Ex Parte Calvani

Board of Patent Appeals and Interferences

Jun 18, 2010

10470999 (B.P.A.I. Jun. 18, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte MENOTTI CALVANI
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Appeal 2010-002014
Application 10/470,999
Technology Center 1600
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Decided: June 21, 2010
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Before CAROL A. SPIEGEL, TONI R. SCHEINER, and
FRANCISCO C. PRATS, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 3, 18, 21, 22, and 25-32, directed to a method of preserving the
oxidant-protective activity of alphaA-crystallin, a method of preserving
crystalline lens clarity, and a method of treating cataract by administering L-
carnitine to a non-diabetic patient. The claims have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
Appeal 2010-002014
Application 10/470,999

STATEMENT OF THE CASE
Claims 3, 18, and 25 are representative of the subject matter on
appeal:
3. A method of preserving oxidant-protective activity of alphaA-
crystallin comprising contacting L-carnitine or a salt thereof to an alphaA-
crystallin such that said alpha-crystallin remains oxidant protective, wherein
said alphaA-crystallin is present in a nondiabetic, human patient.

18. A method of preserving crystalline lens clarity comprising
contacting L-carnitine or a salt thereof to said crystalline lens, wherein said
crystalline lens is present in a nondiabetic, human patient.

25. A method of treating cataract in a nondiabetic, human patient
comprising administering an ophthalmic composition comprised of a
therapeutically effective amount of L-carnitine or a salt thereof to an eye of
said nondiabetic, human patient.

The Examiner rejected claims 3, 18, 21, 22, and 25-32 under 35 U.S.C. §
103(a) as unpatentable over Swamy-Mruthinti,1 Horwitz,2 Oimomi,3 Malina,4
and Cavazza.5

1 S. Swamy-Mruthinti & A. Lee Carter, Acetyl-L-Carnitine Decreases
Glycation of Lens Proteins: in vitro Studies, 69 EXP. EYE RES. 109-115
(1999).
2 Joseph Horwitz, α-Crystallin can function as a molecular chaperone, 89
PNAS USA 10449-10453 (1992).
3 Munetada Oimomi et al., Glycation of Cataractous Lens in Non-diabetic
Senile Subjects and in Diabetic Patients, 46 EXP. EYE RES. 415-420 (1988).
4 Halina Malina et al., Lens epithelial cell apoptosis and intracellular Ca2+
increase in the presence of xanthurenic acid, 2 BMC OPHTHALMOLOGY 1-7
(2002).
5 U.S. Patent 5,037,851, issued August 6, 1991 to Cavazza.
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Application 10/470,999

ISSUE
Has the Examiner established that one of skill in the art would have
had a reason to administer L-carnitine, rather than acetyl-L-carnitine, to the
eye(s) of a non-diabetic patient to treat or prevent cataract(s)?
FINDINGS OF FACT
FF1 Swamy-Mruthinti discloses that:
Aging and diabetes are the major causes of lens
opacification. Since the turnover of lens proteins is extremely
low, they undergo several post-translational protein
modifications including glycation, acetylation, deamidation and
carbamilation . . . Glycation (non-enzymatic glycosylation) is
the major post-translational modification where sugar
aldehydes bind to free amino terminus or ε-amino groups of
lysines to form, initially, a reversible Schiff base intermediate
which undergoes Amadori rearrangement to form a stable
Amadori product. These early glycation products undergo
several dehydration and cyclization reactions to yield advanced
glycation end products (AGEs). Several studies demonstrated
that glycation of lens crystallins seem to be responsible for
insolubilization, aggregation and cross-linking to high
molecular weight protein aggregates . . . .

(Swamy-Mruthinti 109, col. 1.)
FF2 According to Swamy-Mruthinti, “acetyl-L-carnitine (but not L-
carnitine) inhibits in vitro glycation (both early and advanced) of lens
crystallins. Interestingly, α crystallin seem to be the major acetylated
crystallin. The mechanism of inhibition appears to be by acetylation of
potential glycation sites by acetyl-L-carnitine” (Swamy-Mruthinti 113-114).
FF3 Further according to Swamy-Mruthinti,“the role of L-carnitine
systems in the lens is not yet understood, [but] it appears that L-carnitine and
its acyl esters may have several roles . . . Thus, dramatic depletion of L-
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Application 10/470,999

carnitine and its esters shown in diabetic lenses . . . may result in increased
protein and membrane damage leading to cataract formation” (Swamy-
Mruthinti 114, col. 1). “[P]reliminary studies on topical application of L-
carnitine to diabetic rat eyes showed a dramatic increase in the levels of L-
carnitine and acetyl-L-carnitine in both aqueous humor and lenses.
Concomitantly there was a significant delay in the development of cataracts
in about 50% of the L-carnitine treated diabetic rats” (id. at 114, cols. 1-2).
FF4 Oimomi discloses that “[e]arly- and advanced-stage products in
the Maillard reaction, glycation,” are high in both diabetic and senile
cataracts, and “the Maillard reaction plays an important role in causing not
only diabetic cataracts but also senile cataracts” (Oimomi, Abstract).
FF5 Cavazza teaches that “acetyl-L-carnitine and its
pharmacologically acceptable salts are useful in the treatment of senile and
pre-senile degenerative cataract, of diabetic cataract, of juvenile cataract,
and of cataract which has hereditary metabolic causes or nutritional causes,
or develops as a result of poisoning or inflammation” (Cavazza, col. 1, ll.
38-44).
FF6 The Examiner cites the abstract of Horwitz as evidence that
“alpha-crystallins (αA and αB) are major lens structural proteins of the
vertebrate eyes” (Ans. 3).
FF7 The Examiner relies on Malina as evidence that α-crystallin
“has been considered to be the principle component involved in senile
cataract development, wherein the decrease in the chaperone ability of α-
crystallin has been implicated with aging” (Ans. 4).

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Application 10/470,999

PRINCIPLES OF LAW
“[T]he 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).
[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. Although common sense
directs one to look with care at a patent application that claims
as innovation the combination of two known devices according
to their established functions, it 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.

KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). In other words,
“there must be some articulated reasoning with some rational underpinning
to support the legal conclusion of obviousness.” Id. (quoting In re Kahn, 441
F.3d 977, 988 (Fed. Cir. 2006)).
ANALYSIS
In a nutshell, Swamy-Mruthinti teaches that acetyl-L-carnitine, but not
L-carnitine, inhibits in vitro glycation of lens crystallins, and the mechanism
of inhibition appears to be acetylation of potential glycation sites by acetyl-
L-carnitine (FF2). However, Swamy-Mruthinti also teaches that topically-
applied L-carnitine delays the development of cataracts in about 50% of
diabetic rats through some unknown mechanism (FF3), despite its inability
to inhibit glycation of crystallins.
The question that arises, then, is whether the evidence of record is
sufficient to establish that cataracts of diabetic and non-diabetic etiology are
similar enough that one of skill in the art would have expected L-carnitine to
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Application 10/470,999

have a similar effect on the development of cataracts of non-diabetic
etiology.
The Examiner’s position is that:
It would have been prima facie obvious . . . to administer
L-carnitine as taught by Swamy-Mruthinti et al. to a human
patient . . . suffering from a non-diabetic related cataracts, such
as senile cataracts, in view of the teachings of Cavazza and
Oimomi . . . because Oimomi et al teaches that glycation
products play an important role in causing not only diabetic
cataracts but also senile cataracts; and further, as taught by
Cavazza for L-carnitine [sic, acetyl-L-carnitine? See FF5] and
by Swamy-Mruthinti et al. each of the agents have been
individually taught in the prior art to be effective at decreasing
the development of cataracts. As such, the two agents are
recognized in the prior art to be equivalents for the treatment of
cataracts.

(Ans. 4.)
We disagree with the Examiner’s rationale and conclusion. Cavazza
teaches that acetyl-L-carnitine is useful in treating cataracts of diabetic and
non-diabetic etiologies (FF5), and Swamy-Mruthinti teaches that acetyl-L-
carnitine inhibits glycation of lens crystallins by acetylating potential
glycation sites – in other words, acetyl-L-carnitine appears to work by
preempting glycation (FF2). At the same time, Swamy-Mruthinti teaches
that L-carnitine doesn’t inhibit glycation (FF2). L-carnitine does delay the
development of cataracts in about 50% of diabetic rats treated with it, but
apparently by some other mechanism (FF3). That being the case, the mere
fact that Oimomi teaches that glycation products play an important role in
causing cataracts of diabetic and non-diabetic etiology is not sufficient
evidence to establish that one of skill in the art would have expected L-
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carnitine and acetyl-L-carnitine to be equivalent for purposes of treating
cataracts of non-diabetic origin.
CONCLUSIONS OF LAW
The Examiner has not established that one of skill in the art would
have had a reason to administer L-carnitine, rather than acetyl-L-carnitine, to
the eye(s) of a non-diabetic patient to treat or prevent cataract(s).
The rejection of the claims under 35 U.S.C. § 103(a) as unpatentable
over Swamy-Mruthinti, Horwitz, Oimomi, Malina. and Cavazza is reversed.

REVERSED

cdc

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