Ex Parte Liversidge et al

Board of Patent Appeals and Interferences

Mar 1, 2012

11329893 (B.P.A.I. Mar. 1, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
BOARD OF PATENT APPEALS AND INTERFERENCES
____________

Ex parte ELAN PHARMA INTERNATIONAL, LTD.1
(In rem Application 11/329,893)
____________

Appeal 2012-001156
Technology Center 1600
____________

Before FRED E. MCKELVEY, RICHARD E. SCHAFER and RICHARD
TORCZON, Administrative Patent Judges.

TORCZON, Administrative Patent Judge.

DECISION ON APPEAL
The appellant (Elan) seeks relief from the final rejection of its claims 1-4, 6,
8-17 and 19-22. We affirm.
OPINION
BACKGROUND
According to Elan's specification,2 the invention:

1 Appeal Brief (Br.) 4 (real party-in-interest); Reply 5 (same). Office assignment
records indicate additional stakeholders include Alkermes Inc.; Alkermes Pharma
Ireland Limited; Alkermes Controlled Therapeutics Inc. and Morgan Stanley
Senior Funding, Inc.
2 Spec. 1:9-14.
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relates generally to the treatment of cancer and, in particular, to
combination therapies for the treatment of carcinoma of the prostate.
More specifically, the present invention comprises controlled release
compositions consisting of an acylanilide, and preferably
bicalutamide[.]

Elan explains that bicalutamide is:3
a non-steroidal anti-androgen [that] competitively inhibits the action
of androgens by binding to cytosol androgen receptors in the target
tissue. Prostatic carcinoma is known to be androgen sensitive and
responds to treatment that counteracts the effects of androgen[.]

Claim1, the sole independent claim on appeal, defines the invention as:4
A controlled release composition consisting essentially of
a first component comprising a first population of acylanilide
particles and
at least one subsequent component or formulation comprising
a subsequent population of acylanilide particles and
a modified release constituent comprising
a modified release coating,
a modified release matrix material or
mixtures thereof,
wherein the composition[,] following oral delivery to a subject,
delivers the acylanilide in the first and subsequent populations in a
pulsatile manner.

The examiner has rejected all pending claims for encompassing subject matter that
would have been obvious from the combined disclosures of patents to Devane5 and

3 Spec. 5:14-17.
4 The claims have been reproduced and construed as they appear in the claims
appendix of Elan's brief, although indenting has been added in conformity with
35 C.F.R. §1.75(i).
5 J.G. Devane et al., Microparticulate modified release composition, US 6,228,398
B1 (granted 8 May 2001) (naming Elan Corporation, PLC as the assignee).
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to Fahrig,6 except that for claims 3 and 4 the examiner also relied on a Siles Ortega
publication.7 The examiner also rejected the claims under an obviousness-type
double patenting theory, where the Devane patent is the relevant precursor patent,
used in combination with the same additional references against the same groups
of claims.8 In its arguments Elan treats claims 3 and 4 as a separate group from the
other pending claims.9 Claim 1 is representative of the first group of claims.
OBVIOUSNESS: CLAIM 1
The examiner's findings and conclusion
The examiner held that Devane teaches a multi-particulate, modified-release
composition comprising an immediate-release component and modified-release
components. The immediate-release component has a first population of active
ingredient-containing particles. The modified-release component has a second
population of active ingredient-containing particles coated with a controlled-
release coating. The combination delivers the active ingredient in a pulsatile
manner.10 The second population could alternatively or additionally have a
modified-release matrix material.11 The examiner found that Devane was silent
regarding bicalutamide as the active ingredient, but that Devane did teach that any

6 R. Fahrig & A. Steinkamp-Zucht, Utilization of 5' substituted nucleosides for
resistance formation in cytoclastic treatment, and drug containing these
nucleosides, polymers, methods of use and compositions, US 6,589,941 B1
(granted 8 July 2003).
7 A. Siles Ortega & J. Cucala Escoi, Bicalutamide forms, compositions, and
processes thereof, WO2004/100944 A1 (pub'd 25 November 2004).
8 Final Rej. 9-13
9 Br. 15-16. This grouping of claims 3 and 4 for the rejection and the argument is
odd since, according to the claims appendix, claims 8-13 depend directly or
indirectly from claim 3. In light of our determination, this unusual grouping has no
prejudicial effect.
10 Final Rej. 3, citing Devane coversheet (abstract).
11 Final Rej. 3, citing Devane 4:18-21.
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active ingredient would be suitable, particularly those to which patients develop a
tolerance and anti-neoplastic agents.12 We note that antineoplastic is an adjective
indicating the inhibition of the development of tumors.
The examiner found that Fahrig teaches preventing or reducing resistance to
a cytostatic treatment by administering a particular substituted nucleoside (BVDU)
with a cytostatic agent.13 The examiner further found that Fahrig teaches that
bicalutamide is a particular cytostatic agent. We note that cytostatic is an adjective
indicating the inhibition of growth and multiplication of cells. Fahrig teaches that
it has been known for decades that "[t]umors which initially react sensitively to
cytostatic agents very frequently recover after a certain treatment time and then are
resistant to the effects of various types of antineoplastic drugs", for example, by
producing proteins that remove the agent.14
The examiner concluded that a person having ordinary skill in the art would
have reasonably expected that the cytostatic agent (bicalutamide) that Fahrig uses
in a method of reducing patient tolerance would also work as the antineoplastic
agent in Devane's method of reducing patient tolerance.
Elan's contentions
Elan contends that, because Devane is silent regarding bicalutamide,15

12 Final Rej. 4, citing Devane 6:13-25 and claim 30. The examiner actually refers
to Devane column 7, but the typographical nature of the error is readily apparent
and Elan does not identify a prejudice. Cf. Reply 12-13, citing the correct portion
of Devane.
13 Final Rej. 5, citing Fahrig coversheet (abstract). BVDU is an abbreviation for
(E)-5-(2-bromovinyl-)2'-deoxyuridine. Fahrig 2:55-67.
14 Fahrig 1:23-30.
15 Br. at 11-12.
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nothing can be inferred from Devane whether the specific
antineoplastic acylanilide or bicalutamide is an anti-neoplastic agent
or is even susceptible to patient tolerance.

Elan contends that Fahrig does not teach delivering an acylanilide (e.g.,
bicalutamide) in a pulsatile manner. Instead, Fahrig co-administers a cytostatic
agent with a nucleoside analogue (BVDU) that inhibits a tumor's ability to amplify
the genes that would impart resistance to the cytostatic agent.16 Because Devane
and Fahrig address patient tolerance in different ways, Elan contends that a person
of ordinary skill in the art would not have seen a reason to combine their respective
teachings. Elan characterizes the examiner's rejection as "to select the cytostatic
agent, bicalutamide, from Fahrig and formulate it according to Devane because
Devane generally teaches that its formulation approach is suitable for anti-
neoplastic agents."17 Elan contends that the simple possibility of substituting a
different agent into a known formulation is not enough to make out a prima facie
case of obviousness.18
In its reply, Elan clarifies that the question is not whether bicalutamide is an
antineoplastic agent, but rather whether it requires the sort of "wash-out period"
that Devane is targeting.19 The relevant portion of Devane states:
Any active ingredient for which it is useful to combine the advantages
of a pulsatile plasma profile with a reduced frequency dosage regime
may be used in practice of the present invention. Particularly useful in
the practice of the invention include active ingredients whose
pharmacological and/or therapeutic effects benefit from having a
wash-out period between plasma concentration peaks, such as those
active ingredients susceptible to the development of patient tolerance.

16 Br. 12, citing Fahrig 1:23-40.
17 Br. 12-13.
18 Br. 13-14, citing KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
19 Reply 12-13, citing Devane 6:13-21.
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Analysis
Elan argues that a person having ordinary skill in the art would not have
seen a reason to modify the Devane method by using bicalutamide as the active
agent, but provides no evidence beyond the references themselves.20 While the
references both address patient tolerance, they do so in different ways. Fahrig
identifies bicalutamide as appropriate in its method and explains that its method is
driven by the ability of some tumors to amplify genes in tumor cells that eliminate
the active agent by, for example, producing proteins that remove the active agent
from cells. Fahrig attacks the problem by co-administering an agent to impede
gene amplification, but cancer researchers are astute and would appreciate that
keeping the dosing out of phase with gene amplification (dosing in pulses so that
no dosing is occurring when gene amplification is occurring, but dosing resumes
when amplification wanes again) would also be a promising approach. Indeed,
Devane teaches that pulsatile dosing is well-established and simply assumes the
reader knows why a pulsatile approach works to avoid tolerance, instead focusing
on avoiding inadvertently constant plasma levels despite periodic dosing.21 Hence,
the examiner's finding that the combination of references suggests substitution of
one of Fahrig's active agents into Devane's method and composition is consistent
with Devane's broad teachings and suggestions.
By contrast, Elan's argument is inconsistent with the obvious-to-try approach
endorsed in KSR.22 The agents that Devane lists as examples of agents benefiting
from a wash-out period include not just antineoplastics, but also hormone

20 See Monolithic Power Sys., Inc. v. O2 Micro Int'l Ltd., 558 F.3d 1341, 1350
(Fed. Cir. 2009) (explaining attorney argument is not evidence).
21 Devane 1:41-53 and 6:13-63.
22 550 U.S. at 421.
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analogues. 23 For androgen-sensitive tumors, bicalutamide would qualify in both
categories. A cancer researcher of ordinary skill would, more likely than not, have
expected a known chemotherapy agent at the intersection of two of Devane's
categories of agent benefiting from a wash-out period to be a good candidate for
Devane's approach. Elan has not identified any reason in evidence why, despite
the strong suggestion in Devane, a cancer researcher would nevertheless have
doubted the applicability of Devane to acylanilides generally and to bicalutamide
specifically.
The examiner committed no prejudicial error in applying combined
teachings and suggestions of the Devane and Fahrig patents to the subject matter of
claim 1 and in concluding that the claimed subject matter would have been obvious
to those of skill in the art.
OBVIOUSNESS: CLAIMS 3 AND 4
Elan presents separate argument for claims 3 and 4 as a group.24 Claim 4
depends from claim 3 (which depends from claim 2, which depends from claim 1).
Claim 3 adds the limitation "wherein the first and subsequent components
comprise bicalutamide nanoparticles." Claim 4 further adds "wherein said
nanoparticles have an effective average particle size of less than 2000 nm."25 We
note that 1000 nm equals 1micrometer (μm) or micron. Hence, Elan's use of
nanoparticle is broad enough to include microparticles up to something less than
2 microns.

23 Devane 6:13-63.
24 Br. 15.
25 Br. 19.
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The examiner identified the lack of a nanoparticle teaching as a difference
from Devane and Fahrig. The examiner relied on Siles Ortega for a teaching of
bicalutamide in microparticles.26 Siles Ortega explains that
bicalutamide is normally formulated into a pharmaceutical
composition as solid particles, typically having an average particle
size of 0.1 to 100 microns, more typically 1 to 50 microns.

Siles Ortega goes on to prefer ranges at the lower end, although the more preferred
range is 2 to 8 microns,27 which is just outside the range of claim 4.
Elan relies on the arguments advanced unsuccessfully for claim 1, but also
argues the Siles Ortega publication cannot be combined with the teachings of
Devane because Siles Ortega teaches rapid of bicalutamide rather than a pulsatile
delayed release.28
Given the teaching that bicalutamide is normally used in particles within the
scope of claim 4, the examiner's conclusion of obviousness seems warranted.
Elan's argument that Devane and Siles Ortega are incompatible is misplaced
because the putative contradiction in the methods (rapid release versus pulsatile
delayed release) is not really a contradiction. Devane wants distinct dosing peaks
rather than an inadvertent smoothing of the dosage release. Thus, while Devane
teaches delays in releasing the active agent, once it is released, a rapid release
would actually further Devane's goal of producing distinct pulses.
The examiner committed no prejudicial error in finding that a person having
ordinary skill in the art would have known to use bicalutamide in one of its normal
formulations and thus concluding that its use would have been obvious.

26 Final Rej. 7, citing Siles Ortega 6:11-13. We note that Devane's title is "
Microparticulate modified release composition".
27 Siles Ortega 6:7-15.
28 Br. 15, citing Siles Ortega 13:3-5.
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DOUBLE PATENTING
In view of our decision on obviousness, we do not reach the obviousness-
type double-patenting ground of rejection.29
HOLDING
The examiner's rejection of claims 1-4, 6, 8-17 and 19-22 is—
AFFIRMED

KMF

For the appellant:
SARAH KLOSEK
Fox Rothschild LLP
997 Lenox Drive, Building 3
Lawrenceville, New Jersey 08648-2311

For the Commissioner of Patents:
CASEY HAGOPIAN with FEREYDOUN G. SAJJADI , Art Unit 1617,
and ROBERT A. WAX, Art Unit 1615, of Alexandria, Virginia

29 In re Sullivan, 362 F.3d 1324, 1327 (Fed. Cir. 2004) (affirming board discretion,
where one issue is dispositive, not to reach a second issue).