective, . . . when the
dosage was increased to 250 µg/day, all of the treated mice died due to
gossypol toxicity” (id. at ¶ 8).
30. Dr. Holmlund declares that “[r]ecent findings support the
expectation that (–)-gossypol is useful for the treatment of a wide diversity
of cancers in humans” (Holmlund declaration, ¶ 3).
31. Dr. Holmlund declares that (–)-gossypol has been used in clinical
trials to treat chronic lymphocytic leukemia, prostate cancer, and follicular
lymphoma (id. at ¶¶ 5-7).
Principles of Law
Whether a claimed process would have been obvious under 35 U.S.C.
§ 103 depends on “whether the prior art would have suggested to one of
ordinary skill in the art that this process should be carried out and would
have a reasonable likelihood of success, viewed in the light of the prior art.
Both the suggestion and the expectation of success must be founded in the
prior art, not in the applicant’s disclosure.” In re Dow Chemical Co.,
837 F.2d 469, 473 (Fed. Cir. 1988) (citations omitted).

3 Tso et al., 24 Cancer Letters 257-261 (1984), of record.
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“Obviousness does not require absolute predictability of success. . . .
For obviousness under § 103, all that is required is a reasonable expectation
of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).
“Indeed for many inventions that seems quite obvious, there is no
absolute predictability of success until the invention is reduced to practice.
There is always at least a possibility of unexpected results, that would then
provide an objective basis for showing that the invention, although
apparently obvious, was in law nonobvious.” Id. at 903.
Expectation of success is assessed from the perspective of a person of
ordinary skill in the art, at the time the invention was made. See Life Techs.
Inc. v. Clontech Labs. Inc., 224 F.3d 1320, 1326 (Fed. Cir. 2000).
Analysis
Claim 8 is directed to a method of treating cancer by administering (–)-
gossypol. Wu ‘89 discloses that gossypol suppresses proliferation of human
adrenocortical carcinoma cells in mice and that established tumors also
responded to gossypol treatment. Band ‘86 discloses that cancer cell lines
were significantly more sensitive to gossypol than normal cells, and that
gossypol’s (–) enantiomer had much more activity than its (+) enantiomer.
Zhang discloses that (racemic) gossypol had been reported to be an antitumor
drug, and that (–)-gossypol inhibits cell division, DNA synthesis and the
proliferation of HeLa tumor cells. Wu ‘89 and Band ‘86 expressly suggest
use of gossypol to treat cancer. We agree with the Examiner that the cited
references would have suggested the method of claim 8 to those of ordinary
skill in the art.
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For a method to be obvious under § 103, however, the prior art must
also provide a reasonable expectation of success. Appellants argue that this
element of the prima facie case is lacking, because Band ‘89 discloses that
gossypol has antiproliferative activity in vitro toward both cancer cells and
noncancer cells. Appellants argue that this activity “teaches away from the
treatment of cancer with (–)-gossypol as one of ordinary skill in the art would
believe, based upon Band (1989), that (–)-gossypol would have significant
side effects which would prevent the use of doses that are high enough [to] be
useful for treatment of cancer” (Appeal Br. 6).
We do not agree with Appellants’ interpretation of the evidence. Both
Band ‘86 and Band ‘89 specifically state that administration of gossypol to
humans (presumably as a contraceptive) did not result in side effects: Band
‘86 notes the “established absence of side effects in the administration of low
doses of gossypol to humans” (Band ‘86 261), while Band ‘89 states that,
“[i]n view of a general antiproliferative action of gossypol, . . . the lack of any
reported in vivo side effects attributable to such an activity is surprising”
(Band ‘89 276). Thus, the evidence does not support Appellants’ position that
those skilled in the art would have expected gossypol to cause significant side
effects that would prevent its use to treat cancer.
In addition, Band ‘89 does not state that (–)-gossypol is toxic to all
cells, only that it has a “general antiproliferative action.” Band ‘89 therefore
would have led those skilled in the art to expect that (–)-gossypol would kill
normal proliferating cells (e.g., hair follicle cells and epithelial cells of the
intestine), as well as proliferating cancer cells, but not that it would kill all
types of cells indiscriminately. Appellants have not presented persuasive
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evidence to support their position that (–)-gossypol’s general antiproliferative
activity – as opposed to indiscriminate toxicity – would have led those skilled
in the art to expect that it would be ineffective in treating cancer. Rather, the
evidence of record supports the Examiner’s position that the prior art would
have led those skilled in the art to reasonably expect (–)-gossypol to be an
effective treatment for cancer.
Appellants also argue that the Reidenberg declaration shows that,
because of gossypol’s “narrow window of efficacy and safety” in mouse
studies, those of skill in the art “would not have believed that it would have
been possible to successfully determine a safe and effective dosage range in
genetically heterogeneous humans” (Appeal Br. 6).
This argument is also unpersuasive. As discussed above, Band ’86
and Band ’89 disclose that use of gossypol in humans was known not to
cause side effects, and Wu ‘89 and Band ‘86 expressly suggest use of
gossypol to treat cancer in humans. These statements by persons of skill in
the art contradict, and detract from the credibility of, Dr. Reidenberg’s
conclusion.
In addition, Appellants have presented no comparison of the results
reportedly found by Rao and Tso with the results of studies using other
drugs that either were developed as successful cancer treatments or were
found to be too toxic to be used effectively to treat cancer in humans. The
lack of context for the results described by Rao and Tso also casts doubt on
whether Dr. Reidenberg’s conclusion would be shared by a person of
ordinary skill in the art.
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Finally, even Dr. Reidenberg concedes that some of the dosages tested
by Rao and Tso were safe and effective. Appellants have not adequately
shown that, in view of the prior art as a whole, those of ordinary skill in the
art would not have had a reasonable expectation of finding a dosage of (–)-
gossypol that was effective in killing cancer cells in a human patient without
also killing the patient.
Appellants also argue that the Holmlund declaration shows that “(–)-
Gossypol has proven clinically effective in the treatment of several types of
cancer in humans,” and that its effectiveness is surprising “[i]n view of the
experimental data reported in the prior art tending to show that (–)-gossypol
would not be effective in the treatment of cancer in humans” (Appeal Br. 7).
This argument is not persuasive because, as discussed above, those of
skill in the art would have reasonably expected (–)-gossypol to be an
effective treatment of cancer. Appellants have not shown that its actual
effectiveness is any greater than would have been expected based on the
prior art.
In summary, the Examiner has shown that Wu ‘89, Band ‘86, and
Zhang would have suggested the method of claim 8 and would have
provided a reasonable expectation of success. Appellants have not shown
any defect in the Examiner’s prima facie case of obviousness, nor have they
provided secondary evidence of nonobviousness to rebut it.
The Examiner also rejected claims 11-14 as obvious in view of Wu
‘89, Band ‘86, Zhang, and Wu ‘86 (Answer 6-7). The Examiner relies on
Wu ‘89, Band ‘86, and Zhang for the disclosures discussed above, and finds
that Wu ‘86 would have suggested, among other things, the oral dosage
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recited in claim 13 (id. at 7). The Examiner concludes that the method of
claim 13 would have been obvious in view of the combined teachings of the
references (id.). We agree with the Examiner’s reasoning and conclusion.
Appellants argue that:
Wu (1986) . . . is of no consequence inasmuch as Wu (1986)
does not satisfy the deficiencies of the other cited references as
discussed above. In addition, . . . since the cited references do
not disclose the additional features recited in claims 11-14, the
present invention as defined by rejected claims 11-14 is even
further removed from the prior art.
(Appeal Br. 8-9.)
These arguments are not persuasive. First, we do not agree with
Appellants that the rejection based on Wu ‘89, Band ‘86, and Zhang has any
deficiencies that must be remedied by Wu ’86. Second, Appellants have not
provided sufficient evidence or reasoning to support their position that the
disclosure in Wu ‘86 of administration of (–)-gossypol as a single oral dose
of 20 mg would not have suggested the limitation of claim 13 of oral
administration of (–)-gossypol orally at a dose of 20-100 mg per day.
CONCLUSION OF LAW
The Examiner did not err in concluding that the prior art would have
provided a reasonable expectation of success in administering (–)-gossypol
to treat cancer in human patients.
SUMMARY
We affirm the rejection of claims 8-10, 16, and 38-43 under 35 U.S.C. § 103
based on Wu ‘89, Band ‘86, and Zhang; and the rejection of claims 11-14
under 35 U.S.C. § 103 based on Wu ‘89, Band ‘86, Zhang, and Wu ’86.
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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).

AFFIRMED

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