Ex Parte Schmitke et al

Board of Patent Appeals and Interferences

Jul 24, 2007

10179463 (B.P.A.I. Jul. 24, 2007)

The opinion in support of the decision being entered today
is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte JENNIFER L. SCHMITKE, DONGHAO CHEN,
RICHARD P. BATYCKY, and DAVID A. EDWARDS
____________

Appeal 2007-08541
Application 10/179,463
Technology Center 1600
____________

Decided: July 24, 2007
____________

Before DONALD E. ADAMS, LORA M. GREEN, and NANCY J. LINCK,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 5, 7-18, 26, 28-42, 51, 53-64, and

1 Heard June 5, 2007.
Appeal 2007-0854
Application 10/179,463

66-74.2 We have jurisdiction under 35 U.S.C. § 6(b). Claims 5 and 51 are
representative of the claims on appeal, and read as follows:
5. A formulation having particles comprising, by weight, 75% DPPC,
15% insulin and 10% sodium citrate.

51. A method of delivering an effective amount of insulin to the
pulmonary system, comprising:
(a) providing a mass of particles comprising by weight, 75%
DPPC, 15% insulin and 10% sodium citrate; and
b) administering via simultaneous dispersion and inhalation the
particles, from a receptacle having the mass of the particles, to a human
subject’s respiratory tract, wherein release of the insulin is rapid.

The Examiner relies upon the following art in rejecting the claims:
Edwards US 5,985,309 Nov. 16, 1999
Patton US 5,997,848 Dec. 7, 1999

We affirm.

ISSUE
The Examiner contends that the invention as claimed is obvious over
the combination of Edwards and Patton, and that Appellants have not
rebutted the prima facie case.
Appellants contend that the Declaration of Jennifer L. Schmitke
submitted under 37 C.F.R. § 1.132 and dated April 20, 2004 rebuts the
Examiner’s prima facie case of obviousness by demonstrating that the
claimed composition has unexpected properties.

2 This case is related to USSN 09/888,126, Appeal No. 2007-0913. Both
Appeals were heard together, and have been considered and decided
concurrently.
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Application 10/179,463

Thus, the issue is does the evidence submitted by Appellants
demonstrate unexpected results as to the insulin formulation being claimed
and thus rebut the Examiner’s case of prima facie obviousness.

FACTS
The Examiner rejected claims 5, 7-18, 26, 28-42, 51, 53-64, and 66-74
under 35 U.S.C. § 103(a) as being obvious over Patton in view of Edwards
(Office Action mailed August 11, 2004, 2). 3
The Examiner relies on Patton for teaching the systemic delivery of
insulin to a mammalian host through the inhalation of a dry powder that is
rapidly absorbed through the alveolar regions of the lung (Office Action
dated August 11, 2004, 2). The dry powder containing insulin is prepared
by dissolving insulin in an aqueous buffer to form a solution and then spray
drying the solution to produce substantially amorphous particles (id.).
According to the Examiner, the pharmaceutical carrier, which may be an
amino acid such as glycine, lysine, etc., may be optionally dissolved in the
buffer, typically a citrate buffer such as sodium citrate, to form a
homogenous solution, “wherein spray drying of the solution produces
individual particles comprising insulin, carrier buffer, and any other
compounds which were preset in the solution.” (Id. at 2-3.)
Patton is also cited for teaching that dry powders of insulin that may
be used include amorphous insulin, crystalline insulin, and mixtures thereof

3 Claims 5, 7-18, 26, 28-42, 51, 53-64, and 66-74 also stood rejected under
the judicially created doctrine of obviousness-type double patenting as being
unpatentable over the claims of copending 10/179,463 in view of Patton
(Office Action mailed August 11, 2004, 5). The rejection was withdrawn in
the Answer upon the filing of a terminal disclaimer (Answer 6).
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(id. at 2). The insulin concentration may range from 5 to 95%, preferably
from 20 to 80%, with the carrier material ranging from 5 to 95% (id. at 3).
The Examiner notes that “Patton, while teaching amino acids as carriers,
lacks disclosure on DPPC.” (Id.)
Edwards is cited for teaching particles “incorporating a surfactant
and/or a hydrophilic or hydrophobic complex of a positively or negatively
charged therapeutic agent and a charged molecule of opposite charge for
drug delivery to the pulmonary system, methods of preparation, and
administration.” (Id.). Surfactants include dipalmitoylphosphatidylcholine
(DPPC), and exemplary hydrophilic or hydrophobic complexes include
insulin and protamine (id.). Moreover, according to the Examiner, the
formulations of Edwards may include one or more excipients such as sugars,
proteins, and surfactants (id. at 4). In addition, “Edwards discloses that
administration of the particles to the lung by aerosolization permits deep
lung delivery of relatively large diameter therapeutic aerosols, for example
greater than 5 micron in mean diameter. The particles can be fabricated with
features which enhance aerosolization via dry powder inhaler devices, and
lead to lower deposition in the mouth, throat and inhaler device.” (Id.).
The Examiner cites Example 9 of Edwards, which discloses particles
containing 60% DPPC, 2% insulin, 19% albumin, and 19% lactose (id.).
The particles are made from solutions of the ingredients, which are
combined and spray dried to produce the particles (id.).
The Examiner concludes:
It would have been obvious to a person of ordinary skill
in the art at the time the invention was made to have modified
the formulations of Patton containing insulin, buffers and
carriers with insulin formulations and method of delivering the
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insulin formulations to the lung as taught by Edwards and to
have implemented DPPC as the carrier, since it was disclosed
that DPPC is an exemplary surfactant, naturally occurring in the
lung.

Id. at 4-5.
In the Appeal Brief, Appellants do not contest the prima facie case of
obviousness. Instead, Appellants argue that “the evidence of record
establishes significant unexpected results. Simply, the evidence establishes
that the specific amounts of these components are critical. Thus the
selection of presently claimed approximate amounts of 75% DPPC, 15%
insulin and 10% citrate combination is patentable over the myriad of
possible combinations derived from the combination of Patton and
Edwards.” (Br. 3).
Appellants refer to Table 1 of the 132 Declaration, stating that
formulations with an Emitted Dose (ED) greater than 90% are stable at
standard conditions, and that formulations 2, 3 and 74 fall into that category
(Br. 5). But when the temperature and humidity were raised to 30°C/80%
relative humidity (RH), according to Appellants, only formulations 2 and 7
met the target of an excellent ED at standard conditions and good retention
of ED at the higher temperature and humidity, while formulations 3, 5, and 6
did not (id.). Thus, Appellants assert, “[w]hat was discovered was that the
15% insulin formulation unexpectedly withstood extreme conditions as
compared to the 10% insulin formulation.” (Id. at 6.) Appellants argue that
“[t]he robustness of a formulation at different environmental conditions was

4 Formulation 7 is the formulation of the instantly claimed invention.
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considered a critical factor in identifying the chemical compositions that are
suitable from a patient safety perspective.” (Id. at 10.)
Appellants conclude that the “132 declaration clearly shows that the
criticality of the presently claimed formulation (not a range of formulations
as described by the Examiner, but instead a superior single species of
formulation), having particles comprising, by weight, approximately 75%
DPPC, approximately 15% insulin and approximately 10% sodium citrate
possesses unexpected properties as compared to formulations that are even
closer than those of the combination of prior art cited by the Examiner.” (Id.
at 6 (emphasis in original).)
The 132 Declaration of Jennifer Schmitke states at page 2 that the
goal of the study “was to evaluate the dose delivery (emitted dose and
aerodynamic particle size distribution) of representative formulations having
a DPPC/sodium citrate excipient base at selected temperature and humidity
conditions.” Table 1 on page 4 of the Declaration summarizes the emitted
dose results of the selected DPPC based powders at 23°C/30%RH and
30°C/80% RH.
Formulations 1 and 2 are both 60% DPPC, 10% sodium citrate, and
30% insulin; yet at 23°C/30% RH, Formulation 1 exhibited an ED of 78(3),5
while Formulation 2 showed an ED of 94(2). At 30°C/80% RH,
Formulation 1 exhibited an ED of 53(10), while Formulation 2 exhibited an
ED of 71(7). Similarly, Formulations 4 and 5 were both 87% DPPC, 10%
sodium citrate, and 10% insulin, and at 23°C/30% RH, Formulation 4
exhibited an ED of 83(2), and Formulation 5 showed an ED of 87(3). At
30°C/80% RH, Formulation 4 exhibited an ED of 48(11), while Formulation

5 Standard deviations are shown in the parenthesis.
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5 exhibited an ED of 61(6). Formulation 7, which is 75% DPPC, 10%
sodium citrate, and 15% insulin, i.e., the claimed formulation, exhibited an
ED of 93(1) at 23°C/30% RH, and an ED of 69(9) at 30°C/80% RH.
The Specification teaches ““[f]ormulations having particles
comprising, by weight, approximately 40% to approximately 60% DPPC,
approximately 30% to approximately 50% insulin and approximately 10%
sodium citrate.” (Specification 3). Also disclosed are:
Formulations having particles comprising, by weight,
approximately 75% to approximately 80% DPPC,
approximately 10% to approximately 15% insulin and
approximately 10% sodium citrate . . . . In one embodiment,
the particles comprise, by weight, 75% to 80% DPPC, 10% to
15% insulin and 10% sodium citrate. In another embodiment,
the particles comprise, by weight, 75% DPPC, 15% insulin and
10% sodium citrate. In yet another embodiment, the particles
comprise, by weight, 80% DPPC, 10% insulin, and 10%
sodium citrate.

(Id.)
In addition, in the human clinical trial described in the Specification, a
dry powder formulation of 60% DPPC, 30% insulin, and 10% citrate was
used (id. at 51-52). The Specification does not disclose the criticality of
formulations of approximately 75% DPPC, approximately 15% insulin and
approximately 10% sodium citrate.

PRINCIPLES OF LAW
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
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argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532, 28
USPQ2d 1955, 1956 (Fed. Cir. 1993) (citations omitted).
The burden of demonstrating unexpected results rests on the party
asserting them, and “it is not enough to show that results are obtained which
differ from those obtained in the prior art; that difference must be shown to
be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080, 173
USPQ 14, 16 (CCPA 1972). Moreover, it has been long held that “even
though applicant’s modification results in great improvement and utility over
the prior art, it may still not be patentable if the modification was within the
capabilities of one skilled in the art, unless the claimed ranges ‘produce a
new and unexpected result which is different in kind and not merely in
degree from the results of the prior art.” In re Huang, 100 F.3d 135, 139, 40
USPQ2d 1685, 1688 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454,
456, 105 USPQ 233, 235 (1955), and citing In re Woodruff, 919 F.2d 1575,
1578, 16 USPQ2d 1934, 1936-37 (Fed. Cir. 1990)).

ANALYSIS
As to the prima facie case of obviousness, Appellants do not contest it
in the Brief,6 thus, for the purposes of this Appeal, we conclude that
Appellants concede that the Examiner has met the burden of establishing a
prima facie case of obviousness.

6 Appellants state in the Reply Brief at page 2 that they have not admitted,
either explicitly or inferentially, that the Examiner has established a prima
facie case of obviousness. But as they do not point to any arguments made
in the Appeal Brief attacking the prima facie case, and also do not present
any argument as to why the Examiner failed to establish a prima facie case
in the Reply Brief, we find that Appellants have conceded the merits of the
prima facie case for purposes of this Appeal. 37 C.F.R. § 41.37(c)(1)(vii).
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We find that Appellants have not demonstrated that the formulation of
claim 5 has unexpected properties so as to rebut the prima facie case of
obviousness, and the rejection is affirmed.
As set forth above, Table 1 of the 132 Declaration, Formulations 1
and 2 are identical (both 60% DPPC, 10% sodium citrate, and 30% insulin).
Yet at 23°C/30% RH, Formulation 1 exhibited an ED of 78(3), while
Formulation 2 showed an ED of 94(2), and at 30°C/80% RH, Formulation 1
exhibited an ED of 53(10), while Formulation 2 exhibited an ED of 71(7).
These results demonstrate that for the same formulation, there was
substantial variability between the tests. Given the above, Formulation 2
would meet the desired criteria of stability, yet formulation 1 would not,
even though they are both 60% DPPC, 10% sodium citrate, and 30% insulin.
In the Declaration, the Declarant states at page 4 that Formulation 1
was not considered to be representative of the formulation, so consequently
the testing was run again using clinical lot capsules, designated as
Formulation 2. The Declarant does not explain, however, how formulations
1 and 2 differ, nor does the Declarant explain why such disparate results
were obtained.
Formulation 5, which is 87% DPPC, 10% sodium citrate, and 10%
insulin, at 23°C/30% RH exhibited an ED of 87(3), and at 30°C/80% RH,
exhibited an ED of 61(6). Formulation 7, which is 75% DPPC, 10% sodium
citrate, and 15% insulin, i.e., the claimed formulation, exhibited an ED of
93(1) at 23°C/30% RH, and an ED of 69(9) at 30°C/80% RH. However, the
ED values between Formulations 5 and 6 differ very little (if at all) when the
standard deviation is taken into consideration. At 23°C/30% RH,
Formulation 5 had an ED of 87(3), and an ED of 90 would be within an ED
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of 87 with a standard deviation of 5. Similarly, Formulation 7 exhibited an
ED of 93(1), which would also include an ED of 92. The difference
between an ED of 90 and 92, we find, is more a difference in kind than a
difference in degree, which is required to support a finding of unexpected
results. Likewise, at 30°C/80% RH, Formulation 5 has an ED of 61(6), and
Formulation 7 has an ED of 69(9). Thus, at 30°C/80% RH, the ED of
Formulations 5 and 7 overlap when the standard deviation is taken into
consideration.
Thus, given that the same formulation, i.e., Formulations 1 and 2,
gave very disparate results, and given that there is little difference between
Formulation 5, which is 10% insulin, and Formulation 7, i.e., the
formulation of claim 5, we find that Appellants’ 132 Declaration does not
demonstrate that the formulation of claim 5 exhibits properties that are
unexpected.

CONCLUSIONS OF LAW
We conclude that the Examiner has set forth a prima facie case of
obviousness that has not been contested by Appellants, and that the
Declaration of Jennifer L. Schmitke, submitted under 37 C.F.R. § 1.132,
does not demonstrate unexpected results sufficient to rebut the prima facie
case.

CLAIMS 51, 53-64, AND 66
Appellants argue that claim 51 is separately allowable, because
“Claim 51 recites simultaneous inhalation and dispersion of the particles
from a receptacle containing the particles (e.g., breath actuated
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administration,” and that “[n]either Patton nor Edwards disclose or make
obvious this feature.” (Br. 10.)
The Specification teaches at pages 30 and 31 that “[v]arious suitable
devices and methods of inhalation which can be used to administer particles
to a patient’s respiratory tract are known in the art,” and lists a number of
suitable prior art inhalers, as well as “others, such as those known to those
skilled in the art.” In addition, both Patton (for example, see the abstract)
and Edwards (see, for example, column 25, Example 12) teach the delivery
of particles of insulin to the lungs, but do not specifically teach the use of a
breath-actuated inhaler.
The panel cites Bacon (U.S. Patent No. 5,503,144, issued April 2,
1996) to demonstrate that breath actuated dry powder inhalers and their use
were known in the art, and thus, it would have been obvious to dispense the
formulation of claim 51 using any dry powder inhaler known to the ordinary
artisan, such as that taught by Bacon. The rapid release of insulin would be
an inherent result of the delivery of the formulation of claim 5 to lungs using
such breath-actuate, dry powder inhalers. Because our reasoning differs
from that of the Examiner, and in order to give Appellants an opportunity to
respond, we designate this affirmance as new grounds of rejection under 37
C.F.R. § 41.50(b).

CONCLUSION
In summary, we affirm the rejection of claims 5, 7-18, 26, 28-42, 51,
53-64, and 66-74. Because our reasoning as to claims 51, 53-64, and 66
differs from that of the Examiner, we designate the rejection as to those
claims only as new grounds of rejection.
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Regarding the affirmed rejection(s), 37 C.F.R. § 41.52(a)(1) provides
"[A]ppellant may file a single request for rehearing within two months from
the date of the original decision of the Board."

In addition to affirming the Examiner's rejection(s) of one or more
claims, this decision contains a new ground of rejection pursuant to
37 C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960
(August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)).
37 C.F.R. § 41.50(b) provides "[a] new ground of rejection pursuant to this
paragraph shall not be considered final for judicial review."

37 C.F.R. § 41.50(b) also provides that the Appellant, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new ground of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment of
the claims so rejected or new evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
Examiner, in which event the proceeding will be remanded to
the examiner. . . .

(2) Request rehearing. Request that the proceeding be reheard
under § 41.52 by the Board upon the same record. . . .

Should the Appellants elect to prosecute further before the Examiner
pursuant to 37 C.F.R. § 41.50(b)(1), in order to preserve the right to seek
review under 35 U.S.C. §§ 141 or 145 with respect to the affirmed rejection,
the effective date of the affirmance is deferred until conclusion of the
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prosecution before the Examiner unless, as a mere incident to the limited
prosecution, the affirmed rejection is overcome.
If the Appellants elect prosecution before the Examiner and this does
not result in allowance of the application, abandonment or a second appeal,
this case should be returned to the Board of Patent Appeals and Interferences
for final action on the affirmed rejection, including any timely request for
rehearing thereof.

AFFIRMED; 37 C.F.R. § 41.50(b)

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