Ex Parte Yan

Patent Trial and Appeal Board

Dec 21, 2016

12150049 (P.T.A.B. Dec. 21, 2016)

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.
80360.006US1 (384.0011
01
9587
EXAMINER
DENT, ALANA HARRIS
ART UNIT PAPER NUMBER
1643
MAIL DATE DELIVERY MODE
12/150,049 04/24/2008
26813 7590 12/21/2016
MUETING, RAASCH & GEBHARDT, P.A.
P.O. BOX 581336
MINNEAPOLIS, MN 55458-1336
Jun Yan
12/21/2016 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JUN YAN1
Appeal 2014-009804
Application 12/150,049
Technology Center 1600
Before FRANCISCO C. PRATS, RICHARD J. SMITH, and
RYAN H. FLAX, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims directed to
compositions for treating cancer. The Examiner rejected the claims for
obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The sole rejection before us for review is the Examiner’s rejection of
claims 24, 25, and 31—35 under 35 U.S.C. § 103(a) for obviousness over
Hong2 and Ault-Riche.3 Final Action 5—10; Ans. 2-4.
1 Appellant states that the real parties in interest “are the assignee, University
of Louisville and then licensee, Biothera, Inc.” App. Br. 1.
Appeal 2014-009804
Application 12/150,049
Claim 24 is representative and reads as follows (App. Br., Claims
Appendix):
24. A therapeutic composition to treat cancer, the
composition comprising:
a first active agent comprising bevacizumab; and
a second active agent comprising a yeast P-glucan;
wherein the combination of the yeast P-glucan and
bevacizumab, when co-administered parenterally to a subject,
provides a synergistic effect.
OBVIOUSNESS
The Examiner’s Position
The Examiner cited Hong as disclosing “a therapeutic composition
comprising antitumor antibodies and soluble yeast P-glucan for the
intravenous treatment of tumors.” Final Action 6. The Examiner noted in
particular Hong’s disclosure that “P-glucan responses could be improved by
combined administration with antitumor mAbs [monoclonal antibodies] as
compared with antitumor mAb or P-glucan alone.” Id. at 7 (citing Hong
9023 (abstract)).
The Examiner found that Hong’s composition differed from the
composition of representative claim 24 in that “Hong does not teach the
claimed composition wherein the antitumor antibody is bevacizumab (VEGF
antagonist).” Final Action 7.
2 Feng Hong et al., f-Glucan Functions as an Adjuvant for Monoclonal
Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer
Cells, 63 Cancer Res. 9023-31 (2003).
3 US 2006/0018911 Al (published Jan. 26, 2006).
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Application 12/150,049
To address that deficiency the Examiner cited Ault-Riche as
disclosing “therapeutic molecules and components of therapeutic complexes
comprising bevacizumab (Avastin™) [and] P-glucan.” Id.
Among other rationales,4 the Examiner concluded that an ordinary
artisan would have considered it obvious to “combine the teachings of all the
references because they all note therapeutic compositions comprising more
than one agent provides clinical benefit to cancer patients.” Id. at 9. In
particular, the Examiner reasoned:
Hong is replete with teachings setting forth tumor regression is
significantly enhanced by the coadminsitration of i.v. soluble
yeast P-glucan and a therapeutic antitumor mAb, see bridging
paragraph of pages 9023 and 9024; page 9025, Combined
Therapy...section and Figure 1; Figure 2 on page 9026; page
9029, 2nd column, 1st paragraph under Discussion heading;
page 9030, 2nd column 3rd paragraph. It is clear from the
teachings the interactions of the discrete agents renders a total
effect that is greater than the sum or the individual effects, i.e.
synergism.
Id. at 9—10.
4 The Examiner cited the Gelderman reference as providing “impetus to
combine the teachings in the art to predictably arrive at Applicant’s claimed
invention.” Final Action 8. The Examiner, however, did not list Gelderman
among the references upon which the rejection is based. Id. at 5.
Although Appellant does not allege error in this regard, the
Examiner’s failure to list Gelderman as a reference is improper. See In re
Hoch, 428 F.2d 1341, 1342 n.3 (CCPA 1970) (“Where a reference is relied
on to support a rejection,. . . there would appear to be no excuse for not
positively including the reference in the statement of rejection.”).
In any event, as is evident from our analysis, the Examiner’s
conclusion of obviousness is support by Hong and Ault-Riche alone.
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Application 12/150,049
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Appellant does not argue any of the rejected claims separately. We,
therefore, limit our analysis to representative claim 24. See 37 C.F.R.
§ 41.37(c)(l)(iv).5
We have carefully considered Appellant’s arguments and the evidence
advanced in support those arguments. Appellant’s arguments do not
persuade us, however, that a preponderance of the evidence fails to support
the Examiner’s conclusion that representative claim 24 would have been
obvious to an ordinary artisan.
Appellant initially contends the Examiner failed to articulate an
adequate rationale explaining why claim 24 would have been obvious to an
ordinary artisan, and in particular why an ordinary artisan would have been
able to predictably obtain the claimed subject matter. App. Br. 7—9. We are
not persuaded.
As our reviewing court has explained, “[ojbviousness does not require
absolute predictability of success. . . . For obviousness under § 103, all that
is required is a reasonable expectation of success.” In re Kubin, 561 F.3d
5 Although Appellant argues claim 34 alongside claim 24 throughout the
Appeal Brief, Appellant relies on the same arguments for both claims 24 and
34, and does not explain why any limitation in claim 34 provides a
difference as to patentability between claims 24 and 34.
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Application 12/150,049
1351, 1360 (Fed. Cir. 2009) (quotingIn re O’Farrell, 853 F.2d 894, 903-04
(Fed. Cir. 1988) (emphasis removed).
In the present case, representative claim 24 is directed to a
composition that includes two ingredients: (1) bevacizumab, also known as
Avastin (see Spec. 4), and (2) a yeast P-glucan. App. Br., Claims Appendix.
As the Examiner found, Hong teaches that yeast P-glucan significantly
potentiates the antitumor effect of antitumor antibodies. See, e.g., Hong
9023, abstract (“In comparison with antitumor mAb or P-glucan alone,
combined treatment with mAb plus P-glucan produced significantly greater
tumor regression in all models that included mammary, s.c. [subcutaneous],
and hepatic tumors.” (emphasis added)).
Although, as the Examiner found, Hong does not describe combining
bevacizumab with P-glucan as recited in claim 24, it is undisputed on the
current record that bevacizumab was known in the prior art to be an
antitumor monoclonal antibody. See Ault-Riche 1466 (bevacizumab useful
for treating colorectal cancers); see also Spec. 4 (citing prior art discussing
posited mechanisms of bevacizumab’s antitumor activity).
Thus, given Hong’s teaching that yeast P-glucan significantly
potentiates the antitumor effect of antitumor antibodies in all tumor models
it tested, we agree with the Examiner that an ordinary artisan not only had a
good reason for, but also a reasonable expectation of success in, combining
yeast P-glucan and bevacizumab, a known antitumor monoclonal antibody,
to prepare a therapeutic composition to treat cancer.
We acknowledge that claim 24 requires the combination of the two
ingredients to provide a synergistic effect when co-administered parenterally
to a subject. App. Br., Claims Appendix. As Appellant explains, a
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Application 12/150,049
synergistic effect is present when the activity of the two ingredients, when
co-administered, is greater than the separately observed activities of the
individual ingredients, when the separately observed individual activities are
added together. App. Br. 9 (“Synergy is the interaction of elements that
when combined produce a total effect that is greater than the sum of the
individual elements.”).
For example, Appellant cites to page 9 as support for the synergy
limitation of claim 24. App. Br. 2. In the experiment described on page 9,
Appellant shows that administering a P-glucan preparation by itself resulted
in tumors about 300 mm3 smaller than tumors treated using a control
preparation. Spec. 9 (tumor size in control-treated mice 1800 ± 800 mm3;
tumor size in P-glucan-treated mice 1500 ± 800 mm3). Administering a
bevacizumab preparation by itself resulted in tumors about 1000 mm3
smaller than tumors treated using a control preparation. Id. (tumor size in
bevacizumab-treated mice 800 ± 250 mm3).
These data suggest that the additive effect of co-administering
P-glucan (tumors 300 mm3 smaller than control) and bevacizumab (tumors
1000 mm3 smaller than control), reasonably should be tumors 1300 mm3
smaller than control, that is, tumors with a volume of about 500 mm3. As
seen on page 9 of the Specification, however, co-administering P-glucan and
bevacizumab results in tumors of about 400 mm3, an effect that is greater
than the additive effect of the individual activities of P-glucan and
bevacizumab. Id.
The Examiner directs us to Figures 1 and 2 of Hong as demonstrating
that an ordinary artisan would have expected a synergistic effect when
combining P-glucan with antitumor monoclonal antibodies. Final Action 9;
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Ans. 7. Appellant contends that “none of the data presented in Hong et al.
demonstrates a synergistic effect. Rather, the teaching of Hong et al. is
limited to a illustrating only a statistically significant difference in effect.”
App. Br. 10; see also Reply Br. 3^4. Although neither party explains or
supports their assertions with specific discussion about the disclosures in
Hong, we find that the Examiner has the better position.
As seen in Figure 1A of Hong, in the implanted subcutaneous mouse
tumor model used therein, at 21 days post-treatment, tumors in control-
treated mice had a diameter of about 9 mm in size, whereas P-glucan-treated
mice had tumors of about 7 mm, and monoclonal antibody-treated mice had
tumors about 5 mm. Hong 9025, Fig. 1 A. Although this suggests that the
additive effect of P-glucan plus monoclonal antibody, at best, should be
tumors about 3 mm in size, Figure 1A shows that co-administering P-glucan
and monoclonal antibody yielded tumors about 2 mm in size (see id.), a
result beyond the additive effect.
Hong’s survivability data, shown in Figure 2 cited by the Examiner,
provides more dramatic evidence of synergy. As seen in Figure 2C, in the
mouse liver tumor model used therein, survival was essentially the same in
both the control-treated mice and the P-glucan-treated mice, zero percent
survival at about 25 days. Hong 9026, Fig. 2C. In mice treated with
monoclonal antibody, survival was zero percent at about 120 days. Id.
Despite the fact that P-glucan showed no effect greater than control in this
model, co-administering P-glucan and monoclonal antibody yielded a
survival rate of about 20 percent to 200 days. Id. Thus, although the lack of
any effect beyond control would have suggested that P-glucan should not
have a potentiating effect on the monoclonal antibody, co-administering
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Application 12/150,049
P-glucan and monoclonal antibody yielded a survival rate significantly
beyond the additive effect suggested by the individual agents’ separately
observed biological activities, that is, a synergistic result.
Given the results shown in Figures 1 and 2 of Hong, and further given
Hong’s disclosure that the potentiating effects of co-administering P-glucan
and monoclonal antibody were seen “in all models that included mammary,
s.c., and hepatic tumors” (Hong 9023, abstract), Appellant does not persuade
us that the Examiner erred in finding that an ordinary artisan had a
reasonable expectation that combining yeast P-glucan and bevacizumab, as
suggested by Hong, would yield a synergistic result. See also id. at 9023—24
(“Significant enhancement of tumor regression and survival was
demonstrated with each therapeutic mAb when it was used in combination
with P-glucan.” (emphasis added)).
In this regard, we note, as Appellant argues (Reply Br. 4), that Hong’s
antibodies were targeted to different antigens than the VEGF-targeted
bevacizumab of Appellant’s claim 1. Appellant contends, in particular, that
“there is no basis to extrapolate the efficacy of the disclosed monoclonal
antibodies to bevacizumab since bevacizumab binds to a different target.”
Id. Appellant does not, however, provide evidence to support this assertion,
or otherwise explain why an ordinary artisan would reach this conclusion.
“Attorneys’ argument is no substitute for evidence.” Johnston v. IVAC
Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989).
In contrast to Appellant’s assertion, moreover, Hong discloses that the
potentiating effect of P-glucan was seen in all tumor models tested (Hong
9023, abstract), and with each therapeutic monoclonal antibody tested {id. at
9023—24). Accordingly, that Hong’s antitumor monoclonal antibodies
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Application 12/150,049
targeted different antigens than bevacizumab does not persuade us that an
ordinary artisan lacked a reasonable expectation that combining yeast
P-glucan with a known antitumor monoclonal antibody (bevacizumab),
would yield results similar to those disclosed in Hong. See also id. at 9029
(“This investigation showed that both the tumor regression and increased
survival mediated by monoclonal antitumor antibodies could be significantly
enhanced if they were given in combination with P-glucan.”). As noted
above, moreover, “[ojbviousness does not require absolute predictability of
success. . . . For obviousness under § 103, all that is required is a reasonable
expectation of success.” In re Kubin, 561 F.3d at 1360.
In addition, Appellant does not persuade us (see Reply Br. 2) that
Ault-Riche teaches away from the claimed composition. We acknowledge
that Ault-Riche’s invention is directed to therapeutic complexes in which
targeting moieties and effector moieties are physically linked together. See
Ault-Riche Tflf 8—10.
Nonetheless, even interpreting Ault-Riche as expressing a preference
for complexing together ingredients such as P-glucan and bevacizumab, over
simply co-administering those ingredients in an un-complexed composition,
the disclosure of a preference does not teach away from the unpreferred
embodiments. See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
567 F.3d 1314, 1327 (Fed. Cir. 2009) (A reference “does not teach away . . .
if it merely expresses a general preference for an alternative invention but
does not ‘criticize, discredit, or otherwise discourage’ investigation into the
invention claimed.” (citation omitted)). In the present case, Appellant does
not identify any specific teaching in either reference criticizing, discrediting,
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or otherwise discouraging the un-complexed composition containing
P-glucan and bevacizumab, encompassed by Appellant’s claim 24.
In sum, for the reasons discussed, Appellant does not persuade us that
the Examiner erred in finding that an ordinary artisan had a good reason for,
and a reasonable expectation of success in, combining yeast P-glucan and
bevacizumab, to prepare a therapeutic composition to treat cancer, as recited
in claim 24, the composition having the synergistic effect required by claim
24. We, therefore, are not persuaded that the evidence of record fails to
support the Examiner’s prima facie case of obviousness.
Appellant’s arguments (App. Br. 10-11; Reply Br. 5) do not persuade
us, moreover, that sufficient secondary evidence of nonobviousness has been
advanced to outweigh the Examiner’s evidence of prima facie obviousness.
Appellant contends that “the data reported in Appellant’s disclosure showing
a synergistic effect when bevacizumab and a P-glucan are administered as
separate active agents is an unexpected property” of the composition of
representative claim 24. App. Br. 10.
Appellant does not discuss the data reported in the Specification with
any degree of specificity, or explain with any particularity why that data
shows synergy. See App. Br., generally; see also Reply Br., generally.
Nonetheless, as discussed above, page 9 of the Specification shows that co­
administering P-glucan and bevacizumab results an effect that is greater than
the additive effect of the individual activities of P-glucan and bevacizumab,
that is, a synergistic effect.
It is well settled, however, that “[sjynergism, in and of itself, is not
conclusive of unobviousness in that synergism might be expected.” In re
Kollman, 595 F.2d 48, 55 n.6 (CCPA 1979); see also Novo Nordisk A/S v.
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Application 12/150,049
Caraco Pharm. Labs, Ltd., 719 F.3d 1346, 1354—56 (Fed. Cir. 2013)
(affirming holding that synergistic combination of two therapeutic
ingredients was insufficient evidence of unexpected results where prior art
disclosed that first claimed ingredient was known to yield synergy when
combined with agents similar to second claimed ingredient).
In the present case, as discussed above, Hong discloses that
combining P-glucan with antitumor monoclonal antibodies provides a
synergistic result beyond the additive effect suggested by biological
activities of the individual ingredients. See, e.g., Hong 9025—26 (Figs. 1 and
2). Appellant does not persuade us, therefore, that the results presented in
the Specification were, in fact, unexpected.
To that end, we note that the only specific assertions of record that the
showing of synergism would have been unexpected, appear in Appellant’s
briefs. See App. Br. 10-11; Reply Br. 5. It is well settled, however, that
argument by counsel is not an adequate substitute for evidence regarding a
showing of unexpected results. See In re Geisler, 116 F.3d 1465, 1470-71
(Fed. Cir. 1997).
In sum, for the reasons discussed, Appellant does not persuade us that
the evidence of record fails to support the Examiner’s prima facie case of
obviousness as to claim 24. For the reasons discussed, Appellant also does
not persuade us that the secondary evidence of nonobviousness is sufficient
to outweigh the evidence of prima facie obviousness. Accordingly, because
a preponderance of the evidence of record supports the Examiner’s
conclusion that claim 24 would have been obvious in view of Hong and
Ault-Riche, we affirm the Examiner’s rejection of that claim over those
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Application 12/150,049
references. Because they were not argued separately, claims 25 and 31—35
fall with claim 24. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm the Examiner’s rejection of
claims 24, 25 and 31—35 under 35 U.S.C. § 103(a) for obviousness over
Hong and Ault-Riche.
TIME PERIOD
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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