Ex Parte Weers et al

Board of Patent Appeals and Interferences

Sep 29, 2010

10982191 (B.P.A.I. Sep. 29, 2010)

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.
10/982,191 11/04/2004 Jeffry G. Weers 53321-US-CNT 7025
1095 7590 09/29/2010
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 101/2
EAST HANOVER, NJ 07936-1080
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
MAIL DATE DELIVERY MODE
09/29/2010 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 JEFFRY G. WEERS, THOMAS TARARA,
and STELIOS TZANNIS
__________

Appeal 2010-005999
Application 10/982,191
Technology Center 1600
__________

Before CAROL A. SPIEGEL, TONI R. SCHEINER, and STEPHEN WALSH,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a
formulation for pulmonary administration. The claims have been rejected as
obvious and non-enabled. We have jurisdiction under 35 U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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STATEMENT OF THE CASE
The present invention is directed to a storage-stable “dry powder
pharmaceutical formulation that spontaneously encapsulates an active agent
when delivered to the lungs of a user” (Spec. 3: 26-28).
“The pharmaceutical formulation has a gel (or solid) to liquid phase
transition temperature in the hydrated state that is sufficiently low that the
pharmaceutical formulation is in a liquid state after it is deposited in the
fluid lining of the lungs” (id. at 6: 27-29). That is, “[i]n order for the
pharmaceutical formulation to be in liquid state in the lungs of a human, . . .
[it] will have a liquid phase transition temperature in the hydrated state of
less than or equal to 37°C. By being in the liquid state, the lipid molecules
. . . spontaneously reassemble to form liposomes” (id.at 6: 29 to 7: 2),
thereby encapsulating the active agent, and “increas[ing] the amount of time
the active agent is retained in the lungs” (id. at 7: 5-11).
In addition, “[t]he stability of the pharmaceutical formulation . . . can
be improved by increasing its liquid transition temperature in the ambient
[non-hydrated] environment” to greater than 37°C. “By making the non-
hydrated liquid transition temperature higher [than 37°C], the
pharmaceutical formulation can be used in an ambient environment with less
need for refrigeration and can be stored at room temperature for a longer
period of time” (id. at 8: 4-14).
“The storage stability of the pharmaceutical formulation can be
further enhanced by increasing the difference between the hydrated liquid
transition temperature . . . and the non-hydrated liquid transition temperature
. . . [so that] the non-hydrated liquid transition temperature is at least 20°C
higher than the hydrated liquid transition temperature” (id. at 8: 18-22).
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Claims 1-40 and 55-58 are pending and on appeal. Claims 1, 40, 55,
and 57 are representative:
1. A pharmaceutical formulation for pulmonary administration,
the pharmaceutical formulation comprising:
a lipid component; and
an active agent;
wherein the pharmaceutical formulation has a liquid phase transition
temperature of less than or equal to 37°C when hydrated and a liquid phase
transition temperature of greater than 57°C when non-hydrated, whereby the
lipid component spontaneously encapsulates and/or entraps the active agent
when the pharmaceutical formulation is administered to the lungs.

40. A pharmaceutical formulation for pulmonary administration,
the pharmaceutical formulation comprising:
a lipid component;
ciprofloxacin; and
a targeting agent,
wherein the pharmaceutical formulation has a liquid phase transition
temperature of less than or equal to 37°C when hydrated, whereby the lipid
component spontaneously encapsulates and/or entraps the active agent when
the pharmaceutical formulation is administered to the lungs.

55. A pharmaceutical formulation for pulmonary administration,
the pharmaceutical formulation comprising:
a lipid component; and
ciprofloxacin;
wherein the pharmaceutical formulation has a liquid phase transition
temperature of less than or equal to 37°C when hydrated, whereby the lipid
component spontaneously encapsulates and/or entraps the active agent when
the pharmaceutical formulation is administered to the lungs.

57. A pharmaceutical formulation for pulmonary administration,
the pharmaceutical formulation comprising:
a lipid component;
an active agent; and
a targeting agent,
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wherein the pharmaceutical formulation has a liquid phase transition
temperature of less than or equal to 37°C when hydrated, whereby the lipid
component spontaneously encapsulates and/or entraps the active agent when
the pharmaceutical formulation is administered to the lungs.

The Examiner rejected the claims as follows:
claims 1-40 and 55-58 under 35 U.S.C. § 112, first paragraph, as
lacking enablement;
claims 1-6, 9, 11, 13-15, 19-39, and 55-56 under 35 U.S.C. § 102(b)
as anticipated by Weers I 2 or Weers II;3
claims 1-40 and 55-58 under 35 U.S.C. § 103(a) as unpatentable over
Byström,4 Weers I, and Weers II; and
claims 1-40 and 55-58 under the doctrine of obviousness-type double
patenting as unpatentable over claims 1-21 of U.S. Patent 7,393,544.5
We reverse the enablement and anticipation rejections; and affirm the
obviousness rejection with respect to claims 40 and 55-58, but reverse it
with respect to claims 1-39. We do not reach the obviousness-type double
patenting rejection.
FINDINGS OF FACT (FF)
1. According to the Specification, a hydrated environment is “an
environment having at least 90% relative humidity,” while a non-hydrated
environment is one “having less than 30% relative humidity” (Spec. 8: 15-
16).

2 International Application WO 01/85136 A2 of Jeffry G. Weers et al,
published November 15, 2001.
3 U.S. Application US 2002/0037316 A1 of Jeffry G. Weers et al.,
published March 28, 2002.
4 U.S. Patent 6,045,828, issued April 4, 2000 to Katarina Byström et al.
5 U.S. Patent 7,393,544, issued July 1, 2008 to Luis A. Dellamary et al.
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2. The Specification teaches that “[t]he transition temperature
properties of the pharmaceutical formulation may be tailored . . . by proper
selection of the lipid component and/or by mixing lipid components” (Spec.
9: 1-3). “Many phospholipids have a hydrated liquid crystal phase transition
temperature less than or equal to 37°C . . . such as dimyristoylphosphatidyl-
choline (DMPC) which has a hydrated liquid transition temperature of
23.5°C” (id. at 9: 4-8). In addition, the Specification lists a number of other
phospholipids having hydrated liquid transition temperatures of less than
37°C (id. at 9: 8-14).
3. The Specification also teaches that “the lipid component of the
pharmaceutical formulation may comprise a mixture of phospholipids in
order to provide desirable transition temperature characteristics” (Spec. 9:
16-18). A phospholipid having a hydrated liquid transition temperature well
below 37°C may be combined with a phospholipid having a hydrated liquid
transition temperature above 37°C “in a ratio that results in a phospholipid
mixture having a hydrated liquid transition temperature that is 37°C or is just
below 37°C” (id. at 9: 23-24). For example, DMPC can be combined with
dipalmitoylphosphatidylcholine (DPPC) which has a hydrated liquid
transition temperature of 42°C (id. at 9: 25-26). In addition, the
Specification lists a number of other long-chain phospholipids with hydrated
liquid transition temperature above 37ºC (id. at 9: 29 to 10: 2).
4. The Specification teaches that the pharmaceutical formulation
“may also comprise added salts that can impact the hydrated and/or the non-
hydrated liquid transition temperature . . . For example, one or more
polyvalent cations may be added to the pharmaceutical formulation to
increase the non-hydrated liquid transition temperature” (Spec. 11: 20-23).
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In one version, the pharmaceutical formulation comprises
a polyvalent cation that is a divalent cation, such as one or more
of calcium, magnesium, zinc, iron, and the like. The polyvalent
cation may be present in an amount effective to increase the
non-hydrated liquid transition temperature of the phospholipid
such that the particulate composition exhibits a liquid transition
temperature which is greater than its storage temperature by at
least 20°C, preferably at least 40°C. The molar ratio of
polyvalent cation to phospholipid should be at least 0.05,
preferably 0.05-2.0, and most preferably 0.25-1.0.
(Id. at 12: 1-7.)
5. The Specification describes pharmaceutical formulations
wherein the lipid component comprises a mixture of a phospholipids and a
polyvalent cation.
For example, the lipid component may comprise a mixture of
DMPC and DPPC in an amount sufficient to provide a hydrated
liquid transition temperature of just below 37°C, and . . . may
further comprise calcium chloride in a sufficient amount to
raise the non-hydrated liquid transition temperature to at least
80°C, more preferably to at least 90°C. In one version, the lipid
component may comprise from 20% to 50% DMPC and from
50% to 80% DPPC, and the calcium may be present in a molar
ratio of calcium to phospholipids of about 0.5.
(Spec. 12: 15-22.)
6. Weers I discloses “dry powder compositions of phospholipid
suitable for drug delivery” in which “polyvalent cations, preferably divalent
cations, [are used] to dramatically increase the Tm [gel to liquid transition
temperature] of the phospholipids” (Weers I 4: 1-2, 15-16).6

6 The disclosure of Weers II is essentially the same as that of Weers I, so we
will confine our discussion to Weers I.
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7. According to Weers I, increasing the Tm “allow[s] for a large
difference between Tm and the storage temperature, thereby improving
powder stability” and also “yield[s] phospholipids which are able to spread
more effectively upon contact with lung epithelia than hydrated
phospholipids, thereby allowing drugs to be more effectively distributed to
the lung periphery” (Weers I 4: 23-28).
8. The compositions disclosed by Weers I “exhibit a characteristic
gel to liquid crystal phase transition temperature, Tm, which is greater than a
recommended storage temperature, Ts, typically room temperature, by at
least 20°C. Preferably Tm is at least 40°C greater than Ts” (Weers I 5: 2-5).
9. Weers I teaches that suitable phospholipids “comprise those
that have gel to liquid crystal phase transition greater than about 40°C.
Preferably the incorporated phosphlipids are relatively long chain (i.e., C16-
C22) saturated lipids . . . such as dipalmitoylphosphatidylcholine [DPPC]”
(Weers I 9: 22-28).
10. Weers I discloses ciprofloxacin as an active agent suitable for
pulmonary delivery (Weers I 6: 31).
11. Byström discloses “a proliposome powder . . . comprising in a
single phase discrete particles of a biologically active component together
with a lipid or mixture of lipids having a phase transition temperature (Tc) of
below 37ºC” (Byström, col. 2, ll. 27-31).
12. Byström teaches that the powder “can be inhaled directly and in
situ, for example in the upper or lower respiratory system, will form
liposomes in which [the] biologically active component is totally
incorporated” (Byström, col. 2, ll. 43-46).
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13. According to Byström, “[t]he lipid or lipid mixture must have a
phase-transition temperature below body temperature (37ºC) in order for
th[e] product proliposome powder to be . . . able to form liposomes in the
respiratory system” (Byström, col. 2, ll. 49-54).
14. Byström teaches that mixtures of lipids with phase-transition
temperatures below 37ºC include mixtures of DPPC/DMPC, as well as
mixtures of phosphatidylcholine/phosphatidylserine/cholesterol (Byström,
col. 3, ll. 10-12).
15. Byström also teaches that suitable active components include
antibiotics (Byström, col. 3, ll. 40-49).
16. According to the present Specification, phosphatidylserine,
(which may be part of the lipid component of the claimed formulations) also
serves as a “targeting agent” (Spec. 11: 10; 16: 17).

ENABLEMENT
[A] specification disclosure which contains a teaching of the
manner and process of making and using the invention in terms
which correspond in scope to those used in describing and
defining the subject matter sought to be patented must be taken
as in compliance with the enabling requirement of the first
paragraph of § 112 unless there is reason to doubt the objective
truth of the statements contained therein which must be relied
on for enabling support.
In re Marzocchi, 439 F.2d 220, 223 (CCPA 1971).
[It] is incumbent upon the Patent Office, whenever a rejection
on this basis is made, to explain why it doubts the truth or
accuracy of any statement in a supporting disclosure and to
back up assertions of its own with acceptable evidence or
reasoning which is inconsistent with the contested statement.
Id. at 224.
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In other words, “the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of protection
provided by that claim is not adequately enabled by the description of the
invention . . . this includes, of course, providing sufficient reasons for
doubting any assertions in the specification as to the scope of enablement.”
In re Wright, 999 F.2d 1557, 1561-1562 (Fed. Cir. 1993).
Discussion
The Examiner rejected claims 1-40 and 55-58 under the first
paragraph of section 112 because the Specification “does not reasonably
provide enablement for generic ‘pharmaceutical formulation having a liquid
phase transition temperature of less than equal to 37 degrees when hydrated
and a liquid phase transition temperature greater than [ ]57 degrees when
non-hydrated’” (Ans. 3).
The issue raised by this rejection is whether the Examiner has met the
initial burden of providing sufficient reason to doubt that the Specification is
enabling for a pharmaceutical formulation having a liquid phase transition
temperature of less than or equal to 37°C when hydrated and greater than
57°C when non-hydrated.
According to the Examiner, “the temperature at which [a] lipid
changes its state (from solid to liquid) . . . is an inherent property and would
not change whether the lipid is hydrated or not hydrated” (Ans. 3). In
addition, the Examiner found that the Specification “does not provide any
specific examples showing a specific phospholipid or phospholipid
combination and the divalent cations hav[ing] the desired function” (id. at
4). In consequence, the Examiner found that “[o]ne of ordinary skill in the
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art would not be able to prepare a composition which has desired claimed
characteristics . . . without undue experimentation” (id. at 4).
The Examiner has not provided sufficient reason to doubt that the
Specification is enabling for the claimed invention. First, the Examiner cited
Bramhall7 as evidence that the liquid transition temperature of a lipid is the
same whether it’s hydrated or not - but the reference doesn’t support the
Examiner’s assertion. It merely reports that the liquid transition temperature
of DPPC is 41ºC, which is consistent with the liquid transition temperature
reported for hydrated DPPC in the Specification (FF3). In any case, in
response to the Examiner’s assertion, Appellants submitted evidence directly
refuting the Examiner’s assertion. For example, Pfeiffer8 provides evidence
that “[i]t is widely known that dehydration increases the main phase
transition temperature of phospholipids” and “the dehydration-induced shift
of the phase transition temperature” can even be used to calculate hydration
pressure (Pfeiffer, Abstract).
Second, the Specification provides explicit guidance for tailoring the
liquid transition temperature of the lipid component of the formulation under
both hydrated (e.g., in the respiratory system) and non-hydrated (e.g.,
storage) conditions (FF2-5). The Examiner’s apparent requirement for
working examples is overly stringent, and not in keeping with the state of
the law, particularly as the only reason given for doubting the objective truth
of the Specification’s disclosure is not supported by the evidence of record.

7 U.S. patent 4,825,447, issued April 25, 1989 to Bramhall, see col. 5, ll.28-
29.
8 H. Pfeiffer et al, Hydration pressure and phase transitions of
phospholipids: II. Thermotropic approach, 1609 BIOCHIMICA ET BIOPHYSICA
ACTA 148-152 (2003) (Abstract only).
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Conclusion
The Examiner has not met the initial burden of providing sufficient
reason to doubt that the Specification is enabling for a pharmaceutical
formulation having a liquid phase transition temperature of less than or equal
to 37°C when hydrated and greater than 57°C when non-hydrated.
We will reverse the rejection of claims 1-40 and 55-58 under the first
paragraph of 35 U.S.C. § 112 for lack of enablement.

ANTICIPATION
Discussion
The Examiner rejected claims 1-6, 9, 11, 13-15, 19-39, and 55-56 as
anticipated by Weers I or Weers II, and the issue raised by this rejection is
whether either reference9 discloses a pharmaceutical formulation comprising
a lipid component with a liquid phase transition temperature less than or
equal to 37°C when hydrated, the minimal requirement of all the claims
rejected on this ground.
The Examiner finds that Weers I discloses “particulate preparations
containing an active agent, phospholipid and a polyvalent cation in an
amount which increases the gel-to-liquid transition temperature of the
particle compared to particles without the polyvalent cations” (Ans. 4). The
Examiner further finds that “[t]he phospholipids include [the] instantly
claimed dipalmitoylphosphatidylcholine [DPPC]” (Ans. 4), and “since it is
the same composition, one would expect similar properties and applicant has
not shown that instant composition is different” (id. at 10).

9 As discussed above, the disclosures of these two references are essentially
the same, so we will confine our discussion to Weers I.
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Nevertheless, the Examiner has overlooked the fact that DPPC, on its
own, has a liquid phase transition temperature when hydrated of 42°C (FF3),
and the fact that Weers I discloses pharmaceutical formulations where the
lipid component has a liquid phase transition temperature greater than about
40ºC and/or at least 20ºC greater than typical room temperature (FF8, 9).
Weers I doesn’t explicitly say that “greater than about 40ºC” refers to the
hydrated liquid transition temperature. But Weers I does disclose that DPPC
and other long chain phospholipids are suitable for the formulations, and the
evidence of record establishes that these phospholipids have liquid transition
temperatures above 37ºC in the hydrated state (e.g., DPPC’s is 42ºC) (FF3).
It is true that DPPC is disclosed in the present Specification as
suitable for formulations with a lipid component having a hydrated liquid
transition temperature of less than or equal to 37ºC - but only when tailored
according to the methods disclosed (e.g., by mixing it with a phospholipid
with a hydrated liquid transition temperature below 37ºC) (FF3).
We agree with Appellants that the Examiner has not shown that
Weers I discloses “a mixture of phospholipids or other alteration that has a
liquid phase transition temperature of less than or equal to 37ºC when
hydrated” (Reply Br. 5).
Conclusion
The Examiner has not established that either Weers I or Weers II
discloses a pharmaceutical formulation comprising a lipid component with a
liquid phase transition temperature less than or equal to 37°C when
hydrated.

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OBVIOUSNESS
Discussion
The Examiner rejected claims 1-40 and 55-58 as unpatentable over
Byström in view of Weers I or Weers II. Again, all of the claims subject to
this rejection are directed to a formulation comprising a lipid component
with a liquid phase transition temperature less than or equal to 37°C when
hydrated.
Claims 1-39
In addition to requiring a lipid component with a hydrated liquid
phase transition temperature less than or equal to 37°C, claims 1-39
additionally require the lipid component to have a liquid phase transition
temperature greater than 57°C when non-hydrated. The Examiner has not
established that any one of the references relied on discloses this limitation,
or otherwise explained how or why one would combine the teachings of the
references to arrive at this limitation. Accordingly, we will reverse the
obviousness rejection of claims 1-39.
Claims 40 and 55-58
These claims stand on a different footing as they don’t require the
lipid component to have a liquid phase transition temperature greater than
57°C when non-hydrated.
As discussed above, Byström discloses a proliposome powder
comprising discrete particles of an active agent together with a lipid or a
mixture of lipids having a liquid phase transition temperature below 37ºC,
which forms liposomes incorporating the active agent upon inhalation into
the respiratory system. Moreover, Byström discloses a lipid component with
a liquid transition temperature below 37°C comprising a mixture of
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phosphatidylcholine, phosphatidylserine (a targeting agent), and cholesterol
(FF12-14, 16).
Thus, Byström discloses a formulation that meets all the limitations of
these claims, with the exception of specifying that the active agent is the
antibiotic ciprofloxacin (which isn’t even required by claims 57 and 58). In
any case, we agree with the Examiner that it would have been obvious to
include ciprofloxacin in the formulation, as Byström teaches that the
formulations are suitable for delivering antibiotics to the respiratory system
(FF15), and Weers I discloses ciprofloxacin as an active agent suitable for
pulmonary delivery (FF10).
Appellants contend that “[t]he Examiner has taken a liquid
formulation (Bystr[ö]m et al) that is administered as a liquid and combined it
with a powder formulation (Weers et al) and magically concluded it would
have been obvious to have powder that converts to liquid” (Reply Br. 5).
Appellants’ contention is not persuasive because it is plainly contrary
to the facts. Byström is explicitly directed to a powdered phospholipid
formulation that spontaneously forms liposomes encapsulating an active
component upon contact with the hydrating environment of the respiratory
system (FF11-13). Accordingly, we will affirm this rejection with respect
to claims 40 and 55-58.
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DOUBLE PATENTING
The only remaining rejection is the rejection of claims 1-40 and 55-58
under the doctrine of obviousness-type double patenting as unpatentable
over claims 1-21 of U.S. Patent 7,393,544.
Appellants do not traverse the merits of the rejection in their Appeal
Brief, and have previously indicated they “will consider the filing of a
terminal disclaimer . . . if appropriate” (Response filed June 3, 2009).
We decline to decide the appeal as to the obviousness-type double
patenting rejection, as Appellants have waived any appeal of the rejection.

SUMMARY
The rejection of claims 1-40 and 55-58 under the first paragraph of 35
U.S.C. § 112 for lack of enablement is reversed.
The rejection of claims 1-6, 9, 11, 13-15, 19-39, and 55-56 under 35
U.S.C. § 102(b) as anticipated by Weers I or Weers II is reversed.
The rejection of claims 1-40 and 55-58 under 35 U.S.C. § 103(a) as
unpatentable over Byström, Weers I, and Weers II is affirmed with respect
to claims 40 and 55-58, and reversed with respect to claims 1-39.
We do not reach the rejection of claims 1-40 and 55-58 under the
doctrine of obviousness-type double patenting.
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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)(1)(iv)(2006).

AFFIRMED-IN-PART

NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 101/2
EAST HANOVER, NJ 07936-1080