Ex Parte Guilford et al

Board of Patent Appeals and Interferences

Jul 9, 2012

11163979 (B.P.A.I. Jul. 9, 2012)

MOD PTOL-90A (Rev.06/08)

APPLICATION NO./
CONTROL NO.
FILING DATE FIRST NAMED INVENTOR /
PATENT IN REEXAMINATION
ATTORNEY DOCKET NO.
11/163,979 11/06/2005 Guilford, F. Timothy

EXAMINER
Daneker, McIntire, Schumm,
Prince, Manning & Widmann, P.C.
One N. Charles Street
Suite 2450
Baltimore, MD 21201
Kishore, Gollamudi
ART UNIT PAPER NUMBER
1612

MAIL DATE DELIVERY MODE

07/10/2012 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.

UNITED STATES DEPARTMENT OF COMMERCE
U.S. Patent and Trademark Office
Address : COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________________________________________________________________________________
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte F. TIMOTHY GUILFORD and BRIAN CHARLES
__________

Appeal 2012-001137
Application 11/163,979
Technology Center 1600
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to
liposomal formulations containing glutathione. The Examiner has rejected
all pending claims. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.
Appeal 2012-001137
Application 11/163,979

2
STATEMENT OF THE CASE
Claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31, 39, 41, and 48 are on
appeal, and can be found in the Appendix of the Appeal Brief (App. Br. 21-
24). The invention is directed at liposomal formulations containing
glutathione for oral administration. Claim 1 is representative of the claims
on appeal, and reads as follows:
1. A pharmaceutical composition enabling delivery after oral
administration of a therapeutically effective amount of glutathione
(reduced) comprising:
a therapeutic dose of a reduced glutathione stabilized in a
liposomal pharmaceutical carrier capable of being ingested orally,
and capable of delivering glutathione (reduced) in a
physiologically active state to improve symptoms in disease states
by transfer of the glutathione into animal cells, where the
concentration of reduced glutathione in the entrapped aqueous
space of the liposomes is at least about 123 mM.

The following grounds of rejection are before us for review:
I. The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18,
29-31, 39, 41 and 48 under 35 U.S.C. § 112 second paragraph.
II. The Examiner has rejected claims 1, 9, 13 and 17 under 35
U.S.C. § 103(a) as unpatentable over Wendel
1
or Junghans.
2

1
Wendel et al., Drug-Induced Lipid Peroxidation in Mice-III – Glutathione
Content of Liver, Kidney and Spleen After Intravenous Administration of
Free and Liposomally Entrapped Glutathione, 31 Biochemical
Pharmacology 3607-3611 (1981).
2
Junghans et al., Carotenoid-Containing Unilamellar Liposomes Loaded
with Glutathione: a Model to Study Hydrophobic-Hydrophilic Antioxidant
Interaction, 33 Free Rad. Res 801-808 (2000).
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Application 11/163,979

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III. The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18,
30, 31, 39, 41 and 48 under 35 U.S.C. § 103(a) as unpatentable
over Smith.
3

IV. The Examiner has rejected claims 2, 5-6, 10, 14, 18 and 30
under 35 U.S.C. § 103(a) as unpatentable over Wendel or
Junghans in view of Smith and/or Barenholz.
4

V. The Examiner has rejected claims 1, 9, 13, 17, 29, 31, 39 and
48 under 35 U.S.C. § 103(a) as unpatentable over Bharath
5

and/or Sechi
6
in combination with Jellinger
7
and Micklus.
8

VI. The Examiner has rejected claims 2, 5-6, 10, 14, 18, 30 and 41
under 35 U.S.C. § 103(a) as unpatentable over Bharat and/or
Sechi in combination with Jellinger and Micklus, further in
view of Abeliovich
9
and or Barenholz.

3
Smith, US 6,764,693 B1, issued Jul. 20, 2004.
4
Barenholz et al., US 2003/0059462 A1, published Mar. 27, 2003.
5
Bharath et al., Glutathione, iron and Parkinson’s disease, 64 Biochemical
Pharmacology 1037-1048 (2002).
6
Sechi et al., Reduced Intravenous Glutathione in the Treatment of Early
Parkinson’s Disease, 20 Prog. Neuro-Psychopharmacol. & Biol. Psychiat.
1159-1170 (1996).
7
Jellinger, Kurt A., The Role of Iron in Neurodegeneration – Prospects for
Pharmacotherapy of Parkinson’s Disease, 14 Drugs & Aging 115-140
(1999).
8
Micklus et al., US 2002/0025313 A1, published Feb. 28, 2002.
9
Abeliovich et al., US 2006/0171935 A1, published Aug. 3, 2006.
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Application 11/163,979

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ISSUES
 Did the Examiner err in concluding that the claims are
indefinite under 35 U.S.C. §112, second paragraph?

 Does the evidence of record support the Examiner’s conclusion
that the claims are obvious under 35 U.S.C. §103 (a) in light of
the cited references?

FINDINGS OF FACT
FF1. The Examiner acknowledges that different size liposomes “might
contain the same molar concentrations of the active agents” (Ans. 10).
FF2. Wendel disclosed liposomes containing glutathione (GSH) at a
concentration of 25 mg/ml (Wendel 3608).
FF3. Junghans disclosed liposomes containing GSH at 100 mM (Junghans
802). This is equivalent to a concentration of 30.7 mg/ml (Ans. 6).
FF4. Smith disclosed liposomal formulations containing GSH and selenium
(Smith col. 25, l. 60 to col. 26, l. 53). Smith disclosed GSH treatment
protocols with a daily dosing of GSH of 0.5 g/Kg (intravenous) or 1 Kg/M
2

(topical) (Smith, col. 25, ll. 45-60, esp. ll. 56-57). Smith discloses treatment
with a dosage of GSH from 0.001-2.0 g/kg. (Smith claim 1.)
FF5. Smith disclosed oral administration of liposomes even though that
route of administration may be controversial (Smith col. 13, ll. 44-51).
FF6. Barenholz provided generic pharmaceutical compositions comprising
liposomes formulated for oral administration. (Barenholz claims 11, 12, and
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15.) Liposomes included antioxidants such as selenium and GSH. (Id. 3, ¶
0039.)

PRINCIPLES OF LAW
“The test for definiteness is whether one skilled in the art would
understand the bounds of the claim when read in light of the specification.”
Miles Laboratories Inc. v. Shandon Inc., 997 F.2d 870, 875 (Fed. Cir. 1993).

A rejection for obviousness must include “articulated reasoning with
some rational underpinning to support the legal conclusion.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007), quoting In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006).
ANALYSIS
I.
The Examiner has rejected all claims on appeal under 35 U.S.C.§ 112,
second paragraph, on the basis that reciting 123 millimolar (mM) amounts of
the active ingredient without reciting the sizes of the liposomes is not
meaningful (Ans. 5). The Examiner takes the position

[s]ince 1 molar concentration is a molecular weight of a compound in
1000 ml of an aqueous medium (1 mole in 1000 ml), 1 ml of this
solution is still one molar, but the amount of the active agent is 0.001
moles. Therefore, both 1 micrometer size liposomes and 10 nm size
liposomes might contain the same molar concentrations of the active
agents, but the mole or weight amounts of the active agent in 1 nm
size liposome will be 1000 times less than that in 1 micrometer
liposome.

(Ans. 10-11.)
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Appellants argue that the limitation regarding internal GSH
concentration of the liposomes at 123 mM is precise, clear, correct, and
unambiguous (App. Br. 12). Measurements of the concentration of a
compound in solution, such as molarity or percentage solution notation (e.g.,
w/w and w/v), are easily obtainable, convertible and comparable (App. Br.
13).
We agree with Appellants that the Examiner has not adequately
shown the claims are indefinite. “The test for definiteness is whether one
skilled in the art would understand the bounds of the claim when read in
light of the specification.” Miles Laboratories Inc. v. Shandon Inc., 997
F.2d 870, 875 (Fed. Cir. 1993). The claims are directed at the concentration
of the glutathione that is entrapped in the aqueous space of the liposomes.
The liposomes are made using a film of lipids that is then sonicated with an
aqueous solution containing the reduced glutathione (Spec. 17-18, Example
1a; 19, Example 2). In the Specification’s examples, the concentration of
the glutathione in the aqueous phase is at least 123 mM (Keller Dec. 3-4
10
),
and presumably the aqueous phase that is entrapped in the liposomes will
have that same concentration. The Examiner admits that regardless of size,
the liposomes “might contain the same molar concentrations of the active
agents” (FF1). The Examiner asserts that depending on the size of the
liposome the mole or weight amounts will change (Ans. 10). However, the
claims are directed to a composition comprising liposomes with a 123 mM
concentration of GSH, not an amount specified by weight or number of

10
Declaration of Brian Keller under 37 C.F.R. § 1.132, executed on April
13, 2010.
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moles, in the entrapped aqueous phase. The molar concentration of GSH
inside the liposomes is the same as the starting aqueous solution during the
liposome production. Reading the claims in light of the specification we do
not find the claims indefinite. Thus, we reverse the Examiner’s rejection of
the claims on the grounds of lack of clarity.

II.
The Examiner has rejected claims 1, 9, 13, and 17 under 35 U.S.C. §
103(a) as unpatentable over Wendel or Junghans. In making an obviousness
rejection the Examiner must first identify the scope and content of the prior
art. Graham v John Deere Co., 383 U.S. 1, 17 (1966). Thus we first turn to
the prior art. Wendel disclosed the production of liposomes for intravenous
administration of encapsulated GSH. The liposomal GSH concentration is
25 mg/ml (FF2).
11
Junghans disclosed liposomes containing 100 mM or
30.7 mg/ml GSH (FF3). The next step is to identify the difference between
the prior art and the claimed invention. Graham, 383 U.S. at 17. Neither
Wendel nor Junghans disclose liposomes containing 123 mM glutathione.
Once the differences between the prior art and the claimed invention have
been identified, the next step is to identify motivation or a reason why
persons of ordinary skill in the art would have been prompted to combine the
prior art to have made the claimed invention. KSR Int’l Co. v. Teleflex Inc.,
550 U.S. 398 (2007). Here the Examiner asserts “it would have been
obvious to one of ordinary skill in the art . . . to increase the amounts of

11
Since 30.7 mg/ml GSH is equivalent to 100 mM (FF3), 25 mg/ml GSH is
equivalent to 81.4 mM.
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GSH in the liposomes” (Ans. 6).
Appellants contend that the present application contains liposome
having an entrapped GSH concentration of 123 mM (or 37.8 mg/ml) and
neither reference teaches or suggests increasing the internal GSH
concentration of the liposomes (App. Br. 16-17).
We agree with the Appellants that the Examiner has not articulated a
reason for combining the references to arrive at an entrapped aqueous
concentration of 123 mM GSH. A rejection for obviousness must include
“articulated reasoning with some rational underpinning to support the legal
conclusion.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007),
quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). While the
Examiner urges that no criticality has been asserted for the claimed
concentration (Ans. 6), Appellants explained that the 123 mM GSH
concentration was experimentally determined because they needed to
balance taste while providing the highest dose possible in order to increase
patient compliance (Keller Dec. 4). The Examiner even acknowledges that
the Keller Declaration
provides the description of the encapsulation of GSH in 123 mM
amounts and the product made by 'Your Energy Systems, LLC'
markets a liposomal product for oral delivery under the trademark
'READYSORB' and that the product has been and continues to be a
commercially successful product.

(Ans. 14.)

The Examiner has not addressed the reason why the ordinary artisan
based on the prior art would arrive at liposomes with an entrapped reduced
GSH concentration of 123 mM. The Examiner asserts “it would have been
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obvious to one of ordinary skill in the art to encapsulate glutathione at a
desired concentration including the claimed amount in Smith” (Ans. 6).
Smith, however, is silent with regard to the actual liposomal concentrations
of GSH, and the Examiner has provided no evidence or sound technical
reasoning (e.g., because of Smith’s dosages and the solubility of GSH) to
support a conclusion that the claimed concentration would have been
inherent in Smith. Thus, the Examiner has not shown that Smith would
direct the ordinary artisan to increase the liposomal concentration of GSH in
the liposomes of Wendel or Junghans. As noted above, Appellants
explained that the 123 mM GSH concentration was experimentally
determined while balancing factors such as treatment dose and taste with
patient compliance (Keller Dec. 4). Because the Examiner has not
articulated a reason for the ordinary artisan to arrive at a concentration of at
least 123 mM GSH, we reverse the rejection of claims 1, 9, 13 and 17 under
35 U.S.C. § 103(a).

III.
The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18, 30, 31,
39, 41, and 48 under 35 U.S.C. § 103(a) as being obvious over Smith. Smith
disclosed liposomes containing GSH and selenium (FF3). Smith is silent
with regard to the amount of GSH encapsulated within the liposomes (Ans.
6-7). The Examiner takes the position that the ordinary artisan would be
motivated to manipulate the amounts and sizes of the liposomes since they
depend on the condition to be treated and the severity of the disease (Ans.
7).
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Appellants argue that Smith does not disclose the internal GSH
concentrations of the liposomes. (App. Br. 17). We agree with Appellants
that Smith is silent with regard to GSH concentration in the liposomes.
Because the Examiner has not provided us with a rationale to support
arriving at 123 mM GSH concentration, we cannot sustain this rejection.
We reverse the rejection of 1-2, 5-6, 9-10, 13-14, 17-18, 30, 31, 39, 41, and
48 under 35 U.S.C. § 103(a).

IV.
The Examiner has rejected claims 2, 5-6, 10, 14, 18 and 30 under 35
U.S.C. § 103(a) as being obvious over Wendel or Junghans in view of Smith
and/or Barenholz. The disclosures of Wendel, Junghans and Smith have
been discussed above. Wendel and Junghans do not disclose the
incorporation of selenium in the liposomes (Ans. 7). Barenholz disclosed
liposomes that contain selenium and/or glutathione (FF4). The Examiner
takes the position that the ordinary artisan would be motivated to include
additional anti-oxidants such as selenium with the expectation of obtaining
an additive effect (Ans. 7).
We find that Wendel and Junghans disclosed GSH containing
liposomes at a concentration of 100mM or below (FF1, FF2). Smith and/or
Barenholz generically disclosed GSH and selenium containing liposomes.
Both are silent with regard to the concentration of the liposome entrapped
GSH. Based on the evidence before us we conclude that the Examiner has
not established a prima facie case with regards to liposomes having an
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Application 11/163,979

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entrapped glutathione concentration of 123 mM. We reverse the rejection of
2, 5-6, 10, 14, 18 and 30 under 35 U.S.C. § 103(a).

V.
The Examiner has rejected claims 1, 9, 13, 17, 29, 31, 39 and 48 under
35 U.S.C. § 103(a) as unpatentable over Bharath and/or Sechi in
combination with Jellinger and Micklus. Bharat disclosed oxidative stress in
the substantia nigra due to GSH depletion (Ans. 8). Sechi disclosed a
deficiency of reduced GSH in the substantia nigra of Parkinson’s patients
(Ans. 8). Jellinger disclosed the use of anti-oxidants or free radical
scavengers in combination with iron chelators (Ans. 8). Micklus disclosed
liposomal encapsulation of neuromodulators and targeting to the blood brain
barrier (Ans. 9). What is lacking in Bharath, Sechi or Jellinger is the use of
liposomes (Ans. 8). Micklus taught the use of liposomes and directing the
liposomes to the blood brain barrier (Ans. 9). The Examiner takes the
position that encapsulating GSH in liposomes to treat Parkinson’s disease
would be obvious because the references teach the involvement of GSH in
the disease process (Ans. 9).
Appellants argue that the references may recognize the potential
relationship between GSH and Parkinson’s disease, but the references do not
disclose or suggest the presently claimed liposomal compositions (App. Br.
18). We agree with Appellants, that recognizing the association of GSH
depletion with a disease state would not lead the ordinary artisan to arrive at
liposomes containing a concentration of 123 mM GSH. We reverse the
rejection of claims 1, 9, 13, 17, 29, 31, 39 and 48 under 35 U.S.C. § 103(a).
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Application 11/163,979

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VI.
The Examiner has rejected claims 2, 5-6, 10, 14, 18, 30 and 41 under
35 U.S.C. § 103(a) as unpatentable over Bharath and/or Sechi in
combination with Jellinger and Micklus, further in view of Abeliovich and
or Barenholz.
The shortcomings of the Bharath, Sechi, Jellinger and Micklus are
discussed above; in addition, none of the references disclosed the use of
selenium as an antioxidant. Abeliovich disclosed that selenium is commonly
used for the treatment of Parkinson’s disease (Ans. 9), but this does not
make up for the previously discussed shortcomings of the Bharath, Sechi,
Jellinger and Micklus.
We reverse the rejection of claims 2, 5-6, 10, 14, 18, 30 and 41 under
35 U.S.C. § 103(a).

CONCLUSION OF LAW
The Examiner made an error in finding the claims indefinite under 35
U.S.C. §112, second paragraph.
The evidence of record does not support the Examiner conclusion that
the invention as a whole would have been obvious.

SUMMARY
We reverse the rejection of claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31,
39, 41 and 48 under 25 U.S.C. § 112, second paragraph.
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We also reverse the rejection of claims 1-2, 5-6, 9-10, 13-14, 17-18,
29-31, 39, 41 and 48 under 35 U.S.C. § 103(a).

REVERSED

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