Ex Parte Karbassi et al

Board of Patent Appeals and Interferences

Jul 9, 2012

11694370 (B.P.A.I. Jul. 9, 2012)

MOD PTOL-90A (Rev.06/08)

APPLICATION NO./
CONTROL NO.
FILING DATE FIRST NAMED INVENTOR /
PATENT IN REEXAMINATION
ATTORNEY DOCKET NO.
11/694,370 03/30/2007 Karbassi, Behjatolah M.

EXAMINER
HUGH MCTAVISH
MCTAVISH PATENT FIRM
429 BIRCHWOOD COURTS
BIRCHWOOD, MN 55110
Holleran, Anne
ART UNIT PAPER NUMBER
1643
MAIL DATE DELIVERY MODE

07/10/2012 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.

UNITED STATES DEPARTMENT OF COMMERCE
U.S. Patent and Trademark Office
Address : COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________________________________________________________________________________

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte BEHJATOLAH M. KARBASSI and
THOMAS KIEBER-EMMONS
__________

Appeal 2011-012747
Application 11/694,370
Technology Center 1600
__________

Before LORA M. GREEN, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a method of
inhibiting metastasis through the administration of chondroitin sulfate. The
Examiner rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.
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Statement of the Case
Background
The present invention relates to a method of inhibiting metastasis
through the use of chondroitin sulfate to block the interaction of cancer cell
proteoglycans and P-selectin on the surface of blood platelets (see Spec. 3 ¶
0007). By preventing cancer cell-platelet complex formation, chondroitin
sulfate inhibits cancer cells from being carried through the blood stream to
other regions of the body (see Spec. 3 ¶ 0007).
The Claims
Claims 19-22 and 28-35 are on appeal. Claims 19 and 29 are
representative and read as follows:
19. A method of inhibiting metastasis comprising blocking the
interaction of a first cell comprising chondroitin sulfate with a second
cell comprising P-Selectin by contacting said second cell with a P-
Selectin ligand in vivo in a patient in need of inhibiting metastasis,
wherein the P-Selectin ligand is chondroitin sulfate A, chondroitin
sulfate B, chondroitin sulfate C, chondroitin sulfate D, chondroitin
sulfate E.

29. The method of [claim 19 wherein the P-selectin ligand is
chondroitin sulfate E] wherein the method comprises contacting said
second cell with 0.0005 mg/ml chondroitin sulfate E.

The Issues
A. The Examiner rejected claims 19-22 and 28-35 under 35 U.S.C.
§ 103(a) as obvious over Borsig
1
and Kawashima
2
(Ans. 5).

1
Borsig et al., Heparin and cancer revisited: Mechanistic connections
involving platelets, P-selectin, carcinoma mucins, and tumor metastasis, 98
PNAS 3352-3357 (2001).
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B. The Examiner rejected claims 29-32 and 34-35 under 35 U.S.C
§ 103(a) as obvious over Borsig and Kawashima (Ans. 7).
A. Obviousness of Claims 19-22 and 28-35
The Examiner finds Borsig “teaches that heparin is a . . .
glycosaminoglycan” (Ans. 6). The Examiner further finds Borsig teaches
“[h]eparin is an inhibitor of P-selectin binding to its natural ligands” (id.).
Finally, the Examiner finds “Borsig teaches human tumors use the
interactions between P-selectin on platelets and tumor mucin during the
process of metastasis” (id.). The Examiner notes Borsig does not teach
chondroitin sulfate inhibits P-selectin (id.).
The Examiner finds that “Kawashima teaches that P-selectin binds
chondroitin sulfate B and chondroitin sulfate E avidly” (id.). The Examiner
further finds that Kawashima teaches chondroitin sulfate B and E inhibit P-
selectin binding to versican, a proteoglycan that has chondroitin sulfate
chains (id.).
Therefore, the Examiner finds it would have been obvious “to have
substituted chondroitin sulfate B or chondroitin sulfate E for heparin in the
method of Borsig, because heparin is a glycosaminoglycan that binds P-
selectin, as are chondroitin sulfate B or chondroitin sulfate E.” (Id. at 7).
Appellants contend Borsig does not teach metastasis is arrested by
inhibiting P-selectin (App. Br. 7). Appellants also contend neither Borsig
nor Kawashima provide motivation to combine the references (id. at 7-9).
Therefore, the Appellants conclude, the Examiner has not properly
established a prima facie case of obviousness (id. at 9).

2 Kawashima et al., Binding of a Large Chondroitin Sulfate/Dermatan
Sulfate Proteoglycan, Versican, to L-selectin, P-selectin, and CD44, 275 J.
BIOLOGICAL CHEMISTRY 35448-35456 (2000).
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We select claim 19 as representative of the claims subject to this
rejection. See 37 C.F.R. § 41.37(c)(1)(vii). Thus, the issues with respect to
this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Borsig and Kawashima render Claim 19 obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness,
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Borsig teaches that “heparin is not just an anticoagulant, but a
complex set of multifunctional glycosaminoglycan molecules with many
other potential biological effects” (Borsig 3352, col. 2).
2. Borsig teaches that “heparin treatment attenuates tumor
metastasis in mice by inhibiting P-selectin-mediated interactions of platelets
with carcinoma cell-surface mucin ligands” (Borsig 3352, abstract).
3. Borsig demonstrates that “the reduction of spontaneous tumor
cell-platelet interactions in vivo by P-selectin deficiency can be mimicked by
heparin treatment” (Borsig 3354, col. 2).
4. Borsig teaches that “[r]emoval of cell surface mucins from T84
cells decreased metastasis to levels similar to those observed in heparin-
treated mice with no OSGPase treatment” (Borsig 3355, col. 1).
5. Borsig teaches that “we suggest that the use of heparin therapy
to inhibit human carcinoma metastasis deserves to be reexamined” (Borsig
3356, col. 2).
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6. Borsig teaches that “[a]ll previously recognized heparanase
inhibitors we have tested can also inhibit tumor cell adhesion to P-selectin”
(Borsig 3356, col. 2).
7. Borsig teaches that “these polyanionic compounds may have a
multipotent effect on metastasis, the very first of which would be inhibition
of P-selectin-mediated platelet adhesion to tumor cells (Borsig 3356, col. 2).
8. Borsig teaches that the “use of more specific and selective P-
selectin inhibitors… may dissect the relative roles of the different
mechanisms of heparin action” (Borsig 3356, col. 2).
9. Kawashima teaches that “[p]roteoglycans consist of a core
protein to which one or more glycosaminoglycan (GAG) side chains are
covalently attached. There are several types of GAGs, which include heparin
or heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (CS B)”
(Kawashima 35448, col. 1)(internal footnote omitted).
10. Kawashima teaches “proteoglycans sufficiently modified with
CS B and/or CS E should bind L- and P-selectin” (Kawashima 35455, col.
2).
11. Kawashima teaches that “binding of versican to L- and P-
selectin- and CD44-Igs was almost completely inhibited by treatment with
chondroitinase ABC . . . whereas the binding of versican to the anti-versican
mAb 2-B-1 was not affected (Kawashima 35451, col.2 to 35452, col. 1).
12. Kawashima teaches that “[b]inding of versican to the L- and P-
selectin-Igs was strongly inhibited by specific GAGs, i.e. CS B, CS E, and
heparan sulfate (HS) but not by any other GAGs examined” (Kawashima
35452, col. 2).
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13. Kawashima teaches that “CS E was particularly potent in that it
inhibited the binding of versican to the L- and P-selectin-Igs by about 50%
at a concentration as low as 15 ng/ml” (Kawashima 35452, col. 2).

Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima facie case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir.
1992).
“The combination of familiar elements according to known methods is likely to
be obvious when it does no more than yield predictable results.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a
predictable variation, § 103 likely bars its patentability.” Id. at 417.
Moreover, an “[e]xpress suggestion to substitute one equivalent for another
need not be present to render such substitution obvious.” In re Fout, 675 F.2d 297,
301 (CCPA 1982). As noted by the Court in KSR, “[a] person of ordinary skill is also
a person of ordinary creativity, not an automaton.” 550 U.S. at 421.
Analysis
Obviousness
Borsig teaches that “heparin treatment attenuates tumor metastasis in
mice by inhibiting P-selectin-mediated interactions of platelets with
carcinoma cell-surface mucin ligands” (Borsig 3352, abstract; FF 2). Borsig
demonstrates that “the reduction of spontaneous tumor cell-platelet
interactions in vivo by P-selectin deficiency can be mimicked by heparin
treatment” (Borsig 3354, col. 2; FF 3). The Examiner acknowledges Borsig
does not disclose chondroitin sulfate inhibits P-selectin (Ans. 6). Thus, the
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Examiner introduces Kawashima to show that chondroitin sulfate binds to P-
selectin and Kawashima teaches that “[b]inding of versican to the L- and P-
selectin-Igs was strongly inhibited by specific GAGs, i.e. CS B, CS E, and
heparan sulfate (HS) but not by any other GAGs examined” (Kawashima
35452, col. 2; FF 12).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary creativity would have predictably
substituted chondroitin sulfates B and E for heparin as the p-selectin ligand
in Borsig’s method of inhibiting metastasis (FF 2-8 ) since Kawashima
demonstrates that chondroitin sulfates B and E strongly bind to p-selectin
similarly to heparin (FF 10-13). Such a combination is merely a
“predictable use of prior art elements according to their established
functions.” KSR, 550 U.S. at 417.
Appellants contend “while Borsig presents some evidence in support
of its hypothesis that heparin inhibits metastasis in part due to inhibiting of
tumor cells to P-selectin on platelets, it does not even hypothesize that this is
the sole or even the single most important mechanism by which heparin
inhibits metastasis.” (App. Br. 7).
We are not persuaded. Borsig never suggests that P-selectin binding
is the only mechanism by which heparin acts (FF 1, 8). However, Borsig
demonstrates heparin, a glycosaminoglycan, inhibits mucin, a tumor
proteoglycan, binding P-selectin (FF 2-4). Borsig also demonstrates the
removal of mucins has the same effect inhibitory effect on metastasis as
heparin (FF 4). Therefore, the Examiner reasonably finds that Borsig
teaches that heparin functions, in part, by inhibiting the interaction of mucin
with P-selectin (2-8). This, combined with the teaching of Kawashima that
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chondroitin sulfates B and E are equivalent glycosaminoglycans to heparin
(FF 8) and that chondroitin sulfates B and E inhibit P-selectin from binding
versican, a tumor proteoglycan (FF 12), reasonably supports the Examiner’s
obviousness conclusion to substitute chondroitin sulfate for heparin in order
to inhibit metastasis through inhibition of P-selectin.
Appellants contend the Examiner’s prima facie case is faulty as
neither Borsig nor Kawashima provide teaching, suggestion, or motivation
to substitute chondroitin sulfate for heparin (App. Br. 7). In support,
Appellants state “[t]hree criteria must be met in order to establish a prima
facie case of obviousness.” (App. Br. 7). Appellants cite In re Vaeck for the
proposition that a “teaching or suggestion to make the claimed combination
and the reasonable expectation of success must both be found in the prior
art” (App. Br. 7 (citing In re Vaeck, 947 F.2d 488 (Fed. Cir. 1991))).
We are not persuaded of Examiner error. In KSR, the Supreme Court
rejected the rigid application of the teaching, suggestion, and motivation test
by the Federal Circuit, stating that
The principles underlying [earlier] cases are instructive
when the question is whether a patent claiming the
combination of elements of prior art is obvious. When a
work is available in one field of endeavor, design incentives
and other market forces can prompt variations of it, either in
the same field or a different one. If a person of ordinary skill
can implement a predictable variation, § 103 likely bars its
patentability.

550 U.S. at 417. The Examiner reasonably relies upon this predictable
variation rationale for supporting the prima facie case. Particularly, the
Examiner finds that both chondroitin sulfate B and E belong to the same
class of glycosaminoglycans and have similar functions as heparin with
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respect to binding P-selectin (Ans. 7). The Examiner finds that there would
therefore have been a reasonable expectation of success, i.e. a predictable
result, because both chondroitin sulfate B and E inhibit P-selectin binding
versican, a tumor proteoglycan, just as heparin inhibits P-selectin binding
mucin, another tumor proteoglycan (id.). The Examiner reasonably
concluded the use of chondroitin sulfate was simply the substitution of one
known ligand for another known ligand to yield the predictable result of the
inhibition of metastasis. We find no error in the factual or legal basis of the
Examiner’s prima facie case.
Appellants contend that the “Examiner is saying that because with
hindsight she can see some logic to what the Applicants attempted, the
invention is obvious. With hindsight, and even with foresight, one can
almost always see the logic of what an inventor attempted” (App .Br. 9).
We are not persuaded. While we are fully aware that hindsight bias
often plagues determinations of obviousness, Graham v. John Deere Co.,
383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has
clearly stated that “if a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would improve
similar devices in the same way, using the technique is obvious unless its
actual application is beyond his or her skill.” KSR, 550 U.S. at 417.
In the instant situation, the person of ordinary skill and creativity
would have recognized that using Chondroitin Sulfate E in the metastasis
inhibition method using heparin inhibition of p-selectin would have been at
least equivalent to Borsig’s method. In fact, Borsig’s method is reasonably
interpreted as improved by the use of Chondroitin Sulfate E since
Kawashima teaches that “CS E was particularly potent in that it inhibited the
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binding of versican to the L- and P-selectin-Igs by about 50% at a
concentration as low as 15 ng/ml” (Kawashima 35452, col. 2; FF 13). That
is, Kawashima teaches that Chondroitin Sulfate E was superior to heparin in
binding P-selectin and inhibiting the binding of the tumor protein (FF 13).
Unexpected Results
Appellants contend that “FIG. 12 and Example 13 of the specification
show that treating tumor cells with chondroitinase was more effective in
reducing P-selectin binding than treating the cells with heparinase” (App.
Br. 10).
We are not persuaded of Examiner error. We have considered Figure
12 and Example 13 of the Specification; however, Example 13 of the
Specification does not identify the treatment with chondroitinase as
unexpected relative to the treatment with heparinase (see Spec. 25 ¶ 0070).
More importantly, Kawashima compared the binding of chondroitin sulfate
E and heparin sulfate to P-selectin, teaching that “CS E was particularly
potent in that it inhibited the binding of versican to the L- and P-selectin-Igs
by about 50% at a concentration as low as 15 ng/ml” (Kawashima 35452,
col. 2; FF 13). Thus, given the prior art’s recognition that CS E was more
sensitive in binding than heparin, Appellants’ results showing a greater
effect for chondroitinase than heparinase was the expected, not an
unexpected, result. “Expected beneficial results are evidence of obviousness
of a claimed invention. Just as unexpected beneficial results are evidence of
unobviousness.” In re Skoner, 517 F.2d 947, 950 (CCPA 1975).
Appellants also contend that “Applicants presented data showing that
treating tumor cells with chondroitinase ABC before injecting the cells into
mice reduced lung metastases by about 10-fold (Exhibit A, Figure A)” (App.
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Br. 10). Appellants also contend that the “Applicants also presented data
that in a spontaneous metastasis model using a tumor established in
mammary fat pads in mice, subcutaneous injection of 10 mg chondroitin
sulfate mixture reduced spontaneous metastasis to lung by more than 5-fold
as compared to saline injection” (App. Br. 10-11).
We are again not persuaded that these results are sufficient to rebut
the Examiner’s prima facie case. We have considered the Karbassi
3

Declaration, which compares the effectiveness of chondroitin sulfate with
that of saline at inhibiting metastasis (see Declaration 2 ¶ 7). In particular,
the Karbassi Declaration finds that “[c]hondroitin sulfate injection (10 mg
by subcutaneous) reduced spontaneous metastasis to the lung by more than
5-fold as compared to saline injection” (Declaration 2 ¶ 7).
Here, Appellants have failed to compare chondroitin sulfate to
heparin, the closest prior art, shown as effective to reduce metastasis by
Borsig (FF 1-8). Appellants simply show chondroitin sulfate works more
effectively than saline, a control. As noted by the Examiner, “[s]aline has no
effect.” (Ans. 14). See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991) (“[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.”).
Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that
Borsig and Kawashima render Claim 19 obvious.

3 Declaration of Dr. Behjatolah M. Karbassi and Dr. Thomas Kieber-
Emmons, filed April 21, 2010.
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(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.

B. Obviousness of Claims 29-32 and 34-35
The Examiner finds that the “concentrations of claims 29-32, 34 and
35 are not taught by Borsig and Kawashima.” (Ans. 7). The Examiner
concludes “the determination of useful concentrations for the claimed
methods appears to fall within the scope of routine optimization.” (Id.).
Appellants contend that these concentrations “do not reflect optimum
ranges” but rather “they reflect unexpectedly low minimum concentrations
and unexpected results.” (App. Br. 12).
We find that the Examiner has the better position. Kawashima
teaches, in Figure 5, panel B, that 5 µg/ml of chondroitin sulfate E
essentially eliminated binding of versican to p-selectin (see Kawashima
35452, col. 2, figure 5). This is the amount required by claim 30. In fact,
Kawashima teaches that “CS E was particularly potent in that it inhibited the
binding of versican to the L- and P-selectin-Igs by about 50% at a
concentration as low as 15 ng/ml” (Kawashima 35452, col. 2; FF 13). This
15 ng/ml is 33 times less the 500 ng/ml of chondroitin sulfate E than is
required by claim 29, reasonably suggesting efficacy for the larger amount
used in claim 29 (FF 13). “[W]here the general conditions of a claims are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456
(CCPA 1955) (citing In re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite,
168 F.2d 104 (CCPA 1948)).
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SUMMARY
In summary, we affirm the rejection of claim 19 under 35 U.S.C. §
103(a) as obvious over Borsig and Kawashima. Pursuant to 37 C.F.R. §
41.37(c)(1), we also affirm the rejection of claims 20-22 and 28-35 as these
claims were not argued separately.
We affirm the rejection of claims 29-32 and 34-35 under 35 U.S.C.
§ 103(a) as obvious over Borsig and Kawashima.

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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