Ex Parte Patel

Board of Patent Appeals and Interferences

Aug 28, 2009

10632970 (B.P.A.I. Aug. 28, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte SATISHCHANDRA P. PATEL
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Appeal 2009-0028411
Application 10/632,970
Technology Center 1600
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Decided: August 28, 2009
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Before ERIC GRIMES, LORA M. GREEN, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
pharmaceutical composition containing a cyclosporin and a mixture of
monoesters and diesters of propylene glycol with fatty acids. The Examiner
has rejected the claims as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).

1 Satishchandra P. Patel is the real party in interest.
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We reverse.
STATEMENT OF THE CASE
“The cyclosporins are very lipophilic and hydrophobic compounds,
which are sparingly soluble in water, but dissolve readily in organic solvents
such as methanol, ethanol, chloroform and the like. The low solubility in
water results in extremely low bioavailability of the cyclosporins when
administered orally” (Spec. 1).
Because of their low water solubility “[p]rior art formulations of
cyclosporins for oral administration have often involved combinations of the
cyclosporin with a surfactant, an oil, and a co-surfactant” (id.). One prior art
composition combines cyclosporin with “propylene glycol monoesters of
C6-C18 fatty acids. The monoester content employed is typically >90%, and
usually 100%” (id.).
The Specification discloses a carrier medium for cyclosporins with a
mixture of specific fatty acid monoesters and diesters of propylene glycol
that results in a “a particularly good solvent medium for cyclosporins, and
therefore it is possible to avoid co-solvents such as ethanol, propylene
glycol, or the like. The compositions according to the present invention
accordingly preferably do not have such co-solvents, and in particular
preferably do not contain ethanol” (id. at 5).
Claims 1 and 4-20 are pending and on appeal (App. Br. 2-3). Claim 1,
the only independent claim, is representative and reads as follows:
1. A pharmaceutical composition suitable for oral
administration in the form of a homogeneous solution which on
exposure to water or gastrointestinal fluids forms an emulsion
having a particle size of less than 5 microns, the solution
comprising: (a) a pharmaceutically effective amount of a
cyclosporin, (b) a carrier medium comprising a mixture of
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mono- and diesters of propylene glycol with fatty acids having
from 8 to 10 carbon atoms or with mixtures of such fatty acids,
wherein the monoester makes up between 50 and 60 mol % of
the mixture, and (c) a non-ionic surfactant having a hydrophilic
lipophilic balance (HLB) greater than 10.

The Examiner cites the following document as evidence of
unpatentability:
Mulye WO 00/33862 A1 Jun. 15, 2000

Claims 1 and 4-20 stand rejected under 35 U.S.C. § 103(a) as being
obvious in view of Mulye (Ans. 3-4).
OBVIOUSNESS
ISSUE
The Examiner cites Mulye as disclosing a self-emulsifying
composition containing all of the claimed ingredients, except that “Mulye
does not explicitly teach mixture[s] of mono- and diester propylene glycol”
(Ans. 3). The Examiner finds, however, that “Mulye teaches [a] mixture of
fatty acids contain[ing] 60% of monoester propylene glycol (page 16),
and . . . only exclude[s] the presen[ce] of triglycerides” (id. at 4). Based on
these teachings, the Examiner concludes that “it would have been obvious to
one of ordinary skill in the art to include diester propylene glycol in the
mixture, because Mulye does not exclude the use of diester propylene
glycol” (id. at 3).
Appellant contends, among other things, that “Mulye points out, time
and time again, that the [propylene glycol] monoester must be at least about
60% by weight, an amount which when translated into mole % is in excess
of 70 m[ol]%” (App. Br. 8). In contrast, Appellant argues, claim 1 requires
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“the monoester [to be] less than 60 mole percent of the monoester/diester
mixture” (id. at 7).
Appellant urges that “by virtue of the presence of the second ester
moiety, the diester is heavier than the monoester, and therefore, 60 mole
percent [as recited in claim 1] will be substantially less than [the] 60%
monoester on a weight basis” disclosed by Mulye as being the minimum
amount of monoester (id.). Specifically, Appellant calculates that a “60
mole % content of the propylene glycol monoester of the C8 fatty acid in a
mixture with propylene glycol C8 fatty acid diester corresponds to 48 weight
percent; and the corresponding conversions into weight percents for the C9
and C10 fatty acid monoesters are lower than for the C8 fatty acid” (id.
(footnote omitted)).
In performing the calculation, Appellant reasons that “60 moles of
mono-C8 ester of propylene glycol (mol. wt. = 202) weighs 12120 and 40
moles of diester (mol. wt. = 328) weighs 13120; [a]ccordingly, weight
percent = 100(12120/12120 + 13120) = 48 wt% monoester” (id., n. 1).
Therefore, Appellant finds, when comparing Mulye and claim 1 on a weight
percentage basis of the propylene glycol esters, Mulye requires “at least
‘about’ 60 wt% monoester (or 58% and higher according to the Examiner)
while the invention uses less than 50 wt%” (id.).
Appellant further contends that this difference between claim 1 and
Mulye cannot be considered obvious based on an optimization rationale (id.
at 8-9). Specifically, Appellant argues, Mulye’s comparative examples
demonstrate that “the composition must contain more than about 60 wt%
monoester in order to be storage stable and non-hydroscopic [sic,
hygroscopic], and thus teaches the skilled person that a composition in
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which the monoester is less that about 60% by weight will not be storage
stable and will be hydroscopic [sic]” (id. at 8).
In view of the positions advanced by Appellant and the Examiner, the
issue with respect to this rejection is whether Appellant has shown that the
Examiner failed to make a prima facie case that an ordinary artisan viewing
the teachings of Mulye would have considered it obvious to include a
mixture of mono- and diesters of propylene glycol with fatty acids having
from 8 to 10 carbon atoms or with mixtures of such fatty acids, wherein the
monoester makes up between 50 and 60 mol % of the mixture, in Mulye’s
cyclosporin compositions.
FINDINGS OF FACT (“FF”)
1. Mulye states:
The present invention is . . . directed to a method of
orally administering a pharmaceutical composition containing a
lipophilic drug to a patient in need thereof, comprising orally
administering to said patient a pharmaceutical composition
comprising a pharmaceutically effective amount of a lipophilic
drug, a drug solubilizing effective amount of a propylene glycol
ester of C6-C18 fatty acid with at least 60% by weight monoester
based on the total weight of the propylene glycol and a
sufficient amount of a non-ionic surfactant having a HLB
greater than 10, said surfactant being present in sufficient
amounts to form a microemulsion with said lipophilic drug and
said propylene glycol ester when brought in contact with an
aqueous medium, e.g. water.

(Mulye 9.)
2. Mulye states that the “most preferred drugs are cyclosporin and
ibuprofen” (id. at 13). Mulye further states that “it is preferred that the fatty
acid of the propylene glycol monoester contains 6-16 carbon atoms, and
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more preferably 8-12 carbon atoms, and most preferably 8-10 carbon atoms,
and even more preferably 8 or 10 carbon atoms” (id. at 15).
3. Regarding the propylene glycol ester component of its compositions,
Mulye states:
The second component, as indicated hereinabove, is a
lipid fatty acid esterified product of propylene glycol containing
at least about 60% monoester based on the total weight of
propylene glycol ester, i.e., only one of the hydroxy groups is
esterified. The term “ester of propylene glycol containing at
least about 60% monoester by weight” signifies that at least
about 60% by weight up to a maximum of 100% of the esters
formed in the esterification reaction is the monoester. Although
the second component may contain any amount of monoester
above the 60% level based on the total weight of the propylene
glycol ester, including 60%-100% inclusive, e.g. including at
least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or
99% by weight, it is preferred that the propylene glycol ester
contains at least about 70% by weight monoester, and most
preferably at least about 90% by weight monoester. However,
in a preferred embodiment, it contains at least about 95% by
weight monoester and in another preferred embodiment, at least
about 99% by weight monoester.

(Id. at 16.)
4. In Example 8, Mulye performed a comparison between cyclosporin
compositions having different amounts of propylene glycol-caprylate (eight
carbon fatty acid) monoesters (id. at 33). The results are presented in the
following table:
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(Id.)
5. The Examiner does not dispute the accuracy of Appellant’s
calculation (App. Br. 7) that the upper limit of 60 mole % propylene glycol
monoester in claim 1 converts to 48% monoester by weight.
6. The Examiner does not dispute the accuracy of Appellant’s assertion
(App. Br. 8) that Mulye’s lower limit of 60 weight % propylene glycol
converts to greater than 70 mole %.
PRINCIPLES OF LAW
In proceedings before the Patent and Trademark Office,
the Examiner bears the burden of establishing a prima facie
case of obviousness based upon the prior art. “[The Examiner]
can satisfy this burden only by showing some objective
teaching in the prior art or that knowledge generally available to
one of ordinary skill in the art would lead that individual to
combine the relevant teachings of the references.”

In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992) (citations omitted,
bracketed material in original). Furthermore, “[e]ven when obviousness is
based on a single prior art reference, there must be a showing of a suggestion
or motivation to modify the teachings of that reference.” In re Kotzab, 217
F.3d 1365, 1370 (Fed. Cir. 2000).
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In KSR Int’ l Co. v. Teleflex Inc., 550 U.S. 398, 415 (2007), the
Supreme Court emphasized “an expansive and flexible approach” to the
obviousness question. However, the Court nonetheless reaffirmed that “a
patent composed of several elements is not proved obvious merely by
demonstrating that each of its elements was, independently, known in the
prior art.” Id. at 418.
Rather, as the Court stated:
[I]t can be important to identify a reason that would have
prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention
does . . . because inventions in most, if not all, instances rely
upon building blocks long since uncovered, and claimed
discoveries almost of necessity will be combinations of what, in
some sense, is already known.

Id. at 418-419 (emphasis added); see also id. at 418 (requiring a
determination of “whether there was an apparent reason to combine the
known elements in the fashion claimed by the patent at issue”) (emphasis
added).
With respect to the obviousness of ranges, our reviewing court has
stated that “the discovery of an optimum value of a variable in a known
process is usually obvious.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1368 (Fed. Cir. 2007). The rationale for determining the optimal parameters
for prior art result effective variables “flows from the ‘normal desire of
scientists or artisans to improve upon what is already generally known.’” Id.
(quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)).
The Federal Circuit has also stated that, “[i]n cases involving
overlapping ranges, we and our predecessor court have consistently held that
even a slight overlap in range establishes a prima facie case of obviousness.”
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Peterson, 315 F.3d at 1329. Moreover, “a prima facie case of obviousness
exists when the claimed range and the prior art range do not overlap but are
close enough such that one skilled in the art would have expected them to
have the same properties.” Id.
Once a prima facie case of obviousness based on overlapping or close
ranges has been established, however, “an applicant may rebut [the] prima
facie case of obviousness by showing that the prior art teaches away from
the claimed invention in any material respect.” Id. at 1331.
ANALYSIS
We agree with Appellant that the Examiner failed to make a prima
facie case of obviousness. The Examiner argues that claim 1 does not recite
a limitation that differentiates the claimed amounts of propylene glycol
monoesters from the amounts in Mulye’s compositions (Ans. 4).
Specifically, the Examiner urges that “the feature upon which applicant
relies (i.e., less than 50% monoester) is not recited in the rejected claims”
(id.).
We are not persuaded. Claim 1 recites a composition that has “a
mixture of mono- and diesters of propylene glycol with fatty acids having
from 8 to 10 carbon atoms or with mixtures of such fatty acids, wherein the
monoester makes up between 50 and 60 mol % of the mixture” (emphasis
added).
As Appellant points out, and the Examiner does not dispute, the
claimed upper limit of 60 mole percent equates to 48 percent by weight (FF
5). In contrast, Mulye discloses that the lower limit of the corresponding
ingredient in its compositions is “at least about” 60 percent by weight, with
much greater percentages being preferred (FF 3).
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Even in view of the “about” language in Mulye, we do not agree with
the Examiner that an ordinary artisan would consider Mulye’s requirement
of at least about 60 percent monoester by weight to suggest the claimed
amount, which must be less than 48 percent by weight. Moreover, even if
Mulye’s weight percentage is converted to mole percent, Mulye’s
undisputed lower limit of 70 mole percent (FF 6) is significantly higher than
the claimed upper limit of 60 mole percent.
Nor do we agree with the Examiner that an ordinary artisan following
Mulye’s teachings would have arrived at the claimed monoester percentage
through optimization. First, the range recited in claim 1 cannot be said to
overlap, or even abut the range disclosed by Mulye. See In re Peterson, 315
F.3d at 1329.
Also, Mulye shows, through comparative examples, that reducing the
monoester content of the propylene glycol component to about 45 to 50
weight percent of monoesters of lauric acid (twelve carbon fatty acid) yields
a cyclosporin composition that precipitates and crystallizes after two weeks
(FF 4). Thus, we do not agree that a person of ordinary skill in the art
seeking to optimize Mulye’s compositions would have done so by reducing
the monoester content of the propylene glycol component below the lower
limit described by Mulye.
In sum, for the reasons discussed, we agree with Appellant that the
Examiner failed to make a prima facie case that an ordinary artisan viewing
the teachings of Mulye would have considered it obvious to include a
mixture of mono- and diesters of propylene glycol with fatty acids having
from 8 to 10 carbon atoms or with mixtures of such fatty acids, wherein the
monoester makes up between 50 and 60 mol % of the mixture, in Mulye’s
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cyclosporin compositions. We therefore reverse the Examiner’s rejection of
claim 1 and its dependent claims as being obvious over Mulye.

REVERSED

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