Ex Parte 6680320 et al

Board of Patent Appeals and Interferences

Oct 27, 2009

90007935 (B.P.A.I. Oct. 27, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte WILEX AG,
Patent Owner and Appellant1
____________________

Appeal 2009-010,915
Reexamination Control No. 90/007,935
Patent No. 6,680,320 B22
Technology Center 3900
____________________

Decided: October 27, 2009
____________________

Before CAROL A. SPIEGEL, ROMULO H. DELMENDO, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL

1 Appellant's Amended Brief Under 37 C.F.R. §41.37 (filed 9 January 2009),
2 [hereinafter App. Br.].
2 Wilhelm et al., Urokinase Inhibitors, U.S. Patent No. 6,680,320 B2 (issued
20 January 2004) [hereinafter 320 patent]; based on U. S. Patent Application
No. 10/202,850 (filed 26 July 2002), which is a division of U.S. Patent
Application No. 09/743,800 (filed 3 April 2001), which is the national phase
under 35 U.S.C. § 371 of PCT/EP99/05145, filed 20 July 1999, which
claims priority to European Patent Office Application No. EP 98113519,
filed 20 July 1998.
Appeal 2009-010,915
Reexamination Control No. 90/007,935
Patent 6,680,320 B2

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Appellant appeals under 35 U.S.C. §§ 134(b) and 306 from an
Examiner's final rejection of claims 2-5, all of the pending claims. We have
jurisdiction under 35 U.S.C. §§ 134(b) and 306. We AFFIRM.
I. Statement of the Case
The subject matter on appeal is directed to a pharmaceutical
composition containing Nα-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-
(L)-phenylalanine-4-ethoxycarbonyl-piperazide [hereinafter the L-isomer] or
Nα-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(D, L)-phenylalanine-4-
ethoxycarbonyl-piperazide [hereinafter the racemate]; or a pharmaceutically
acceptable salt thereof; and a pharmaceutically acceptable carrier, and its use
(320 patent 7:27-31, 41-45). The composition is a urokinase [hereinafter
uPA] inhibitor and, therefore, useful in treating uPA-associated conditions,
such as controlling the growth of malignant tumors, diagnosing diseases of
the lymphatic tissues, and preventing blister formation in cases of
pemphigus vulgaris (id. 1:6-7; 2:39-43; 7:27-60; 8:23-26).
Claims 2 and 4 read are illustrative and read as follows (App. Br. 22,
bracketing and underlining omitted):
2. A pharmaceutical composition comprising Nα-(2,4,6-
Triisopropyl-phenylsulfonyl)-3-amidino-(L)-phenylalanine-4-
ethoxycarbonyl-piperazide or Nα-(2,4,6-Triisopropyl-
phenylsulfonyl)-3-amidino-(D,L)-phenylalanine-4-
ethoxycarbonyl-piperazide; or a pharmaceutically suitable salt
thereof; and a pharmaceutically acceptable carrier.

4. A method for inhibiting plasminogen activator urokinase
(uPA) comprising administering a composition according to
claim 2, to a patient in need of such inhibition.
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Reexamination Control No. 90/007,935
Patent 6,680,320 B2

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The Examiner relies on the following evidence3 of record:
Bridges 5,340,833 Aug. 23, 1994
Wilhelm 6,624,169 B1 Sept. 23, 2003

Jerzy Jankun, Inhibitors of Urokinase Reduce Size of Prostate Cancer
Xenografts in Severe Combined Immunodeficient Mice, 57 Cancer Research
559 (15 February 1997).

PENTAPHARM LTD, Product Catalogue 1-37 (July 1997) [hereinafter
Pentapharm]4. (Ans. 3.5)

PENTAPHARM, Product Catalog, 1-47 (1998) [hereinafter Pentapharm
1998].

Jörg Stűrzebecher, Synthesis and Structure-Activity Relationships of Potent
Thrombin Inhibitors: Piperazides of 3-Amidinophenylalanine, 40 J. of
Medicinal Chemistry 3091 (1997) [hereinafter Sturzebecher 1997].

Jörg Stűrzebecher, 3-Amidinophenylalanine-based Inhibitors of Urokinase,
9 Bioorganic & Medicinal Chemistry Letters 3147 (1999) [hereinafter
Sturzebecher 1999].

Rosie Hongmei Xing, Prevention of Breast Cancer Growth, Invasion, and
Metastasis by Antiestrogen Tamoxifen Alone or in Combination with
Urokinase Inhibitor B-428, 57 Cancer Research 3585 (15 August 1997).
The Examiner has rejected claims 2-5 as unpatentable under the
judicially created doctrine of obviousness-type double patenting over claims
1-14 of Wilhelm (Ans. 3). The Examiner has also rejected claims 2, 4, and 5
as unpatentable under 35 U.S.C. § 103(a) over Pentapharm or Pentapharm
1998, each together with Bridges (Ans. 4-5); and claim 3 as unpatentable

3 No references to "et al." are made in this decision.
4 Appellant has not challenged the publication date given by the Examiner.
5 Examiner's Answer (mailed 3 August 2007) [hereinafter Ans.].
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under 35 U.S.C. § 103(a) over Pentapharm or Pentapharm 1998, each
together with Bridges and Xing (Ans. 5-6).
Appellant has relied on the following evidence of record:
Bradley A. Katz, Structural basis for selectivity of a small molecule, S1-
binding, submicromolar inhibitor of urokinase-type plasminogen activator,
7 Chemistry & Biology 299 (2000).

Murray J. Towle, Inhibition of Urokinase by 4-substituted
Benzo[b]thiophene-2-carboxamidines: An Important New Class of Selective
Synthetic Urokinase Inhibitor, 53 Cancer Research 2553 (1 June 1993).

Todd W. Rockway, Inhibitors of the Proteolytic Activity of Urokinase Type
Plasminogen Activator, 9 Current Pharmaceutical Design 1483 (2003).

Declaration of John Foekens dated 27 December 2006 [hereinafter Foekens
Decl.].

Declaration of Roger B. Cohen dated 21 December 2006 [hereinafter Cohen
Decl.].
II. Obviousness-type Double Patenting
Appellant does not appeal the rejection of claims 2-5 under the
judicially created doctrine of obviousness-type double patenting over claims
1-14 of Wilhelm (App. Br. 5). According to Appellant, "[a] terminal
disclaimer will be submitted upon an indication of allowability of the
pending claims" (id.). Therefore, we summarily affirm the Examiner's
rejection of claims 2-5 under the judicially created doctrine of obviousness-
type double patenting.

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Patent 6,680,320 B2

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III. Obviousness
Appellant does not separately argue the patentability of claim 3 or 5
(App. Br. 5-20). Therefore, we decide the appeal of the obviousness
rejections on the basis of claims 2 and 4. 37 C.F.R. § 41.37(c)(1)(vii).
Claims 2 and 4 have been rejected under 35 U.S.C. § 103(a) over
either Pentapharm or Pentapharm 1998 (collectively "the Pentapharm
catalogs") in view of Bridges.
A. Composition claim 2
1. the Examiner's position and Appellant's rebuttal
Claim 2 broadly recites a pharmaceutical composition comprising the
racemate or the L-isomer, or a pharmaceutically suitable salt of these two
compounds, in combination with a pharmaceutically acceptable carrier.
The Pentapharm catalogs disclose multiple synthetic serine proteinase
inhibitors and compares the inhibitory constants (Kis) of these inhibitors for
various serine proteases (Pentapharm 17; Pentapharm 1998 18). Pentapharm
and Pentapharm 1998 disclose the racemate and the L-isomer of claim 2,
respectively, as low molecular weight inhibitors of urokinases (uPA),
commercially available as "Pefabloc® uPA (Pefa-0888)" (Pentapharm 23;
Pentapharm 1998 23). According to the Pentapharm catalogs, the racemate
and the L-isomer have the following Kis (in µM) for various serine proteases
(Pentapharm 24; Pentapharm 1998 25):
Enzyme trypsin thrombin
(bovine)
plasmin uPA sc-tPA
racemate 0.12 0.67 1.0 0.54 9.5
L-isomer 0.039 0.67 1.0 0.41 9.5
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According to the Examiner, the pharmaceutical potential of the
racemate and the L-isomer is evident from the compound's ability to inhibit
a serine protease, such as uPA or thrombin, as taught by the Pentapharm
catalogs (Ans. 8-9, 12, and 17). Thus, "it is the examiner's position that a
person having ordinary skill in the art would be motivated to make a
pharmaceutical composition of a compound for in vivo use, including animal
testing, once that compound demonstrates potent in vitro enzyme (serine
protease) inhibition correlative to a single human utility; potential side-
effects notwithstanding" (Ans. 19). The Examiner points to Sturzebecher
1997 and Xing, for example, in further support of her position (Ans. 9 and
23). The Examiner specifically points to Sturzebecher 1997's teaching that
"[t]hrombin is the key enzyme in the blood coagulation system, and
inhibitors of its proteolytic activity are of therapeutic interest since they are
potential anticoagulants" (Sturzebecher 1997 abstract) and to Xing's use of
an animal model to evaluate the compounds' ability to achieve biological
effects (Xing abstract) (Ans. 9).
Appellant argues that the Pentapharm catalogs indicate that the
Pefabloc compounds are for "research, analytical applications and
purification processes" (Pentapharm 17; Pentapharm 1998 18) (Reply Br.6
2). In particular, Appellant argues that "a person having ordinary skill in the
art would have thought that Pefabloc uPA, having strong inhibitory activities
to many enzymes involved in the blood clotting cascade, including sc-tPA
and plasmin, would be unsuitable for a pharmaceutical use, particularly, for
an anti-invasiveness or anti-proliferation use" (Reply Br. 2). Appellant

6 Reply Brief (filed 3 October 1997) [hereinafter Reply Br.].
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points to Towle, Katz, Bridges, and the Foekens and Cohen declarations, for
example, in support of its position (App. Br. 6-7, 10; Reply Br. 2-3).
According to Towle (Towle 2553, col. 2, ¶2, endnotes omitted),
[s]ince both uPA and its fibrinolytic counterpart
tPA share identical specificity for the Arg560-Val561
bond in plasminogen (2-4), most low molecular
weight protease inhibitors which inhibit uPA also
inhibit tPA. Such inhibitors are unsuitable for use
as antiinvasiveness drugs due to the potential
undesired inhibition of tPA-mediated fibrinolysis.
Similarly, antiinvasiveness uPA inhibitors should
not inhibit plasmin, since both uPA- and tPA-
mediated pathways converge through this enzyme.
According to Katz, therapeutic inhibitors of uPA must not appreciably
inhibit the closely related enzymes thrombin and tPA, which are critical
components of the blood-clotting pathway (Katz 300, col. 1, ¶ 1).
According to Bridges, which discloses benzothiophene and thienothiophene
derivatives as potent and specific uPA inhibitors (Bridges abstract; 2:18-
9:63; 10:61-11:3), the derivatives "are generally 60-800-fold more active at
inhibiting urokinase than tPA and are generally 400-10,000-fold more
selective for urokinase over plasmin" (id. 10:43-45). Finally, Drs. Foekens
and Cohen both testified that one of ordinary skill in the art would not have
considered either the racemate or the L-isomer suitable for pharmaceutical
use for cancer therapy because, rather than being highly selective for uPA,
the compounds inhibit a broad spectrum of serine proteases, including uPA,
plasmin, thrombin, and trypsin (Foekens Decl. ¶¶ 2-7; Cohen Decl. ¶ 4).

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2. issue
Thus, at issue is whether Appellant has shown that the Examiner
failed to provide a reason for providing the racemate and/or L-isomer as a
pharmaceutical composition as recited in claim 2; and, if not, whether
Appellant has provided rebuttal evidence sufficient to overcome the
Examiner's reasoning.
3. discussion
The intended function of the racemate or the L-isomer as a cancer
therapeutic is entitled to little, if any, patentable weight where there is an
independent reason to use the racemate or the L-isomer as a pharmaceutical
composition. Cf. In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990). As
shown by the Pentapharm catalogs, the serine protease inhibitory properties
of the racemate and the L-isomer were well known to those skilled in the art.
Such persons would have been motivated to test the racemate and/or the L-
isomer, e.g., in an in vivo animal model system, to evaluate the compounds'
ability to achieve the expected inhibitory effect as evidenced by
Sturzebecher 1997 and Xing. Indeed, the claim term "pharmaceutical
composition" provides no explicit or implicit indication to one of skill in the
art of the specific usefulness or the specific amounts or routes of
administration of the recited racemate or L-isomer therein. Further,
Appellant has failed to point us to where the 320 patent specifically defines
the claimed "pharmaceutical composition" as limited to a composition
intended for use in treating a specific disease(s) (as opposed to clinical
research, for example) or as requiring highly selective uPA inhibition vis-à-
vis inhibition of other serine proteases. To the contrary, the 320 patent
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Patent 6,680,320 B2

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expressly states that the disclosed uPA inhibitors, which includes the
racemate and the L-isomer, may be used for diagnosis (the 320 patent 7:27-
31). In addition, Pentapharm 1998 indicates that the L-isomer is more than
ten times more selective for inhibiting trypsin than uPA (Pentapharm 1998
25). Thus, the Examiner has provided a sufficient reason for providing the
racemate and/or L-isomer together with a pharmaceutically acceptable
carrier as a pharmaceutical composition.
In rebuttal, Appellant does not contest the Examiner's finding that
"there is no comparative evidence of record demonstrating an unexpected
reduction in toxicity or any evidence of unexpected results regarding
efficacy" (Ans. 23). Instead, Appellant replies that one skilled in the art
would have predicted the claimed composition to have significant
thrombogenic side effects (Reply Br. 4). However, as noted by the
Examiner (Ans. 23) and acknowledged by Appellant (Reply Br. 4), safety
and efficacy such as required by the Food and Drug Administration (FDA),
are not required for the purposes of patentability. Moreover, one of ordinary
skill in the art would have reasonably expected the occurrence and severity
(significance) of side effects to correlate to the dosage and/or route of
administration of active agent in a pharmaceutical composition. For
example, Appellant has not shown that an amount of L-isomer minimally
effective to inhibit trypsin produces "significant" thrombogenic side effects,
e.g., is lethal upon administration (i.e., unusable). Nor has Appellant
demonstrated any discovery beyond what would have been suggested by the
prior art. Moreover, Katz's indication that "appreciable" inhibition of
thrombin should be avoided implies that some inhibition of thrombin is
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Patent 6,680,320 B2

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acceptable. Further, while Towle indicates most uPA inhibitors are
unsuitable as antiinvasiveness drugs, Towle is silent on their suitability for
other purposes, e.g., as a topical medicament. Finally, the uPA inhibitors of
Bridges are not structurally identical to the racemate or L-isomer of the
claims and Appellant has not pointed us to evidence of record showing that
the two sets of uPA inhibitors bind uPA at the same site, etc. Therefore, we
agree with the Examiner that Appellant's rebuttal evidence is not
commensurate in scope with the claimed invention.
4. conclusion
Based on the foregoing, we sustain the rejection of claim 2 under
§ 103 over the Pentapharm catalogs and Bridges. Appellant has not shown
that the Examiner failed to provide a reason for providing the racemate
and/or L-isomer as a pharmaceutical composition as recited in claim 2.
Appellant has not provided rebuttal evidence sufficient to overcome the
Examiner's reasoning.
B. Method claim 4
1. the Examiner's position and Appellant's rebuttal
Claim 4 broadly recites a method of inhibiting uPA comprising
administering the composition of claim 2 "to a patient in need of such
inhibition."
Bridges discloses that uPA mediates a broad range of biological
processes including, but not limited to, “angiogenesis (neovascularization),
bone restructuring, embryo implantation in the uterus, infiltration of immune
cells into inflammatory sites, ovulation, spermatogenesis, tissue remodeling
during wound repair and organ differentiation, fibrosis, local invasion of
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Patent 6,680,320 B2

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tumors into adjacent areas, metastatic spread of tumor cells from primary to
secondary sites, and tissue destruction in arthritis” (Bridges 10:61-11:3).
According to the Examiner, Bridges discloses a list of art-recognized
uPA-associated disorders and teaches that inhibiting uPA would reasonably
be expected to treat a patient having any of a variety of disorders including,
but not limited to, cancer (Ans. 10). Further according to the Examiner,
claim 4 does not require a specific degree of inhibition (Ans. 16) and the
Pentapharm catalogs indicate that the racemate and L-isomer are ten times7
more selective for uPA than for sc-tPA (Ans. 17). Thus, the Examiner
concluded that it would have been obvious to formulate the racemate and/or
L-isomer uPA inhibitors of the Pentapharm catalogs into pharmaceutical
compositions with an expectation of providing a suitable treatment for a
uPA-associated disorder including, but not limited to, cancer based on the
teachings of Bridges (Ans. 5 and 10).
Appellant reiterates his arguments regarding claim 2, specifically that
one of ordinary skill in the art would have considered the racemate and L-
isomer uPA inhibitors of the Pentapharm catalogs unsuitable for a
pharmaceutical use, particularly, as a cancer therapy to prevent proliferation
or metastasis of the cancer, because these inhibitors are not highly selective
for uPA vis-à-vis other serine protease inhibitors such as sc-tPA and
plasmin, citing Towle, Katz, Bridges, and the Foekens and Cohen
declarations (see e.g., App. Br. 6-7 and 10; Reply Br. 2-3).

7 Based on the data in the Pentapharm catalogs, the racemate is
approximately 18 times more selective for uPA than for sc-tPA (9.5/0.54)
and the L-isomer is approximately 23 times more selective for uPA than for
sc-tPA (9.5/0.41).
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Patent 6,680,320 B2

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2. issue
Thus, at issue is whether Appellant has shown that the Examiner erred
in concluding that it would have been obvious to inhibit uPA in a patient in
need of such inhibition by administering the pharmaceutical composition of
claim 2 to said patient; and, if not, whether Appellant has provided rebuttal
evidence sufficient to overcome the Examiner's conclusion.
3. discussion
Appellant does not challenge the Examiner's conclusion that inhibiting
uPA would engender a reasonable expectation of treating a variety of uPA-
associated disease states (see e.g., Ans. 10). Rather, Appellant argues that
most uPA inhibitors are unsuitable for cancer therapy as evidenced by
Towle, Katz, Bridges, and the Foekens and Cohen declarations. However,
as noted by the Examiner, method claim 4 is neither limited to cancer
therapy (Ans. 10) nor requires any specific degree of uPA inhibition (Ans.
16). Moreover, as also noted by the Examiner (Ans. 14), the racemate and
L-isomers are "selective" uPA inhibitors as defined by the 320 patent.
Specifically, according to the 320 patent, "the uPA inhibitor according to the
invention has a Ki for urokinase which according to the invention has a Ki
for urokinase which [sic] is more than ten times smaller than the Ki for
single chain tPA (Sc-tPA). Thus, the substances of the invention are suitable
as selective urokinase inhibitors" (320 patent 11:34-39). According to the
Pentapharm catalogs, the racemate and the L-isomer are approximately 18
and 23 times more selective for uPA than for sc-tPA, respectively
(Pentapharm 24; Pentapharm 1998 25). Therefore, these arguments are
unpersuasive of Examiner error.
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Patent 6,680,320 B2

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We also agree with the Examiner that Appellant's rebuttal evidence is
not commensurate in scope with claim 4 for essentially the same reasons set
forth above in regard to claim 2. The rebuttal evidence is focused on cancer
treatment, while claim 4 recites inhibiting uPA in a patient in need thereof.
4. conclusion
Based on the foregoing, we sustain the rejection of claim 4 under
§ 103 over the Pentapharm catalogs and Bridges. Appellant has not shown
that the Examiner erred in concluding that it would have been obvious to
inhibit uPA in a patient in need of such inhibition by administering the
pharmaceutical composition of claim 2 to said patient. Appellant has not
provided rebuttal evidence sufficient to overcome the Examiner's reasoning.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claims 2-5 as
unpatentable under the judicially created doctrine of obviousness-type
double patenting over claims 1-14 of Wilhelm is AFFIRMED;
FURTHER ORDERED that the decision of the Examiner to reject
claims 2, 4, and 5 as unpatentable under 35 U.S.C. § 103(a) over
Pentapharm or Pentapharm 1998, each together with Bridges is
AFFIRMED;
FURTHER ORDERED that the decision of the Examiner to reject
claim 3 as unpatentable under 35 U.S.C. § 103(a) over Pentapharm or
Pentapharm 1998, each together with Bridges and Xing is AFFIRMED and,
FURTHER ORDERED that no time period for taking any subsequent
action in connection with this appeal may be extended under 37 C.F.R.
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Reexamination Control No. 90/007,935
Patent 6,680,320 B2

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§ 1.136(a)(1)(iv).
AFFIRMED

KMF

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