Ex Parte Lasic et al

Board of Patent Appeals and Interferences

Sep 22, 2006

09771151 (B.P.A.I. Sep. 22, 2006)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DANILO D. LASIC, ROBERT M. ABRA,
YECHEZKEL BARENHOLZ, and TAL PELEG-SHULMAN
__________

Appeal No. 2006-2213
Application No. 09/771,151
__________

ON BRIEF
__________

Before ADAMS, GRIMES, and GREEN, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL

This appeal involves claims directed to methods of preparing liposomes
containing supersaturated solutions of drug compounds. The examiner has rejected the
claims as anticipated. We have jurisdiction under 35 U.S.C. § 134. We affirm.
Background
“Liposomes are completely closed Iipid bilayer membranes containing an
entrapped aqueous volume.” Specification, page 1. “A primary use of Iiposomes is to
serve as carriers for a variety of materials, such as, drugs, cosmetics, diagnostic
reagents, bioactive compounds, and the like.” Id. “[L]oading of uncharged and non-
lipophilic drugs [into liposomes], and in particular drugs having low solubility in aqueous
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phase at a sufficiently high drug-to-lipid ratio for efficacious therapy remains a
problematic issue.” Page 2. The specification discloses that one may obtain a
liposome having an increased drug to lipid ratio by entrapping a supersaturated solution
of a drug within the liposome. Page 3.
To prepare a supersaturated solution of a drug compound, one must first select a
compound whose solubility can be increased at least two-fold over its room temperature
solubility. Page 6. The compound’s solubility can be increased by, e.g., raising the
temperature of the solvent, adding a co-solvent, or changing the pH of the solvent. Id.
The specification discloses that the anticancer drug cisplatin is suitable for use in
preparing supersaturated solutions because it is much more soluble at elevated
temperatures than at room temperature. Id. Thus, for example, a supersaturated
solution of cisplatin can be obtained by heating a solution containing cisplatin at a
concentration greater than its room temperature solubility limit. Pages 6-7.
To entrap the supersaturated solution within liposomes, a separately prepared
lipid composition is hydrated with the supersaturated solution of the drug. Page 7. The
specification discloses that the lipid preparation may contain lipids which are derivatized
with polymers such as polyethylene glycol. Id.
The resulting liposomes containing entrapped supersaturated solutions of drug
compounds can be prepared in desired sizes by known methods including sonication,
homogenization or extrusion. Page 8. The specification discloses that by adjusting the
size of the liposomes appropriately, one can inhibit precipitation of the drug from the
entrapped supersaturated solution, even under conditions in which the drug would
normally precipitate. Id.

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Thus, for example, when a supersaturated solution of a drug is prepared by
heating the solution to increase drug solubility, the temperature can be lowered once
the supersaturated solution is entrapped within a liposome preparation. Id. If the
liposomes are of the correct size, the drug will not precipitate, even at a temperature
that would not normally support a supersaturated solution. Id. To ascertain whether the
drug within the liposome has precipitated, one may use spectroscopic techniques or
visual methods such as microscopy. Id. The specification discloses that liposome sizes
preferred for maintaining supersaturated solutions range from about 70-500 nm, with
liposomes of about 60-1,000 nm being “suitable.” Id.
Discussion
1. Claim construction
Claims 1, 3-9, and 16 are pending and stand rejected.
Appellants’ argument focuses entirely on whether the prior art describes
elements within claims 1 and 16, the appealed independent claims.1 We will therefore
focus on claims 1 and 16, which read as follows:
1. A method for preparing Iiposomes having an entrapped compound in
the form of a supersaturated solution, comprising:

selecting a compound having room temperature water solubility capable of
exhibiting at least a two-fold increase in response to a condition selected from
the group consisting of: (i) increasing solvent temperature, (ii) adding a co-
solvent, and (iii) changing solvent pH;

preparing from a supersaturated solution of the compound Iiposomes at
selected size intervals;

analyzing said Iiposomes for the presence or absence of precipitated

1 Page 2 of the Brief inadvertently lists claim 1 as the only independent claim. (“Sole independent claim 1
describes . . . .”). However, claim 16 is also independent.

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Application No. 09/771,151

compound; and

based on said analyzing, selecting Iiposomes of a size that corresponds to
liposomes having no entrapped precipitated compound.

16. A method for preparing Iiposomes which contain a supersaturated
solution of a compound, comprising:

preparing an aqueous supersaturated solution of a compound;

hydrating a Iipid film or a Iipid solution with said supersaturated solution of
the compound to form Iiposomes;

sizing the Iiposomes to selected sizes;

analyzing the Iiposomes at each size for the presence or absence of
precipitated compound; and

based on said analyzing, selecting Iiposomes having a size that
corresponds to liposomes having no precipitated compound.

Thus, claims 1 and 16 are directed to methods of preparing liposomes having
supersaturated solutions of compounds entrapped within them. Claim 1 requires: (a)
selecting a compound showing at least a two-fold solubility increase under specified
conditions; (b) preparing liposomes of selected sizes that contain a supersaturated
solution of the compound; (c) determining whether the liposomes contain precipitated
compound; and (d) “based on the analyzing step,” selecting liposomes of a size having
no precipitated compound in them.
Claim 16 is similar to claim 1 but differs by (a) not requiring the solubility of the
compound to be at least two-fold higher under specified conditions, and (b) requiring
that the liposomes be formed by hydrating a lipid film or solution with a supersaturated
solution of the compound.

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2. Anticipation by Abra
The examiner rejected claims 1, 3-9, and 16, all of the pending claims, under
35 U.S.C. § 102(b) on the basis that the claimed method is anticipated by Abra.2 The
examiner stated that Abra “discloses a method of preparation of liposomes containing
supersaturated solution of an active compound. The Iiposomes further contain a
hydrophilic polymer (PEG) (note the abstract, page 2 line 15 through page 3, line 24,
page 6, lines 14-26, page 12, lines 4-21, Example 3 and claims).” Answer, page 4.
In response, Appellants argue that “Abra et al. fail to teach selection of liposome
size in order to maintain the compound in the form of a supersaturated solution.
Specifically, Abra et al. fail to teach each of steps (ii), (iii) and (iv) as set forth in
independent claims 1 and 16.” Brief, page 8. Appellants urge that Abra’s process
comprises only the two steps of (a) heating a cisplatin solution to increase the drug’s
solubility, and (b) producing liposomes from the heated drug solution, and that
“[n]owhere does Abra et al. teach steps of ‘preparing liposomes at selected size
intervals’, ‘analyzing the liposomes as a function of size for the presence of precipitated
compound’, or ‘based on the analyzing selecting a liposome size that corresponds to
liposomes having no precipitated compound’ as presently claimed.” Id.
Appellants emphasize Abra’s explicit statement, at page 4, lines 34-35, that the
cisplatin is entrapped within the liposomes “in dissolved form or in precipitated form.”
Id., at pages 8 and 9. Thus, Appellants urge, “[b]ecause the liposomes of Abra et al.
could include the cisplatin drug in precipitated form, it cannot be said that Abra et al.
inherently anticipates the claimed process of preparing liposomes with drug solely in the

2 Abra, WO 98/07409, published February 26, 1998

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supersaturated form, or that claim steps (ii), (iii), and (iv) that are undisclosed by Abra et
al. are inherent in the document’s disclosure.” Id., at page 9, emphasis in original.
Patentability determinations are based on a preponderance of the evidence.
In re Oetiker, 977 F.2d 1443, 1445, 24 USPQ2d 1443, 1444 (Fed. Cir. 1992) (“After
evidence or argument is submitted by the applicant in response, patentability is
determined on the totality of the record, by a preponderance of the evidence with due
consideration to persuasiveness of argument.”).
As pointed out by Appellants (Brief, page 4), “[a] claim is anticipated only if each
and every element as set forth in the claim is found, either expressly or inherently
described, in a single prior art reference.” Verdegaal Bros., Inc. v. Union Oil Co.,
814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). However, discovery of a
property inherent to a prior art process does not render that process patentable, even if
the prior art did not appreciate the property. Id. at 632-33, 2 USPQ2d at 1054. Thus,
“[n]ewly discovered results of known processes directed to the same purpose are not
patentable because such results are inherent.” Bristol-Myers Squibb Co. v. Ben Venue
Labs., Inc., 246 F.3d 1368, 1376, 58 USPQ2d 1508, 1514 (Fed. Cir. 2001).
Furthermore, “[i]nsufficient prior understanding of the inherent properties of a known
composition does not defeat a finding of anticipation.” Atlas Powder Co. v. IRECO Inc.,
190 F.3d 1342, 1349, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
Based on a preponderance of the evidence, we agree with the examiner that
Abra discloses all of the claimed process steps, including the steps of preparing
liposomes at selected size intervals, analyzing the liposomes for the presence of

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precipitated compound, and selecting a liposome size that corresponds to liposomes
having no precipitated compound.3
Regarding the claimed step of preparing liposomes at selected sizes, page 12 of
Abra (cited in the examiner’s rejection) states at lines 13-14, that “[t]he liposomes,
following diafiltration and dialysis, were extruded through 0.2 μm and 0.1 μm
polycarbonate filters to size the liposomes to between about 100-120 nm.” (Emphasis
added.) In our view, this disclosure meets the limitation in claims 1 and 16 requiring
the preparation of liposomes of selected sizes.
Regarding the claimed step of analyzing the liposomes for the presence or
absence of precipitated compound, Abra performed a number of analyses on the
liposomes described on page 12. Specifically, Abra determined (page 12, lines 17-18)
the concentration of cisplatin within the internal phase of the liposomes. (“The final
liposomes contained an internal phase of cisplatin encapsulated at a concentration of
8.5 mg/ml in 0.9% sodium chloride . . . .”). Abra also evaluated the stability of the
liposomes (page 12, line 23, through page 14, line 8). The stability analysis required
“determining the percent of encapsulated platinum” (page 12, lines 25-26), as well as
verifying that the encapsulated platinum was “in the form of cisplatin” (page 13, lines 32-
33).

3 Regarding Appellants’ statement that “Abra et al. fail to teach each of steps (ii), (iii) and (iv) as set forth
in independent claims 1 and 16” (Brief, page 8), we note that the second, third, and fourth steps of claim 1
actually correspond, albeit not identically, to the third, fourth and fifth steps of claim 16. Despite
Appellants’ numbering scheme, however, it is clear from their argument that Appellants assert that Abra
does not disclose the claimed steps of preparing liposomes at selected size intervals, analyzing the
liposomes for the presence or absence of precipitated compound, and based on the analyzing, selecting
a liposome size that corresponds to liposomes having no precipitated compound.

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In view of Abra’s extensive analysis of the liposomes (pages 12-16), it is
reasonable to expect that precipitated cisplatin would have been detected if it had been
present. Abra’s liposome analysis therefore reasonably appears to be a step of
“analyzing . . . liposomes for the presence or absence of precipitated compound,” as
recited in claim 1.
As pointed out by Appellants, Abra states on page 4, lines 34-35, that “[t]he drug
is entrapped in the inner aqueous compartment [26] in dissolved form or in precipitated
form.” At no point, however, does Abra describe the cisplatin in the liposomes as
precipitated. In fact, Abra expressly states that the cisplatin that was entrapped in the
liposomes was in dissolved form, not solid (precipitated). See page 12, lines 7-12: “An
aqueous solution of cisplatin (8.5 mg/ml cisplatin in 0.9% sodium chloride) was
warmed. . . . The cisplatin solution and the lipid solution were added together to form
liposomes” (emphases added). Abra states that the liposomes were cooled and the
“final liposomes contained an internal phase of cisplatin encapsulated at a concentration
of 8.5 mg/ml in 0.9% sodium chloride.” Page 12, lines 17-18. That is, the internal
phase of the liposomes was the “aqueous solution of cisplatin” that was used to form
the liposomes.
Abra also describes the claimed step requiring selection of a liposome size that
corresponds to liposomes having no precipitated compound. As noted above, Abra
selected liposomes with a particle size of 100-120 nm (page 12, lines 13-14). (“The
liposomes, following diafiltration and dialysis, were extruded through 0.2 μm and 0.1 μm
polycarbonate filters to size the liposomes to between about 100-120 nm.”) (Emphasis
added.) Liposomes within the range of 100-120 nm are disclosed in Appellants’

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specification (page 8, lines 13-14) as being a size suitable for maintaining
supersaturated solutions. (“Typically, liposomes having a size of between 60-1,000 nm
are suitable, preferably a size of between about 70-500 nm.”)
Appellants’ Example 1 (Specification, pages 22-24), which reads identically to
Abra’s Example 3 (pages 21-23), provides additional evidence that Abra selected
liposomes of a size that does not contain precipitated compound. Specifically, Abra
produced (page 12, lines 4-21) liposomes containing the same concentration of cisplatin
present in liposomes prepared according to Appellants’ Example 1, 8.5 mg/ml
(Specification, page 24, lines 9-10). Abra used precisely the same steps used in
Appellants’ Example 1, and the resulting liposomes had a size range explicitly disclosed
in Appellants’ specification (page 8, lines 13-14) as being capable of maintaining a
supersaturated solution without precipitation of the dissolved compound.
In our view these facts demonstrate, based on a preponderance of the evidence,
that Abra selected liposomes of a size corresponding to liposomes having no
precipitated compound therein. While Abra does not state that the selection was “based
on said analyzing,” as recited in claims 1 and 16, Abra performed a process step
outwardly identical to that recited in claims. Therefore, in our view, Abra meets the
claim limitation requiring the selection of liposomes having a size corresponding to
liposomes having no entrapped precipitated compound.
Based on the evidence before us, it is reasonable to conclude that the 100-120
nm liposomes prepared as described on page 12 and Example 3 of Abra would not
have contained precipitated cisplatin. As discussed above, the liposomes ranging in
size from 100-120 nm disclosed by Abra at page 12 are within a size range disclosed in

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the specification as being “preferably” used to entrap supersaturated drug solutions.
Specification, page 8, lines 13-14 (“Typically, liposomes having a size of between 60-
1,000 nm are suitable, preferably a size of between about 70-500 nm.”). (Emphasis
added.) As also discussed above, the liposomes disclosed at page 12 of Abra contain
exactly the same concentration of entrapped cisplatin, 8.5 mg/ml in 0.9% sodium
chloride, as is present in the liposomes prepared in Example 1 of Appellants’
specification. Thus, because the liposomes described on page 12 of Abra are the same
as the liposomes demonstrated by Appellants’ own disclosure to contain dissolved
rather than precipitated cisplatin, we conclude that the liposomes prepared as described
on page 12 of Abra would not contain precipitated cisplatin.
To summarize, the fact that Appellants may have discovered an unrecognized
result of an old process does not entitle them to claims to the old process. Despite
Abra’s failure to disclose the relationship between liposome size and the ability to
maintain supersaturated solutions in the dissolved state under ambient conditions,
based on the evidence before us, Abra in fact produced the same product recited in the
claims, using the claimed process steps. Therefore, because a preponderance of the
evidence supports the examiner’s holding that the process steps and the product made
by those steps are the same as disclosed in the prior art, we affirm the rejection.
Summary
Because Abra describes a process having all of the steps recited in claims 1 and
16, we find no error in the examiner’s anticipation rejection. We therefore affirm the
examiner’s rejection of claims 1, 3-9, and 16, over Abra. The examiner also rejected

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claims 1, 3-6, 8, 9, and 16 as anticipated by Yamamoto,4 and rejected claim 7 as
obvious in view of Yamamoto and Woodle.5 Because Abra anticipates all pending
claims, however, the rejection over Abra is dispositive of this appeal. We therefore find
it unnecessary to reach the other grounds of rejection.
No time period for taking any subsequent action in connection with this appeal
may be extended under 37 CFR § 1.136(a).

AFFIRMED

Donald E. Adams )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
Eric Grimes )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
Lora M. Green )
Administrative Patent Judge )

EG/FP/jlb

4 Yamamoto et al., EP 0 551 169, published July 14, 1993
5 Woodle et al., U.S. Patent 5,013,556, issued May 7, 1991

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