Ex Parte Hovey et al

Board of Patent Appeals and Interferences

Feb 13, 2012

11093149 (B.P.A.I. Feb. 13, 2012)

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.
11/093,149 03/30/2005 Douglas Hovey 029318-1084 5740
31049 7590 02/13/2012
Elan Drug Delivery, Inc. c/o Foley & Lardner
3000 K Street, N.W.
Suite 500
Washington, DC 20007-5109
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
MAIL DATE DELIVERY MODE
02/13/2012 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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DOUGLAS HOVEY, JOHN PRUITT, and
TUULA RYDE
__________

Appeal 2011-007658
Application 11/093,149
Technology Center 1600
__________

Before DONALD E. ADAMS, ERIC GRIMES, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
pharmaceutical composition, which the Examiner has rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
“Megestrol acetate . . . is a synthetic progestin with progestational
effects similar to those of progesterone. . . . Megestrol acetate is also
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frequently prescribed as an appetite enhancer for patients in a wasting state,
such as HIV wasting, cancer wasting, or anorexia.” (Spec. 5, ¶ 7.)
Claims 113-131 are on appeal. The claims have not been argued
separately and therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii).
Claim 113 is representative and reads as follows:
113. A megestrol acetate composition comprising:
(a) particles of megestrol acetate having an effective average particle
size of less than about 2000 nm; and
(b) adsorbed on or associated with the surface thereof a first surface
stabilizer selected from the group consisting of hydroxypropylcellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, and a random
copolymer of vinyl acetate and vinyl pyrrolidone, and a second surface
stabilizer selected from the group consisting of dioctylsulfosuccinate and
sodium lauryl sulfate.

All of the claims on appeal stand rejected under 35 U.S.C. § 103(a)
based on: Brubaker,1 Liversidge ‘989,2 Jain,3 Wood,4 and Liversidge ‘2155
(Answer 4); Liversidge ‘215 alone (Answer 6); and Jain and Liversidge ‘215
(Answer 7).
In addition, claims 126-130 stand rejected under 35 U.S.C. § 103(a)
based on any of the above, and Bell6 or McKearn7 (Answer 9).

1 Brubaker et al., Patent Application Publication US 2002/0028794 A1,
Mar. 7, 2002
2 Liversidge et al., US 6,267,989 B1, July 31, 2001
3 Jain et al., US 6,316,029 B1, Nov. 13, 2001
4 Wood et al., US 6,264,922 B1, July 24, 2001
5 Liversidge et al., EP 0 577 215 B1, Mar. 22, 2000
6 Bell, US 6,165,504, Dec. 26, 2000
7 McKearn et al., US 6,833,373 B1, Dec. 21, 2004
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Issues
The Examiner has rejected all of the claims on appeal based on prior
art that, in every rejection, includes Liversidge ‘215. Because we conclude
that the disclosure of Liversidge ‘215, by itself, supports a prima facie case
of obviousness with respect to claim 113, and Appellants have not separately
argued the rejected claims, we will not discuss the additional references with
respect to the prima facie case.
The Examiner finds that Liversidge ‘215 teaches “particles of
crystalline anticancer drugs having a surface modifier adsorbed on the
surface in an amount to maintain an effective average particle size of less
than about 1000 nm. . . . One of the drugs taught . . . is megestrol acetate.”
(Answer 7.) The Examiner also finds that the surface modifiers taught by
Liversidge ‘215 “include claimed modifiers by themselves or in
combination” (id.). The Examiner concludes that the composition of claim
113 would have been obvious based on Liversidge ‘215 (id.).
Appellants contend that Liversidge ‘215 teaches a variety of
anticancer agents and does not indicate that megestrol acetate is preferred
(Appeal Br. 19). Appellants also argue that they have shown that the
claimed composition is unexpectedly stable to aggregation (id. at 14-15) and
unexpectedly reduces “fed/fasted variability” or a “food effect” (id. at 15-
17).
The issues presented are: Does Liversidge ‘215 support a prima facie
case of obviousness?
And, have Appellants provided evidence of unexpected results that
outweighs the evidence supporting the prima facie case of obviousness?
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Findings of Fact – Prima facie obviousness
1. Liversidge ‘215 discloses “[a]nticancer compositions comprising
anticancer agents in the form of surface modified nanoparticles . . . [that]
exhibit reduced toxicity and/or enhanced efficacy” (Liversidge ‘215, ¶ 58).
2. Liversidge ‘215 discloses that its particles “hav[e] a surface
modifier adsorbed on the surface thereof in an amount sufficient to maintain
an effective average particle size of less than 400 nm” (id. at ¶ 6).
3. Liversidge ‘215 discloses that “[p]articularly preferred surface
modifiers include PVP [polyvinylpyrrolidone; see id. at ¶ 20], tyloxapol,
polaxomers . . . and poloxamines . . . , dextran, lecithin, Aerosol OTTM
(AOT), which is a dioctyl ester of sodium sulfosuccinic acid, available from
American Cyanamid, DuponolTM P, which is a sodium lauryl sulfate,
available from DuPont,” etc. (id. at ¶ 21).
4. Liversidge ‘215 discloses that “[t]wo or more surface modifiers
can be used in combination” (id. at ¶ 20).
5. Liversidge ‘215 discloses that its particles can include megesterol
acetate (id. at claim 1).
Analysis – Prima facie obviousness
Liversidge ‘215 discloses particles, which can include megestrol
acetate, having an effective particle size of less than 400 nm. Liversidge
‘215 discloses that its particles include a surface modifier, that two or more
surface modifiers can be combined, and that particularly preferred surface
modifiers include sodium lauryl sulfate and polyvinylpyrrolidone. We agree

8 The record copy of Liversidge ‘215 does not include page numbers.
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with the Examiner that, based on these teachings, the composition of claim
113 would have been prima facie obvious. Specifically, it would have been
obvious to choose megestrol acetate from among the anticancer agents that
are expressly suggested by Liversidge ‘215, and it would have been obvious
to choose sodium lauryl sulfate and polyvinylpyrrolidone as surface
modifiers because Liversidge ‘215 discloses that they are particularly
preferred and expressly suggests using two or more surface modifiers in
combination.
Appellants argue that Liversidge ‘215 does not “teach or suggest that
megestrol acetate is somehow preferred among the other pharmaceutical
agents” and that it would be chosen only with the benefit of hindsight
(Appeal Br. 19).
This argument is unpersuasive, because Liversidge ‘215 expressly
suggests including megestrol acetate in its particles. The fact that it suggests
that other anticancer agents would also be appropriate to use in its particles
does not make the selection of megestrol acetate any less obvious.
Appellants also argue that there is no motivation to combine
Liversidge ‘215 with Brubaker (Appeal Br. 19-20), but the Examiner has
rejected all of the claims based on Liversidge ‘215 alone, and no
combination with Brubaker is required to render the claims obvious.
Finally, Appellants argue that the claimed combination of megestrol
acetate and the recited surface stabilizers provides unexpected results with
respect to stability against aggregation and increased absorption in patients
under fasting conditions. We therefore turn to the evidence of unexpected
results.
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Findings of Fact – Unexpected results
6. The Specification discloses that “not every combination of surface
stabilizer and active agent will result in a stable nanoparticulate composition.
It was surprisingly discovered that stable nanoparticulate megestrol
compositions can be made.” (Spec. 9, ¶ 16.)
7. The Specification’s Example 2 “compares the pharmacokinetic
parameters of nanoparticulate megestrol acetate formulations of the present
invention with conventional microparticulate formulations of megestrol
acetate” (id. at 44, ¶ 147).
8. The inventive formulations of Example 2 include megestrol acetate
and either HPMC and DOSS (Formulation A) or HPMC and SLS
(Formulation B) (id. at 44, ¶ 149). HPMC is hydroxypropyl methyl-
cellulose, DOSS is dioctyl sodium sulfosuccinate, SLS is sodium lauryl
sulfate (see id. at 9, ¶ 17).
9. The comparative formulations of Example 2 are “Formulation C
(suspension of microparticulate megestrol acetate, Par Pharmaceutical, Inc.
New York) [and] Formulation D (Megace® Oral Suspension, which is a
suspension of microparticulate megestrol acetate)” (id.).
10. The Specification discloses “pharmacokinetic data of the four
formulations administered to fasted dogs and fed dogs, respectively” (id. at
45, ¶ 151).
11. The Specification states that Formulations A and B showed
“dramatically superior bioavailability” in both fed and fasted dogs “as
compared to the conventional microparticulate megestrol formulations
(Formulations C and D)” (id. at 46, ¶¶ 152, 154).
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12. The Specification’s Example 7 compares the stability of
nanoparticulate compositions of megestrol acetate with various surface
stabilizers (id. at 51, ¶ 173; 52, ¶ 178).
13. The Specification states that “[t]he HPC-SL [hydroxypropyl-
cellulose; see id. at 50, ¶ 168] formulation (Exp. No. 8) showed substantial
aggregation indicating that a secondary charged stabilizer would be needed.
SLS was added. . . . The SLS appeared effective at preventing the
aggregation but the sample showed some particle size growth.” (Id. at 55,
¶ 182.)
14. The Specification states that “[t]he HPMC formulation (Exp. No.
7) showed substantial aggregation indicating that a secondary charged
stabilizer would be needed. SLS was added. . . . The SLS was effective at
preventing the aggregation without causing significant crystal growth.” (Id.
at 55, ¶ 183.)
15. Appellants have provided a declaration under 37 C.F.R. § 1.132
of Tuula Ryde (dated June 5, 2009).
16. The Ryde Declaration reproduces the data shown in the
Specification’s Table 8 (rearranged and presented as Table 1 in the
declaration) (Ryde Declaration, ¶ 3) and the Specification’s Tables 2 and 3
(see Ryde Declaration, ¶ 17).
17. Dr. Ryde concludes that the data “demonstrate the superior
physical stability and bioavailability of nanoparticulate megestrol
compositions” (id. at ¶ 15).
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18. Wood discloses “an aerosol comprising droplets of an aqueous
dispersion of nanoparticles . . . having a surface modifier on the surface
thereof” (Wood, col. 2, ll. 18-21).
19. Wood discloses that “[p]articularly preferred auxiliary surface
modifiers are those which impart resistance to particle aggregation during
sterilization and include dioctylsulfosuccinate (DOSS), polyethylene glycol,
glycerol, sodium dodecyl sulfate,” etc. (id. at col. 6, ll. 8-11).
20. The Examiner finds that sodium dodecyl sulfate is another name
for sodium lauryl sulfate (Answer 5). Appellants do not dispute this finding.
21. Liversidge ‘989 discloses that “[n]anoparticulate compositions
are superior to macro-sized particulate drug formulations, as nanoparticulate
drug formulations can exhibit . . . enhanced bioavailability” (Liversidge
‘989, col. 1, ll. 19-23).
22. Liversidge ‘989 discloses that, “for oral formulations, the
presence of crystals and/or particle aggregation, and therefore varying
particle sizes, creates a variable bioavailability profile because smaller
particles dissolve faster than the larger aggregates or larger crystal particles.
For drugs whose bioavailability is dissolution-rate limited, a faster rate of
dissolution is associated with greater bioavailability.” (Id. at col. 1,
ll. 49-53.)
Analysis – Unexpected results
Appellants argue that the results shown in the Specification,
demonstrating that the claimed compositions are stable against aggregation
and show a reduced food effect, were unexpected and are evidence of
nonobviousness (Appeal Br. 14-17, 21).
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We are not persuaded. The Specification and Ryde Declaration do
show that using a combination of either HPC or HPMC with either SLS or
DOSS as surface stabilizers generates nanoparticles that are more stable to
aggregation than using HPC or HPMC alone (Spec. 53-54; Ryde
Declaration, ¶ 3). The evidence of record, however, does not show that this
result was unexpected.
Although the Specification states that “[i]t was surprisingly
discovered that stable nanoparticulate megestrol compositions can be made”
(FF 6), the only basis presented for this statement is that “not every
combination of surface stabilizer and active agent will result in a stable
nanoparticulate composition” (id.), which is not an adequate basis for
concluding that the properties of the specific combination of surface
stabilizers recited in the claims were unexpected.
Notably, Dr. Ryde does not characterize the Specification’s data as
unexpected (see FF 17), and the Specification itself suggests that the effect
of adding SLS to HPC or to HPMC was predictable. That is, the
Specification states that the failure of HPC or HPMC alone to stabilize the
nanoparticles “indicat[ed] that a secondary charged stabilizer would be
needed” (FFs 13, 14), and therefore SLS was added (id.). This is supported
by Wood’s disclosure that both DOSS and SLS (a.k.a. sodium dodecyl
sulfate; FF 20) were known to “impart resistance to particle aggregation
during sterilization” (FF 19). Thus, the evidence of record, as a whole, does
not support Appellants’ argument that the nanoparticles in the claimed
compositions are unexpectedly stable to aggregation.
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The same is true of Appellants’ argument that the claimed
compositions have an unexpectedly reduced food effect. While the
Specification states that nanoparticulate compositions showed “dramatically
superior bioavailability” in both fasted and fed dogs (FF 11), compared to
“conventional microparticulate megestrol formulations” (id.), neither the
Specification nor the Ryde Declaration characterize this result as surprising
or unexpected.
The evidence of record, in fact, shows that increased bioavailability
would have been expected. Liversidge ‘989 expressly states that
nanoparticulate formulations “can exhibit . . . enhanced bioavailability”
relative to “macro-sized drug formulations” (FF 21). Liversidge ‘989 also
discloses that particle aggregation in oral formulations creates variable
bioavailability because smaller particles dissolve faster and provide greater
bioavailability (FF 22).
Thus, a formulation of nanoparticles that is stable to aggregation
would have been expected to provide high bioavailability. This is especially
true if the comparative formulations included larger particles than those in
the inventive formulations, which appears to be the case here: the
Specification does not disclose the size of the particles in comparative
Formulations C and D, but characterizes them as suspensions of
“microparticulate” megestrol acetate. A microparticulate composition (like
the comparative formulations) implies particles in the micrometer size range,
whereas a nanoparticulate composition (like the inventive formulations)
implies particles in the nanometer size range; in other words, nanoparticles
are much smaller than microparticles. In view of the disclosure of
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Liversidge ‘989 that smaller particles provide greater bioavailability, the
Specification’s results showing superior bioavailability for nanoparticulate
formulations compared to microparticulate formulations seems to be
precisely what would have been expected.
“[T]he burden of showing unexpected results rests on he who asserts
them. Thus it is not enough to show that results are obtained which differ
from those obtained in the prior art: that difference must be shown to be an
unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
Appellants have not carried this burden because they have not shown that
the properties that are relied on to rebut the Examiner’s rejections were
unexpected.
SUMMARY
Because Liversidge ‘215 supports a prima facie case of obviousness,
and Appellants have not provided adequate evidence to rebut the prima facie
case, we affirm the rejection of claims 113-131 based on Brubaker,
Liversidge ‘989, Jain, Wood, and Liversidge ‘215; the rejection of claims
113-131 based on Liversidge ‘215 alone; and the rejection of claims 113-131
based on Jain and Liversidge ‘215.
Because Appellants have waived any argument based on Baker or
McKearn, we also affirm the rejection of claims 126-130 based on any of the
above, plus Bell or McKearn.
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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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