Ex Parte Lichtenberger

Patent Trial and Appeal Board

Jun 17, 2014

12883873 (P.T.A.B. Jun. 17, 2014)

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.
12/883,873 09/16/2010 Lenard M. Lichtenberger 102087-0102 5669
22428 7590 06/17/2014
FOLEY AND LARDNER LLP
SUITE 500
3000 K STREET NW
WASHINGTON, DC 20007
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
MAIL DATE DELIVERY MODE
06/17/2014 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 PATENT TRIAL AND APPEAL BOARD
__________

Ex parte LENARD M. LICHTENBERGER
__________

Appeal 2014-002745
Application 12/883,873
Technology Center 1600
__________

Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a
pharmaceutical composition that is a NSAID-in-oil suspension. The
Examiner rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We reverse.

1 Appellant identifies the Real Party in Interest as The Board of
Regents of the University of Texas System (see App. Br. 1).
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Statement of the Case
Background
“NSAIDs constitute a family of compounds, the first of which to be
discovered being aspirin, that have the capacity to inhibit a number of
biological pathogenic processes including; fever, inflammation, pain,
thrombosis and carcinogenesis” (Spec. 1, ll. 22-24).
The Specification teaches that “our group evaluated the GI toxicity of
a number of NSAIDs that were chemically pre-associated with synthetic or
purified PC [phosphatidylcholine], prior to administration, and obtained
evidence that these novel drugs were far less injurious, with regards to GI
lesion formation and bleeding than the unmodified NSAIDs” (Spec. 5, ll. 13-
16). The Specification teaches that the “applicability of this approach to
human disease was recently confirmed when pilot clinical studies revealed
that PC - aspirin, employing purified (93% pure) PC, induced significantly
fewer gastric lesions in human subjects than unmodified aspirin” (Spec. 5, ll.
16-19).
The Claims
Claims 53-56 and 59-64 are on appeal. Independent claim 53 is
representative and reads as follows:
53. A pharmaceutical composition that is a non-
steroidal anti-inflammatory drug (NSAID)-in-oil suspension,
comprising
a lecithin oil consisting of soy lecithin components in
sunflower oil, wherein said lecithin oil has about 33-40 wt.%
phosphatidylcholine (PC), about 26-31 wt.% triglycerides,
about 8-13 wt.% free fatty acids, and about 5-9 wt. %
glycolipids and
a solid NSAID, wherein
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(a) the NSAID associates with a phospholipid of the
lecithin oil,
(b) the NSAID is present in a therapeutically effective
amount, and
(c) the composition has a gastrointestinal (GI) toxicity
that is reduced relative to the NSAID alone.

The issue
The Examiner rejected claims 53-56 and 59-64 under 35 U.S.C.
§ 103(a) as obvious over Lichtenberger ’4512 or Lichtenberger ’7803 or
Lichtenberger ’0734 and Dickinson5 and Ghyczy6 (Ans. 3-5).
The Examiner finds that “Lichtenberger discloses formulations
containing a phospholipid and NSAIDs for the treatment of pain and
inflammation. The phospholipids taught are DPPC and lecithin” (Ans. 3).
The Examiner finds that “[s]ince Lichtenberger uses lecithin which is [the]
same as applicant's, it is the examiner’s position that lecithin in
Lichtenberger contains the same amounts of phosphatidylcholine” (Ans. 3).
The Examiner finds that “Dickinson discloses ibuprofen and lecithin
formulations. The process of preparing aqueous suspensions of ibuprofen by
the addition [of] ibuprofen to lecithin such as soybean lecithin” (Ans. 4).
The Examiner finds that “Ghyczy teaches that NSAIDs have side effects
such as bleeding and stomach ulcers and administration together with

2 Lichtenberger et al., US 5,955,451, issued Sept. 21, 1999.
3 Lichtenberger et al., WO 96/22780 A1, published Aug. 1, 1996.
4 Lichtenberger et al., WO 98/13073 A1, published Apr. 2, 1998.
5 Dickinson, J., US 6,287,592 B1, issued Sept. 11, 2001.
6 Ghyczy et al, US 4,421,747, issued Dec. 20, 1983.
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phospholipids reduces the ulceration. The phospholipids taught include
those from soy bean [sic] and eggs” (Ans. 4).
The Examiner finds that “Lichtenberger, WO 98 and 96 do not
specifically teach ‘lecithin oil’” (Ans. 4). The Examiner finds it obvious
[T]o include an oil in additional amounts in the lecithin
preparations of Dickinson and/or Ghyczy with a reasonable
expectation of success would have been obvious to one of
ordinary skill in the art since Lichtenberger, WO 96 and WO
98 teach that the complexes of NSAID and phospholipids or
lecithin or these complexes along with an oil could be used.
(Ans. 5).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that the cited prior art renders obvious a composition comprising “a lecithin
oil consisting of soy lecithin components in sunflower oil” and “a solid
NSAID” where the lecithin oil has “about 33-40 wt.% phosphatidylcholine
(PC), about 26-31 wt.% triglycerides, about 8-13 wt.% free fatty acids, and
about 5-9 wt. % glycolipids” as required by claim 53?
(ii) If so, has Appellant presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Lichtenberger ’451 teaches that “the combination of low
amounts of nonsteroidal anti-inflammatory drugs with phospholipid have
potent pharmacological activity, while doses of the drug alone (i.e., without
zwitterionic phospholipid) do not” (Lichtenberger ’451, col. 4, ll. 8-12).
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2. Lichtenberger ’451 teaches an example where “the NSAID is
aspirin, salicylate, a salt thereof, or a combination thereof. While any of a
number of different zwitterionic phospholipids may be employed in the
composition of the method, in some embodiments, the phospholipid is
dipalmitoyl phosphatidyl choline, phosphatidyl choline, or a combination
thereof” (Lichtenberger ’451, col. 5, ll. 57-62).
3. Lichtenberger ’451 teaches that “the sodium salts of the
NSAIDs are readily soluble in either saline or water, and are removed from
solution as a complex within minutes after an equimolar concentration of
DPPC is added as a lipidic suspension” (Lichtenberger ’451, col. 16, ll.
45-49).
4. Lichtenberger ‘451 teaches that:
NSAID was added to chloroform at a 30 nM final
concentration. DPPC was dissolved in the chloroform that
was contained in half the tubes at a final concentration
which ranged between 5-40 nM, prior to the addition of the
NSAID salt. DPPC, as well as PC and other zwitterionic
phospholipids useful in the practice of the invention, may
also be dissolved in other organic solvents, such as ethanol,
in the practice of the present invention. The tubes were
gently mixed at 25° C. for 16 hrs

(Lichtenberger ‘451, col. 16, ll. 1-9).
5. Dickinson teaches that
The ibuprofen and soybean lecithin were milled
together and then blended with the remaining powder
excipients until a homogeneous mixture was obtained. . . .
The contents of the sachet were placed into a cup and
200 ml substantially boiling water added. The ibuprofen
melted and was immediately emulsified to form a
satisfactory drink formulation. The emulsified phase was
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present as small droplets distributed evenly throughout the
drink to give satisfactory slightly cloudy homogeneous
appearance.

(Dickinson, col. 14, ll. 8-17.)
6. Dickinson teaches that the “granular mixture may also be
prepared by granulating the ibuprofen, soybean lecithin and sodium lauryl
sulphate in a high speed mixture using aqueous ethanol as the granulating
liquid” (Dickinson, col. 14, ll. 30-33).
7. Ghyczy teaches that the “novel mixture of the present invention
comprising non-steroidal antiphlogistic substances and phospholipid is
particularly suitable for oral application where the molar ratio of
antiphlogistic substance to phospholipid ranges from about 1:0.1 to about
1:20, and preferably from about 1:0.5 to about 1:2” (Ghyczy, col. 3, ll.
17 22).
8. Ghyczy teaches that:
The mixture can be prepared by dissolving the
antiphlogistic substance and the phospholipid in a suitable
organic solvent such as methanol, ethanol or chloroform and
by subsequently separating the solvent from the mixture by
distillation. The antiphlogistic substance can also be
dissolved in water at a suitable pH with the phospholipid
being stirred into the solution.

(Ghyczy, col. 3, ll. 23-28.)
9. The Shaw Declaration7 teaches that:
[A] person knowledgeable in the lipids field would read
“lecithin oil” in the ’873 application as referring to a free-

7 Declaration of Dr. Walter A. Shaw, filed Oct. 11, 2012.
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flowing composition of lecithin (USP/NF definition) in an
oil, as illustrated by the product PHOSAL 35 SB. This
interpretation of the ’873 application pertains, I believe,
because the term “lecithin oil” is generally not used in the
field to designate a purified PC dispersed in an oil. Rather,
this terminology typically would be used for products
similar to Phosal® 35 SB, i.e., to denote crude lipid mixtures
dissolved in oil.

(Shaw Decl. 3 ¶ 10.)
10. The Marathi Declaration8 teaches that “the suspensions of
NSAID in lecithin oil, as described in the ’873 application, exhibit properties
that distinguish the suspensions both from NSAIDS alone and from
microemulsions, per the ‘073 publication, that contain aspirin, PC, and
triglyceride” (Marathi 2 ¶ 7).
11. Figure 6 of the Marathi Declaration is reproduced below:

8 First Declaration of Dr. Upendra K. Marathi, submitted Feb. 21,
2013.
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“As shown in Figure 6 . . . the aspirin tablet (composition V) exhibited rapid
release into simulated gastric fluid, while composition VI exhibited only a
slightly delayed and slightly reduced release in simulated gastric fluid. By
contrast, composition VII was characterized by a different ASA release
profile, displaying not only a substantial reduction of ASA release, but also a
significant delay in ASA release” (Marathi Decl. 6 ¶ 18).
12. The Lichtenberger Declaration9 teaches:
[S]everal observations about NSAID-in-lecithin oil
suspensions that were unexpected in light of conventional
knowledge, as evidenced by the above-discussed documents.
That is, NSAID-in-lecithin oil suspensions (1) exhibit a
reduced GI toxicity, relative to an NSAID alone, that (2)
pertains even in formulations that contain a lower amount of
PC than the 1: 1 molar ratio of PC:NSAID formulations that
W096, W098 and the ‘451 patent disclose and that the field
favored before the subject application was filed, and (3) they
also display an increase in NSAID long-term stability,
compared to the NSAID:PC emulsions or aqueous lipidic
suspensions made heretofore.

(Lichtenberger Decl. 3 ¶ 8.)
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.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir.
1992).

9 Declaration of Dr. Lenard M. Lichtenberger, submitted Jul. 31,
2013.
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“[O]bviousness requires a suggestion of all limitations in a claim.”
CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003).
“[E]vidence rising out of the so-called ‘secondary considerations’
must always when present be considered en route to a determination of
obviousness.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed.
Cir. 1983).
Analysis
Prima facie case
The Examiner finds that
Since Lichtenberger, WO 98, WO 96 teach the same
NSAIDs and lecithin and oil, they would be in the same
form (either as a suspension or solution) just as in instant
case whether the references hint at a suspension or not. It is
unclear to the examiner how compositions containing the
same ingredients would be in a solution form in one case
and in a suspension form in another case

(Ans. 6).
We find the Examiner’s position unpersuasive. The compositions of
Lichtenberger ’451, Dickinson, and Ghyczy differ from the claimed
composition, which requires “soy lecithin components in sunflower oil,”
with a specific lipid composition. None of the references teach placing soy
lecithin in sunflower oil, as required by both independent claims, nor do the
references teach the specific lipid component concentrations.
For example, the Examiner finds that “egg lecithin contains 69 %
phosphatidylcholine and soybean lecithin contains 21 %
phosphatidylcholine; Further according to Dickenson [sic], lecithin contains
various other phospholipids, triglycerides (oils), fatty acids and
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carbohydrates” (Ans. 4). Even if we, incorrectly, assumed that these sources
had 26-31 wt% triglycerides, 8-13 wt% free fatty acids, and 5-9 wt.%
glycolipids, both soybean lecithin and egg lecithin differ from the claimed
33-40 wt% phosphatidylcholine amount required by both claims 53 and 54.
However, we cannot correctly assume that egg lecithin or soybean lecithin
inherently have the required amounts of triglycerides, free fatty acids, and
glycolipids required by claims 53 and 54. “Inherency, however, may not be
established by probabilities or possibilities. The mere fact that a certain
thing may result from a given set of circumstances is not sufficient.”
MEHL/Biophile Int’l Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir.
1999). Nor has the Examiner established that the changes in ranges would
have been obvious, since neither the 21 % phosphatidylcholine in soybean
lecithin or the 69 % phosphatidylcholine in egg lecithin either falls into, or
adjacent to, the claimed 33-40 wt% range claimed. The Examiner also does
not establish that the amounts of triglycerides, free fatty acids or glycolipids
in the prior art fall into, or adjacent, the claimed ranges, as required for a
presumption of obviousness. See, e.g., In re Peterson, 315 F.3d 1325, 1329
(Fed. Cir. 2003).
Thus, the Examiner provides no example in the prior art of an NSAID
in an “in-oil suspension” with “soy lecithin components in sunflower oil”
and where the lecithin oil has “about 33-40 wt.% phosphatidylcholine (PC),
about 26-31 wt.% triglycerides, about 8-13 wt.% free fatty acids, and about
5-9 wt. % glycolipids” as required by both independent claims 53 and 54.
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Unexpected results
Appellant contends that “the declaration from Dr. Upendra Marathi
details the unexpectedly greater hydrophobicity and surprisingly different
NSAID release profile in simulated gastric fluid of the presently claimed
NSAID-in-lecithin oil suspensions as compared to emulsions that contain
aspirin, PC and a triglyceride oil as disclosed in the Lichtenberger
references” (App. Br. 19).
We agree with Appellant. As noted by Appellant, Figure 6 of the
Marathi Declaration shows a comparison between a product formed by the
claimed method and a product formed by the closest prior art method of
Lichtenberger ’451 (FF 11). We agree that Lichtenberger ’451 is at least as
close prior art as either Dickinson or Ghyczy, since none of the prior art uses
the same oil, sunflower oil, or the same lipid concentrations as required by
claims 53 and 54.
In the comparison of the claimed invention with Lichtenberger ’451,
the dissolution rate of aspirin in mock stomach acid at the 60 minute
timepoint differed from 80% dissolution for the prior art with only 20%
dissolution in the instantly claimed invention (FF 11). In the absence of any
evidence presented by the Examiner explaining why such a difference would
have been expected, we agree with Appellant that this represents a
substantial and unexpected difference, which is consistent with the claimed
invention, and represents a comparison with the closest prior art.
Conclusion of Law
(i) The evidence of record does not support the Examiner’s conclusion
that the cited prior art renders obvious a composition comprising “a lecithin
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oil consisting of soy lecithin components in sunflower oil” and “a solid
NSAID” where the lecithin oil has “about 33-40 wt.% phosphatidylcholine
(PC), about 26-31 wt.% triglycerides, about 8-13 wt.% free fatty acids, and
about 5-9 wt. % glycolipids” as required by claim 53.
(ii) In addition, Appellant has presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.

SUMMARY
In summary, we reverse the rejection of claims 53-56 and 59-64 under
35 U.S.C. § 103(a) as obvious over Lichtenberger ’451 or Lichtenberger
’780 or Lichtenberger ’073 and Dickinson and Ghyczy.

REVERSED

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