Ex Parte Lin et al

Board of Patent Appeals and Interferences

Nov 19, 2007

10376420 (B.P.A.I. Nov. 19, 2007)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte AI J. LIN, JOHN VANHAMONT, WILBUR K. MILHOUS
__________

Appeal 2007-4552
Application 10/376,420
Technology Center 1600
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Decided: November 19, 2007
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Before, DONALD E. ADAMS, DEMETRA J. MILLS, and
LORA M. GREEN, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
Claim 1 is representative.
Appeal 2007-4552
Application 10/376,420

1. A composition comprising artelinic acid/L-lysine salt having the
following formula:

.

Grounds of Rejection
Claims 1-9, 16, and 17 stand rejected under 35 U.S.C. § 103 as
obvious over Lin in view of Okada and Fujisawa.

Cited References
Okada (’357) US 3,925,357 Dec. 9, 1975
Fujisawa (’403) US 3,984,403 Oct. 5, 1976
Lin (’135) US 4,791,135 Dec. 13, 1988

DISCUSSION
Background
“Artelinic acid (AL) was patented in 1988 (Lin, et al., US 4,791,135)
as antimalarial agents … and is currently under development as [a]
parenteral drug for treatment of severe and complicated malaria.”
(Specification 5 (endnote omitted).) “Unexpectedly, AL formulation has
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encountered numerous problems which are unique to artelinic acid and not
commonly observed with other acidic drugs.” (Id.)
“Artelinic acid is not water soluble until it was converted to a salt
form. The most commonly used water soluble salt for acidic drugs is
sodium salt. … The freshly prepared sodium artelinate (Na-AL) is highly
water soluble (> 60 mg/ml). However, portions of the sodium artelinate
were converted to free artelinic acid on exposure to atmospheric carbon
dioxide and moisture which formed carbonic acid. The carbonic acid is
acidic enough to convert some of the Na-AL salt back to AL free acid.”
(Specification 5-6.)
“Similar problems were observed with freshly prepared sodium
artelinate aqueous solution which turned turbidity on standing at room
temperature because of the formation of free AL on standing.”
(Specification 6.) “[O]n standing at room temperature for a longer period of
time, white crystalline material (free artelinic acid) crystallized out from all
solutions with various concentrations of sodium carbonate. Heating of the
solution at 40º C accelerated the crystal formation.” (Id.)

Obviousness
Claims 1-9, 16, and 17 stand rejected under 35 U.S.C. § 103 as
obvious over Lin (’135) in view of Okada (’357) and Fujisawa (’403). We
select claim 1 as representative of the rejection before us since Appellants
have not separately argued individual claims. 37 C.F.R. § 41.37(c)(1)(vii).
The Examiner finds that Lin teaches artelinic acid and its alkaline
earth metal salts as useful in treating malaria (See the abstract and claims 1-
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8). (Answer 3.) The Examiner acknowledges that Lin does not expressly
teach the L-lysine salt of artelinic acid and that the Lin patent does not
expressly teach the method of preparing L-lysine salt of artelinic acid.
(Answer 4.)
The Examiner relies on Okada and Fujisawa for teaching
a method of preparing lysine salts of α-sulfobenzylpenicillin as
carried in a solvent such as water or mixtures of alcohols such
as ethanol ’357 also teaches the collection of the lysine salt
product being performed by lyophilization or recrystalization
(See col. 2, line 60 to col. 3, line 22). ’357 also teaches the
lysine or I-lysine salt as being more stable, less hygroscopic and
less local irritation or pain when injected (See col. 1, lines 59-
68, also col. 2, lines 7-11).
’403 teaches lysine salt[s] of cephalosporins that have
superior stability, increased solubilities and reduced pain of
injection (See the abstract and col. 1, lines 5-30). ’403 also
teaches the method of preparing lysine salts as reacting the
lysine and the acidic cephalosporins in aqueous medium or with
additional organic solvents (See col. 3, lines 17-46).

(Answer 4.)

The Examiner concludes

[i]t would have been obvious to one of ordinary skill in
the art at the time of invention to employ the methods of ’357
and/or ’403 to prepare the composition comprising lysine salts
of artelinic acid.
One of ordinary skill in the art would have been
motivated to employ the methods of ’357 and/or ’403 to
prepare the composition comprising lysine salts of artelinic
acid. Examiner notes that the pharmaceutically acceptable salts
of artelinic acid as known. It is also known in the art that lysine
salt of antibiotic can increase stability and solubilities, as well
as reduce pain of injection. Therefore, possessing the teachings
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of the cited prior arts, one of ordinary skill I[n] the art would
have been reasonably expected to formulate the L-lysine salts
of artelinic acid in the manner described in ’357 and ’403 to
increase stability and solubilities, as well as reduce pain of
injection. Furthermore, formulating the L-lysine salt of
artelinic acid with conventional carriers, such as 5% glucose or
saline, into a conventional parenteral formulation is obvious as
being within the purview of the skilled artisan.

(Answer 4-5.)

The Examiner further relies on the case law of Pfizer v. Apotex, 480 F.
3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) in support of a prima facie case
of obviousness in the present case. (Answer 6.)
We agree that the Examiner has provided sufficient evidence to
support a prima facie case of obviousness. We further agree with the
Examiner that the Pfizer case is particularly relevant to the facts of the
obviousness rejection before us.
In Pfizer, the primary reference disclosed pharmaceutically acceptable
salts of amlodipine, but did not expressly disclose the claimed benzene
sulfonate (besylate) salt. (Id., at 1361.) The secondary references disclosed
besylate salts of pharmaceutical compounds and indicated that the besylate
salt had good stability, good solubility, nonhygroscopicity and good
processability. (Id., at 1355.) Like Appellants in the present case, Pfizer
argued there was no motivation to combine the cited references because the
pharmaceutical compound besylate salts of the secondary references were
unrelated to the claimed compound, amlodipine. (Id., at 1362.) In Pfizer,
there was “irrefutable evidence that a skilled chemist at the time would
simply make known pharmaceutically-acceptable salts of whatever active
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ingredient with which he or she was working at the time.” (Id., at 1362.)
The court held that one skilled in the art facing the problem of the inventor
would have been motivated to combine the teachings of the prior art to
produce the besylate salt of amlodipine. (Id., at 1364.)
Like Pfizer, in the present case, the prior art describes pharmaceutical
salts of artelinic acid and lysine salts of pharmaceu-tical compounds
unrelated to artelinic acid, and also describes advantages associated with the
use of lysine salts of the unrelated pharmaceutical compounds. In particular,
the prior art cites the advantages of water solubility and stability of alkaline
earth metal salts of artelinic acid (Lin, col. 9, ll. 33-37). The prior art further
describes good solubility, stability and reduced pain when lysine salts of
unrelated pharmaceutical compounds are injected intramuscularly or
subcutaneously (Fujisawa, col. 1, ll. 5-30; Okada col. 1, ll. 10-15, 30-58).
Each of Lin, Okada and Fujisawa teach subcutaneous administration
of a pharmaceutical salt. (Lin, col. 10, ll. 20-34; Okada, col. 3, ll. 40-47;
Fujisawa, col. 1, ll. 8-30.) Okada and Fujisawa each teach that one of
ordinary skill in the art addressing the problem of pain associated with
subcutaneous injection would look to prior art pharmaceutically acceptable
salts, such as lysine salts, which have good solubility and stability properties
as well as properties that do not cause pain upon subcutaneous injection.
We find that one of ordinary skill in the art desiring to administer artelinic
acid subcutaneously as set forth in Lin (Lin, col. 10, ll. 20-24) would look to
prior art pharmaceutically acceptable salts, such as lysine salts, which have
good solubility and stability properties as well as properties that do not cause
pain upon subcutaneous injection. (Lin, col. 10, ll. 20-34; Okada, col. 3, ll.
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40-47; Fujisawa, col. 1, ll. 8-30.) Thus, we find one of ordinary skill in the
art facing the problem of subcutaneous injection of a pharmaceutical
compound such as artelinic acid, would have been motivated to combine the
teachings of the prior art to make the claimed lysine salt of artelinic acid.
The motivation to combine references does not have to be identical to patent
owner’s to establish obviousness. In re Kemps, 97 F.3d 1427, 1430, 40
USPQ2d 1309, 1311 (Fed. Cir. 1996).
We acknowledge that Appellants' primary emphasis is on intravenous
delivery of the claimed artelinic acid lysine salt (Br. 4-5). While Appellants
argue their composition is for intravenous administration, Appellants’
composition claim, which we have selected as a representative claim, is not
so limited. Moreover, an intended use, such as intravenous administration,
that merely states the purpose of the claimed subject matter, without adding
additional structure to it, is generally not treated as limiting the scope of the
claim. See Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
320 F.3d 1339, 1345, 65 USPQ2d 1961, 1964-65 (Fed. Cir. 2003); Rowe v.
Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997). In the
present case one of ordinary skill in the art, desiring to administer the
artelinic acid compound of Lin subcutaneously, would have been motivated
by the prior art of Okada and Fujisawa to administer the lysine salt of
artelinic acid, which lessen the pain of subcutaneous injection.
Thus, the cited prior art references provide motivation to one of
ordinary skill in the art to prepare and administer the claimed lysine salt
subcutaneously, and that is sufficient to support a prima facie case of
obviousness of the claimed artelinic acid lysine salt composition.
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Where the prior art, as here, gives reason or motivation to make the
claimed invention, the burden then falls on Appellants to rebut that prima
facie case. Such rebuttal or argument can consist of any other argument or
presentation of evidence that is pertinent. In re Dillon, 919 F.2d 688,
692-93, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).
Appellants contend that

[a]lthough ’135 indicates that its dyhydroartemisinin salts can
be used for intravenous administration (1988), it was later
found that they had problems. It has since been found that
when dihydroartemisinin-succinic acid monoester (artesunic
acid) was used for the treatment of malaria, it penetrated into
the cerebral fluid after IV administration and was toxic in the
cerebral fluid over time. Further, ’135 does not indicate that L-
lysine salts or any other salt other than its disclosed alkali and
alkaline earth metal salts (col. 2, lines 66-68) would be suitable
the treatment of malaria or for intravenous administration. This
motivation is necessary for arriving at the present invention.

(Br. 3.)

Appellants argue that Fujisawa teaches the use of lysine salts of
cephalosporins and that cephalosporines are taught to be antibacterial agents
and that malaria parasites are not bacteria. (Br. 3.) Appellants argue that a
lysine salt of a cephalosporine is different in chemical structure than a lysine
salt of artelinic acid. (Br. 4.) “Still further, the cephalosporin salts of ’403
are only disclosed to be for intramuscular (IM) or subcutaneous injection
(column 1, line 9) and not for intravenous injection.” (Br. 4.) Appellants
argue that the prior art states that their lysine salts give no local pain or
irritation with intramuscular injection or subcutaneous injection, but neither
indicate that they would not cause a negative reaction inside of the vein.
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(Id.) Appellants argue that “[o]ne of ordinary skill in the art would have
known that not all substances that are safe for IM or subcutaneous injection
are safe for intravenous injection. The tissue inside of the vein walls is
different than muscle or skin tissue.” (Br. 4.)
For the reasons discussed herein, we find it of no consequence to the
Examiner’s prima facie case that the lysine salts of the prior art, Fujisawa
and Okada, are for antibacterial agents having a chemical structure unrelated
to artelinic acid, and are not for the treatment of malaria. As discussed in
Pfizer, “a skilled chemist at the time would simply make known
pharmaceutically-acceptable salts of whatever active ingredient with which
he or she was working at the time.” (Pfizer, 480 F. 3d at 1362.) For the
reasons herein, we find that one of ordinary skill in the art facing the
problem of pain associated with subcutaneous injection of a pharmaceutical
compound such as artelinic acid, would have been motivated to combine the
teachings of the prior art, Okada and Fujisawa, to make the claimed lysine
salt of artelinic acid, as lysine salt is taught in the prior art to alleviate the
pain of subcutaneous injection.
In view of the above, the rejection of the claim 1 for obviousness is
affirmed. Claims 2-9, 16 and 17 fall with claim 1.

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SUMMARY
The rejection of claims 1-9 and 16-17 under 35 U.S.C. § 103 as
obvious over Lin in view of Okada and Fujisawa is affirmed.
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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