Ex Parte Béjar et al

Patent Trials and Appeals Board

May 31, 2019

14420684 - (D) (P.T.A.B. May. 31, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/420,684 02/10/2015
22827 7590 06/04/2019
DORITY & MANNING, P.A.
POST OFFICE BOX 1449
GREENVILLE, SC 29602-1449
FIRST NAMED INVENTOR
Juan Gil Bejar
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
ATTORNEY DOCKET NO.
KSW-15-PCT-US
142387US TE
CONFIRMATION NO.
8154
EXAMINER
THOMAS, TIMOTHY P
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
06/04/2019 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
USDOCKETING@DORITY-MANNING.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JUAN GIL BEJAR and CRISTINA TIMONEDA RAMIA 1
Appeal2018-008328
Application 14/420,684
Technology Center 1600
Before DONALD E. ADAMS, DEMETRA J. MILLS, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
The claims in this appeal are directed to an aqueous composition
comprising a rocuronium salt and D-glucono-delta-lactone. The Examiner
rejected the claims under 35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C.
§ 134, Appellants appeal the Examiner's determination that the claims are
unpatentable. We have jurisdiction for the appeal under 35 U.S.C. § 6(b).
The Examiner's decision is affirmed.
1 The Appeal Brief ("Br." entered Feb. 22, 2018) lists B. Braun Melsungen
AG as the Real Party in Interest. Br. 2.
Appeal2018-008328
Application 14/420,684
STATEMENT OF THE CASE
Claims 1, 5-7, 14, and 24--29 stand finally rejected by the Examiner
as follows:
1. Claims 1, 5-7, 14, and 25-29 under pre-AIA 35 U.S.C. § I03(a) as
obvious in view of Anderson (US Pat. 7,838,515 B2, issued Nov. 23, 2010)
and Zaludek (US Pat. Appl. Publ. 2010/0093849 Al, published Apr. 15,
2010). Ans. 3.
2. Claims 1, 5-7, 14, and 24--29 under pre-AIA 35 U.S.C. § I03(a) as
obvious in view of Anderson, Zaludek, and "Disclosed Anonymously"
(Stable Parenteral Composition of Quaternary Ammonium Neuromuscular
Blocking Agent and Process of Preparation Thereof, 1-7 (published Oct. 31,
2008) (IP.com number IPCOM000I 76002D)). Ans. 3.
Claim 1, the only independent claim on appeal, reads as follows:
1. An aqueous composition comprising:
(i) a steroidal neuromuscular blocking agent substituted
with one or more quaternary ammonium groups and one or
more carboxylates, wherein the steroidal neuromuscular
blocking agent is a Rocuronium salt, further wherein the
steroidal neuromuscular blocking agent is present at a
concentration ranging from 5 mg/ml to 20 mg/ml based on the
total volume of the aqueous composition; and
(ii) an excipient selected from a polyhydroxy acid of the
following formula:
HO-CH2-[CH(OH)]n-COOH, wherein n is an integer from 1 to
8, an intramolecular lactone of said polyhydroxy acid or a
mixture thereof, wherein the excipient comprises D-glucono-
delta-lactone, further wherein the excipient is present at a
concentration ranging from 15 mg/ml to 35 mg/ml based on the
total volume of the aqueous composition.
2
Appeal2018-008328
Application 14/420,684
OBVIOUSNESS BASED ON ANDERSON AND ZALUDEK
The claimed composition comprises (i) a rocuronium salt ("steroidal
neuromuscular blocking agent") at a concentration ranging from 5 mg/ml to
20 mg/ml based on the total volume of the aqueous composition; and (ii)
D-glucono-delta-lactone ("polyhydroxy acid") at a concentration ranging
from 15 mg/ml to 3 5 mg/ml based on the total volume of the aqueous
composition.
The Examiner found that Anderson discloses a muscle relaxant
formulation comprising rocuronium. Final Act. 5. The Examiner found that
Anderson discloses that the acetate ester groups of rocuronium hydrolyze
over time in an aqueous solution. Id. The Examiner also found that
Anderson teaches
a high degree of partitioning of the drug into a protective, and
in particular, hydrophobic or amphiphilic, milieu has been
found to be a very effective measure for limiting hydrolytic
decomposition of the drug, due most likely to the limited
contact between water and the hydrolytically labile group(s) on
the drug molecule when that group is in a hydrophobic domain
or local milieu (2:42-48).
Final Act. 5-6 ( emphasis added). The Examiner stated that "Anderson
teaches that a six-carbon or more compound with an acid moiety can
perform as a stabilizing agent, to minimize the hydrolysis of the steroid
compound." Id. at 7.
The Examiner acknowledged that Anderson does not disclose
the claimed concentration range of the rocuronium salt or the claimed
D-glucono-delta-lactone. Final Act. 7. However, the Examiner found that
Example 7 of Anderson describes using a vecuronium at a concentration of
3
Appeal2018-008328
Application 14/420,684
10 mg/ml which would have led one or ordinary skill in the art to "have
targeted similar concentrations when preparing rocuronium salts." Id.
The Examiner stated that D-glucono-delta-lactone ( or its alternative
acid form, D-gluconic acid; terms are used interchangeably herein) is within
the scope of compounds described by Anderson, but not specifically
disclosed in it. Final Act. 7. To meet this deficiency, the Examiner cited
Zaludek as teaching gluconic acid for the stabilization of oxaliplatinum. Id.
at 9. The Examiner explained:
Gluconic acid exhibits a number of properties that are
advantageous for stabilization of oxaliplatinum; gluconic acid is
a polyhydroxy compound which may, similarly to mannitol or
sorbitol, to a certain extent stabilize the structure of water and
thus decrease the availability of water molecules as reaction
components in hydrolysis of the platinum complex.
Final Act. 9.
The Examiner found reason to use Zaludek' s compound in
Anderson's composition comprising rocuronium:
Thus, Zaludek establishes that gluconic acid ( a C6
compound containing a carboxylic acid; i.e., within the scope of
the stabilizing compounds taught by Anderson to stabilize
steroids including rocuronium bromide) and glucono-8-lactone
are excellent stabilizer agents for oxaliplatinum, which is
subject to degradation via hydrolysis (i.e., the same type of
degradation mechanism that Anderson teaches for carboxylate
steroids including rocuronium bromide).
Final Act. 10.
The Examiner stated the skilled worker would have been motivated to
use gluconic acid as described in Zaludek because "this compound is
effective for stabilizing against hydrolysis based degradation mechanism,
likely modifying the structure of water and decreasing the availability of
4
Appeal2018-008328
Application 14/420,684
water molecules in the hydrolysis reaction involving the rocuronium." Final
Act. 11. In other words, the Examiner found that both Anderson and
Zaludek described the same type of compounds to protect drugs against
hydrolysis, providing a reason to use Zaludek's compound to protect
Anderson's rocuronium.
With respect to the claimed concentration range of the
glucono-delta-lactone, the Examiner calculated, based on Anderson's
disclosure of the molar ratio of anion to rocuronium salt, an amount of
glucono-delta-lactone that falls within the claimed range of 15 mg/ml to 35
mg/ml based on the total volume of the aqueous composition. Final Act. 11.
Discussion
Reason to combine
Appellants contend that one of ordinary skill in the art would not have
modified Anderson with Zaludek' s teachings because rocuronium, the
neuromuscular blocking agent of the rejected claims and of Anderson, "is a
purely organic compound, while the oxaliplatinum-based composition" of
Zaludek "is an organometallic compound." Br. 7. Appellants argue that
"one of skill in the art would not expect that a suitable excipient for an
organometallic compound that undergoes ether cleavage could also be used
to stabilize an organic compound that undergoes ester cleavage." Id.
Specifically, Appellants contend that "the mechanism of hydrolysis of
oxaliplatinum is completely specific to oxaliplatinum and fundamentally
different to the mechanism of hydrolysis described in Anderson and,
therefore, the skilled person in the art would simply never have transferred
the teachings of Zaludek et al. to Anderson." Id. Appellants discuss the
5
Appeal2018-008328
Application 14/420,684
different mechanisms of degradation between rocuronium ( acid-catalyzed
hydrolysis of ester bond) and oxaliplatinum. Id. at 7-8.
Appellants' argument does not persuasively show error in the
Examiner's rejection. While it may be correct that chemical degradation of
rocuronium differs from the chemical degradation of oxaliplatinum, the
Examiner did not rely on these mechanisms as the basis for the rejection.
As explained above, the Examiner found that Anderson discloses that
rocuronium could be protected from degradation by limiting contact between
water and the hydrolytically labile groups on the rocuronium molecule.
Final Act. 6. This finding is supporting by the evidence. Anderson
discloses:
According to the invention, a high degree of partitioning
of the drug into a protective, and in particular, hydrophobic or
amphiphilic, milieu has been found to be a very effective
measure for limiting hydrolytic decomposition of the drug, due
most likely to the limited contact between water and the
hydrolytically labile group(s) on the drug molecule when that
group is in a hydrophobic domain or local milieu. Certain
additives have been found to be surprisingly effective at
improving drug stability. These additives are organic anions
with 6 or more carbon atoms (for establishing a sufficiently
hydrophobic milieu) ....
Anderson 2:42-52.
As discussed by the Examiner, Zaludek also discloses limiting
decomposition of a drug in an aqueous solution by utilizing a stabilizing
agent that decreases the availability of the water to hydrolyze the drug, i.e.,
by limiting the contact between the water and the drug. While the chemical
bond degraded in rocuronium and oxaliplatinum are different, water is the
culprit in both Anderson and Zaludek.
6
Appeal2018-008328
Application 14/420,684
Zaludek explains that an "important decomposition reaction is the loss
of the oxalate ligand and its replacement with water under formation of aqua
complexes." Zaludek ,r 37. Zaludek states that the "loss of the oxalate
ligand is a hydrolytic reaction which generally may be catalyzed by acids or
bases." Id. ,r 40 ( emphasis added). Zaludek teaches that gluconic acid 2 "is a
polyhydroxy compound which may, similarly to mannitol or sorbitol, to a
certain extent stabilize the structure of water and thus decrease the
availability of water molecules as reaction components in hydrolysis of the
platinum complex." Id. ,r 61.
Thus, as found by the Examiner, both Anderson and Zaludek teach
that limiting the contact of the drug with water by using a stabilizing
compound improves the stability of the drug in water. The difference in the
bonds degraded is not the pertinent consideration, but instead it is the fact
that water in both instances is involved with the drug's breakdown,
providing a reason to use Zaludek's gluconic acid in Anderson's
composition comprising rocuronium.
Concentration
Claim 1 recites that the rocuronium salt "is present at a concentration
ranging from 5 mg/ml to 20 mg/ml based on the total volume of the aqueous
composition." To meet the claimed concentration, the Examiner relied upon
the teaching in Anderson of an experiment utilizing 10 mg/ml vercuronium,
a neuromuscular blocking agent structurally related to rocuronium. Final
2 "Herein after, the term 'gluconic acid' will be used for a solution obtained
by dissolution of glucono-8-lactone in water." Zaludek ,r 60.
7
Appeal2018-008328
Application 14/420,684
Act. 7. The Examiner explained in detail how this example made obvious
both the concentration of rocuronium and gluconic acid:
With respect to the amount of rocuronium bromide, the
concentration of claim 1 is construed as obvious as a result of
routine optimization ( considering amounts of vecuronium
taught by Anderson include 10 mg/ml). 10 mg/ml corresponds
to 0.018ss M rocuronium bromide (MW 529.774 g/mol). 2-9
fold molar excess of corresponds to 0.0377s to 0.1698 M
glucono-8-lactone concentration range, or 6.7-30 mg/ml (MW
178.14 g/mol), having substantial overlap with the recited
15-3 5 mg/ml range of the claim 1 amendment. Thus, amounts
within the recited glucono-8-lactone concentration range would
have been obvious when an amount such as 10 mg/ml of
rocuronium bromide is used, by following the teachings of
Anderson, and as a result of routine optimization.
Final Act. 11.
Appellants contend that the Examiner erred because Anderson teaches
a vercuronium concentration of only 0.006 mg/ml, well below the claimed
concentration, and the corresponding gluconic acid would also be below the
claimed amounts. Br. 9-10.
Appellants' argument does not demonstrate persuasive error in the
Examiner's rejection. Example 7 of Anderson describes an experiment
demonstrating the effect of a charged surfactant, glycocholate, on the
partitioning of vecuronium into a lipid-based cubic phase over water.
Anderson 13: 59---60. The experiment showed that vecuronium in the lipid
phase was 10 mg/ml and 0.006 mg/ml in the aqueous phase. Id. at 14:8-10.
However, when glycocholate was included in the lipid phase with the
vecuronium, the concentration of vecuronium in the lipid phase was 10.6
mg/ml and 0.001 mg/ml in the aqueous phase. Id. at 14:14--15. Based on
these results, it was concluded that "incorporation of the glycocholate
8
Appeal2018-008328
Application 14/420,684
increased the partitioning into the lipid phase by an order of magnitude." Id.
at 14: 18-19.
Appellants focus on the 0.006 mg/ml in the aqueous layer, but do not
explain how a 0.006 mg/ml could give rise to 10 mg/ml of vercuronium
partitioned in the lipid layer? This evidence supports the Examiner's finding
that a solution of at least about 10 mg/ml was utilized in Anderson's
example. Accordingly, we are not persuaded that Anderson does not
describe a composition comprising 10 mg/ml vercuronium. Appellants do
not otherwise identify a deficiency in the Examiner's calculation regarding
how much gluconic acid would be used in a 10 mg/ml solution of
rocuromum.
Appellants further argue that Zaludek only describes D-glucono-delta
lactone at a concentration range of 0.0005 mg/ml to 0.5 mg/ml and "states
that such a concentration is sufficient for stabilization and suppression of
hydrolysis but is not sufficient to enable an effective bonding of the
gluconate ligand." Br. 10. Based on this disclosure in Zaludek, Appellants
argue that "one of skill in the art would not have increased the concentration
range of the D-glucono-delta lactone from 0.0005 mg/ml to 0.5 mg/ml as
required by Zaludek to 15 mg/ml to 3 5 mg/ml as required by claim 1 of the
present application." Id. ( emphasis omitted).
This argument is not persuasive. As argued by Appellants, the
compound utilized in Zaludek is structurally different from the compound
described by Anderson. The Examiner found that Anderson teaches a molar
ratio of its anion to compound and calculated how much anion to use if the
compound is present at 10 mg/ml. Final Act. 11. Thus, the amount of
9
Appeal2018-008328
Application 14/420,684
D-glucono-delta lactone was determined by the Examiner based on the
teachings in Anderson and its pertinent to rocuronium. As explained by the
Examiner: "Increase of the amount of glucono-8-lactone concentration
range would have been based on the molar excess amounts taught by
Anderson to be protective, as set forth above." Ans. 11.
Declaration
A declaration under 37 C.F.R. § 1.132 by Meritxell Boixad6s
Carol was provided during the prosecution of the application ("Carol
Deel."). Mr. Carol described a study of the stability of rocuronium in the
presence of D-glucono-delta-lactone. The study compared D-glucono-delta-
lactone at the claimed concentration ranging from 15 mg/ml to 3 5 mg/ml to
0.0005 mg/ml to 0.5 mg/ml of D-glucono-delta-lactone as described in
Zaludek. Carol Deel. ,r 4. Mr. Carol reported that "the stability of aqueous
Rocuronium solutions in the Zaludek, et al. excipient range are 50% less
stable then the range required by pending claim 1 of the present application."
Id. No statement was made by Mr. Carol that such results were unexpected. 3
3 "One way for a patent applicant to rebut a prima facie case of obviousness
is to make a showing of 'unexpected results,' i.e., to show that the claimed
invention exhibits some superior property or advantage that a person of
ordinary skill in the relevant art would have found surprising or
unexpected." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (emphasis
omitted). See also Soni, 54 F.3d at 751 ("Mere improvement in properties
does not always suffice to show unexpected results .... [W]hen an applicant
demonstrates substantially improved results ... and states that the results
were unexpected, this should suffice to establish unexpected results in the
absence of evidence to the contrary.") (emphasis omitted).
10
Appeal2018-008328
Application 14/420,684
The Examiner did not find the declaration persuasive because "it is
not considered unexpected that higher concentrations achieve even better
stability than lower concentrations." Final Act. 13. The Examiner found
that Appellants did not establish the criticality of the claimed range because
a concentration effect would have been expected by a skilled
artisan, based on the recognition that gluconolactone has a
protective effect against hydrolysis by modification of and
decrease of availability of water molecules involved in
hydrolysis. Higher gluconolactone amount would interacted to
a greater degree with water, reducing the effective free water
concentration available for hydrolysis reactivity. The net effect
would have been a concentration based effect of protection
from hydrolysis based degradation.
Ans. 12 -13. Appellants did not identify a defect in the Examiner's
reasoning and we find none. Accordingly, for the reasons set forth by the
Examiner, we conclude that the declaration does not establish patentability
of the claimed subject matter.
Claim 28
Claim 28 depends from claim 1, and further recites "wherein the
composition has a pH ranging from 2 to less than 5."
The Examiner found that the pKa of gluconic acid "of 3.70 is near the
desired pKa of the Anderson stabilizing compounds, having a pKa from 0.5
up to 'about 3.5' (3:55-57)." Final Act. 12. The Examiner found that using
compounds with a pKa of about 3.5 would have led to formulation having a
pH within the claimed range. Id. The Examiner also found that Anderson
teaches a formulation of pancuronium bromide with a pH from 3.8--4.2 (id.
at col. 1, 11. 50-52), and that Zaludek (id. ,r 69) describes using
11
Appeal2018-008328
Application 14/420,684
gluconolactone as stabilizing agent at a pH of 3.8-5.0, which overlaps with
the claimed range, making the claimed range obvious. Final Act. 12.
Appellants argue that Anderson teaches away from the claimed
limitation of an aqueous composition having a pH ranging from 2 to less
than 5. Br. 12. Appellants state that Anderson teaches:
two problems result from the lower pH: (1) stinging upon
injection, and (2) a tendency to induce dangerous precipitation
of other drug formulations administered in conjunction with the
quaternary ammonium compounds. (Anderson at col. 1, lines
51-65). In addition, Anderson notes that lowering the pH also
does not solve the hydrolysis problem with the quaternary
ammonium compounds in aqueous solutions. (Anderson at col.
1, lines 65-68).
Br. 12 ( emphasis omitted).
Appellants' arguments do not persuade us that the Examiner erred in
determining claim 28 would have been obvious to one of ordinary skill in
the art. While Anderson mentions "problems" with a low pH and that the
low pH does not solve the hydrolysis problem ("but only lengthen the
shelf-life moderately") (Anderson 1 :48-58), the low pH was still used in the
prior art. Simply because a product is described as "inferior" does not by
itself constitute a teaching away from using the "inferior" product. In re
Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). "[J]ust because better
alternatives exist in the prior art does not mean that an inferior combination
is inapt for obviousness purposes." In re Mouttet, 686 F.3d 1322, 1334
(Fed. Cir. 2012). While the low pH range might have been inferior, that
does not by itself constitute a teaching away from using it, as long as the
range was taught in the prior art as "usable" and had "been used" for the
stated purpose as it was here. Gurley, 27 F.3d at 553. Moreover, the pH is
not being used alone as it had been in the prior art. The rejection is based on
12
Appeal2018-008328
Application 14/420,684
using D-glucono-delta-lactone to stabilize the rocuronium. As explained
above, the Examiner provided a scientific reason as to why the claimed pH
range would have been obvious to the skilled worker at the time of the
invention. Appellants did not identify a deficiency in the Examiner's cogent
reasoning. Accordingly, we are not persuaded that claim 28 is not obvious
in view of Anderson and Zaludek.
Dependent claims
Claims 5-7, 14, 24--27, and 29 were not argued separately and,
therefore, fall with claim 1 for the reasons set forth by the Examiner. 3 7
C.F.R. § 4I.37(c)(l)(iv).
Summary
Obviousness rejections 1 and 2 of claims 1, 5-7, 14, and 24--29 are
affirmed.
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv).
AFFIRMED
13