Ex Parte Cipolla et al

Patent Trial and Appeal Board

Jun 14, 2016

12693739 (P.T.A.B. Jun. 14, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/693,739 01/26/2010
93726 7590 06/16/2016
EPA - Bozicevic Field & Francis LLP
Bozicevic, Field & Francis
1900 University Ave
Suite 200
East Palo Alto, CA 94303
FIRST NAMED INVENTOR
David C. Cipolla
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. CONFIRMATION NO.
AERX-127 4689
EXAMINER
GOTFREDSON,GAREN
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
06/16/2016 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID C. CIPOLLA and IGOR GONDA 1
Appeal2014-006013
Application 12/693,739
Technology Center 1600
Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
pulmonary delivery of an antibiotic formulation, which have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
There are a large number of drugs administered by some type of
injection. (Spec. i-f 2.) However, "at times, for some patients [such
administration] is inconvenient, can be painful [and/ or] may cause
1 Appellants identify the Real Party in Interest as Aradigm Corp. (Appeal
Br. 2.)
Appeal2014-006013
Application 12/693,739
transmission of infection." (Id.) The invention relates generally to the
aerosolized delivery of a drug formulation having a pH that is below or
above neutral but becomes more neutral after administration. (Id. at i-f 1.)
Claims 33 and 34 are on appeal and read as follows:
33. A method of treating a bacterial infection, comprising:
aerosolizing a volume of0.1mLto3.0 mL of
formulation to create aerosolized particles having an
aerodynamic diameter in a range of 4.0 microns to 10.0
microns;
administering the aerosolized particles to patient's
respiratory tract by inhalation in a single delivery dose, wherein
the formulation is comprised of antibiotic, a pharmaceutically
acceptable carrier and a pH affecting agent which increases
solubility of the antibiotic in the carrier and is present in a
molarity so as to deviate formulation pH by at least 2. 7 log
units and not more than 5.4 log units away from 7.4; and
allowing the formulation to remain in contact with the
patient's respiratory tract fluids for a period of time and under
conditions such that the formulation moves closer to a pH of
7.4 by 0.5 log unit or more relative to the pH of the formulation
prior to administration; and
further wherein the antibiotic becomes less soluble as
compared to its solubility in the formulation prior to
administration.
34. A method of treating a bacterial infection, comprising:
administering an aerosolized volume of formulation in an
amount of 0.1 mL to 3.0 mL to a patient's respiratory tract by
inhalation, wherein the formulation is comprised of
ciprofloxacin, a pharmaceutically acceptable carrier and a pH
affecting agent which increases solubility of the ciprofloxacin
in the carrier and is present in a molarity so as to deviate
formulation pH by at least 3.0 log units and not more than 5.4
log units away from 7.4;
allowing the formulation to remain in contact with the
patient's respiratory tract fluids for a period of time and under
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Application 12/693,739
conditions such that the formulation moves closer to a pH of
7.4 by 0.5 log unit or more relative to the pH of the formulation
prior to administration; and
further wherein the ciprofloxacin becomes less soluble as
compared to its solubility in the formulation prior to
administration; and
wherein the pH affecting agent is selected from the group
consisting of hydrochloric acid, phosphoric acid, acetic acid,
citric acid, lactic acid, ascorbic acid, sulfuric acid, succinic acid,
benzoic acid, lipoic acid and malic acid.
(Appeal Br. 22.)
There is a single ground of rejection by the Examiner before us on
review, namely that claims 33 and 34 are unpatentable under 35 U.S.C.
§ 103(a) over Lowry, 2 Yu, 3 Weber, 4 and Keller. 5
DISCUSSION
The Examiner finds that Lowry discloses a method of administering
aerosolized formulations that do not cause lung irritation. (Final Action 3;
Ans. 2-3.) The Examiner explains that Lowry exemplifies delivery of
formulations having a pH of 4.8 and pH 8 with aerosol particles having a
median diameter of 6-8 microns to a patient's respiratory tract through
inhalation of a single dose. (Final Action 3; Ans. 2-3, 8.) The Examiner
2 R.H. Lowry et al., Effects of pH and osmolarity on aerosol-induced cough
in normal volunteers, 74 Clin. Sci. 373-376 (1988) ("Lowry").
3 Xuanqiang Yu. et al., The Effect of Temperature and pH on the Solubility
of Quinolone Compounds: Estimation of Heat of Fusion, 11(4) Pharm. Res.,
522-527 (1994) ("Yu").
4 Allan Weber et al., Effect of Nebulizer Type and Antibiotic Concentration
on Device Performance, 23 Pediatr. Pulmonol. 249-260 (1997) ("Weber").
5 Keller et al., US 2009/0025713 Al, published Jan. 29, 2009 ("Keller").
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Application 12/693,739
acknowledges that Lowry does not teach inclusion of an antibiotic in the
formulation or disclose the claimed volume of aerosol for delivery. (Final
Action 3--4; Ans. 3.) The Examiner identifies two prior art references,
Keller and Weber, though, that disclose aerosolizing antibiotics, such as
ciprofloxacin. (Final Action 4; Ans. 3.)
In particular, the Examiner finds that Keller discloses pharmaceutical
aerosols comprising a bioactive, which could be ciprofloxacin, where the pH
of the formulation is between 4 and 8 "to strike a balance between storage
stability and the need for the aerosol to be well tolerated," and that are
delivered in an amount of less than 5 ml at a rate of at least 0.1 ml/min.
(Final Action 4; Ans. 3). The Examiner further finds that Keller teaches a
specific embodiment aerosolizing 1.5 ml of an antibiotic. (Ans. 5.)
The Examiner finds Weber discloses aerosol administration of
ciprofloxacin for treating cystic fibrosis, notes that a ciprofloxacin
formulation will precipitate at a pH of more than 5.5, and that a pH of as low
as 3 .98--4.10 of a formulation "is at the threshold of causing an adverse
reaction in cystic fibrosis patients." (Final Action 3; Ans. 3, 8.) The
Examiner points out that Weber did not study high concentrations of
ciprofloxacin because of that antibiotic's low solubility in water and saline.
(Id.) However, the Examiner points out that Yu discloses that it was known
that the solubility of ciprofloxacin is strongly dependent on pH-being
largely insoluble at a neutral pH and reaching maximum solubility at a pH of
less than 6 or greater than 9. (Final Action 4; Ans. 3.)
In light of these prior art teachings, the Examiner concludes that it
would have been obvious to modify the method of Lowry by selecting
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ciprofloxacin as a drug for delivery using the aerosol of Lowry and to
provide for the pH of the composition to be within the claimed range
because (a) Weber teaches that ciprofloxacin can be efficaciously
administered via aerosol to the lung, (b) Yu teaches a pH of less than 6
would allow the ciprofloxacin to dissolve in the aerosol, thus, solving the
problem noted by Weber regarding the difficulty of working with aerosols
comprising high concentrations of ciprofloxacin due to low solubility and ( c)
Keller teaches that one can make a formulation that includes ciprofloxacin
with a pH as low as 4. (Final Action 4--5; Ans. 4.) The Examiner explains
one of ordinary skill would have been highly motivated to
search, with a reasonable expectation of success, for an
aerosolized ciprofloxacin formulation having a pH range within
the range of 4--8 that is taught as safe by Keller, reasonably near
the pH value of 4.8 that is taught by Lowry as well tolerated,
higher than the 4 .1 disclosed by [Weber] 6 as being at the
threshold of causing an adverse reaction, but below the pH of
5.5 that \vould cause the ciprofloxacin to precipitate as taught
by [Weber]. Such a search would lead directly to the
generation of aerosol formulations that are within the claimed
ranges, including, for example, a pH of 4.7 (within the scope of
claim 33), and a pH of 4.4 (within the scope of claim 34).
(Ans. 9.)
The Examiner further concludes that it would have been prima facie
obvious to modify the Lowry method to deliver less than 5 ml of
formulation, such as 1.5 ml, because Keller discloses this volume is
6 The Examiner inadvertently referred here to Keller, but the prior
paragraph's description (Ans. 8) clearly indicates that the Examiner meant to
refer to Weber.
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preferred for the delivery of an aerosol comprising an antibiotic. (Final
Action 5; Ans. 4, 6.) The Examiner notes that
[t]he altered pH of the aerosol administered by the modified
method [would] necessarily increase the solubility of the
ciprofloxacin antibiotic as recited by the claims as taught by
Yu, and once administered to a patient, the formulation [would]
necessarily remain in contact with the respiratory tract fluids for
a period of time, such that the formulation moves closer to a pH
of 7.4 by 0.5 log unit or more or 1-2 log units as claimed,
which [would] necessarily cause the ciprofloxacin to become
less soluble.
(Final Action 5; Ans. 4.) We agree with the Examiner's fact-findings and
conclusion of obviousness.
pH
Appellants contest the Examiner's rejection because none of the
references teach aerosolized antibiotic formulations having the pH ranges
claimed (Appeal Br. 16) and the "the vast majority of the publications teach
away from using formulations such as those taught by applicants and
encompassed by the currently pending claims" (Appeal Br. 12). These
arguments are not persuasive.
As Appellants recognize, the claims are directed to a range of pH
values. (See, e.g., Appeal Br. 13-14.) Claim 33 states that the formulation's
pH affecting agent, "which increases [the] solubility of the antibiotic in the
carrier," can "deviate [the] formulation pH by at least 2.7 log units and not
more than 5.4 log units away from 7.4" and for claim 34 it can "deviate [the]
formulation pH by at least 3.0 log units and not more than 5.4 log units away
from 7.4." (Appeal Br. 22.) Thus, for claim 33, the pH of the formulation
can range from pH 2.0-4.7 and pH 10.1-12.8, and, for claim 34, the pH can
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range from pH 2.0-4.4 and pH 10.4--12.8. (See e.g., Appeal Br. 13-14
(Figs. 3 and 4).) Keller's disclosed safe pH range of 4--8 includes several
pH log units within both claim 33 and 34, 7 as the Examiner indicated, i.e.,
4.0-4.7 (claim 33) and 4.0-4.4 (claim 34). (Final Action 7; Ans. 7.)
We do not agree with Appellants that the prior art teaches away from
the full range of pH values encompassed by the claims. This matters
because it is well settled that when ranges recited in a claim overlap with
and/ or touch ranges disclosed in the prior art, a prima facie case of
obviousness typically exists and the burden of proof is shifted to the
applicants to show that the claimed invention would not have been obvious.
In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003); In re Geisler, 116
F.3d 1465, 1469 (Fed. Cir. 1997).
Notwithstanding that the prior art cited by Appellants may support
"the general assertion that aerosolized formulations having a pH that is too
far from 7.4 may cause adverse reactions when administered in sufficiently
large volumes," (Ans. 6 (emphasis added)), we agree with the Examiner that
such does not teach away from the claimed pH range. Here, the prior art
indicates a safe range for aerosolized antibiotic delivery, said safe range
overlapping with the pH values in the claimed range. (Ans. 7-8.)
7 Appellants contend all formulations of Keller "are excluded by claim 34."
(Appeal Br. 19-20.) That contention is premised on the Appellants'
assertion that Keller teaches a pH range of between 4. 5-7. 5. (Id.) Contrary
to Appellants' assertion, Keller teaches the pH range of a ciprofloxacin
aerosol composition can be used in a pH range of from 4--8. (Keller i-f 79.)
A pH range between pH 4.5-7.5 is identified as a "particularly preferred"
subrange in Keller. (Id.; Ans. 7 and 10.) Keller's pH range of from pH 4--8
overlaps the range embraced in claim 34 at from pH 4--4.4.
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Labiris8 does not indicate what pH is considered "too low" such that it
"may induce bronchoconstriction, coughing and irritation of the lung
mucosa [8, 9]." (Appeal Br. 10.) Publication 8 referenced in Labiris
(Appeal Br. 10), which is the Weber reference relied on by the Examiner in
rejecting claims 33 and 34 for obviousness, notes that "inappropriate
extremes" in pH are problematic and that for patients with cystic fibrosis pH
extremes range from 4.10 to 3.98. (Weber 259; Ans. 8.) Lee, 9 Wong, 10 and
Dicpinigaitis 11 (Appeal Br. 11 ), all teach that strong acids, such as citric
acid, gastric acid, and acetic acid, can induce a cough response. (See Ans.
7.) None of Lee, Wong, or Dicpinigaitis teach that a pH of an aerosolized
antibiotic formulation that is between pH 4--8 would induce a cough
response. 12 And at most, Weber suggests that a pH of 4--4.1 in Keller's safe
pH range of 4--8 would not be tolerable for patients having cystic fibrosis.
(Ans. 8-9.)
8 N.R. Labiris and M.B. Dolovich, Pulmonary drug delivery. Part II: The
role of inhalant delivery devices and drug formulations in therapeutic
effectiveness of aerosolized medications, 56 J. Clin. Pharmacol. 600-612
(2003) ("Labiris").
9 Lu-Yuan Lee et al., Acid-sensing by airway afferent nerves, 26 Pulmonary
Pharmacol. & Therap. 491--497 (2013) ("Lee").
1° C.H. Wong et al., Cough induced by low pH, 93 Resp. Med. 58---61 (1999)
("Wong").
11 Peter V. Dicpinigaitis, Experimentally induced cough, 20 Pulmonary
Pharmacol. & Therap. 319-324 (2007) ("Dicpinigaitis").
12 Christine M. Smith et al., Review: Inhalation provocation tests using
nonisotonic aerosols, 84 J. Allergy Clin. Immunol. 781-790 (1989)
("Smith") cited by Appellants (Appeal Br. 11) does not concern pH and
cough response, but rather osmolarity or noniostonic solutions, including
dense aerosols of water.
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We also disagree with Appellants' assertion that Lowry teaches away
from the claimed pH range. (Appeal Br. 17.) Even though the claimed
formulations exclude the pH of 4.8 and 8.0 tested and shown not to induce a
cough response in Lowry (Appeal Br. 17), Lowry does not teach
formulations having pH values between 4.0-4.7 (or 4.0-4.4}-pH values
encompassed within the range claimed-would be intolerable. Rather, we
find that Lowry suggests to one of ordinary skill in the art that pH values
within that range would not be expected to cause a cough response in light
of the fact that pH 4.8 and 8.0 did not cause a cough response, whereas the
pH values of 2.0, 2.6, 3.6, 8.5, 8.6, and 10.0 did. (Lowry 374 (Table 1) and
375 (Table 3); Ans. 8-9.) Keller's teaching that ciprofloxacin formulations
may be administered safely at pH values between 4--8 (Ans. 8-9) further
supports that conclusion.
Furthermore, Appellants' argument that the rejection for obviousness
is improper because none of the references teach aerosolized antibiotic
formulations having the pH ranges claimed is grounded in reading the
references in isolation and not for what is fairly taught by them. "Non-
obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
references. . . . [The reference] must be read, not in isolation, but for what it
fairly teaches in combination with the prior art as a whole." In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). We agree with the Examiner's
conclusion that it would have been obvious to modify the method of Lowry
by selecting ciprofloxacin as a drug for delivery using the aerosol of Lowry
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and to provide for the pH of the composition to be within 4.1--4.7 (or 4.1-
4.4) in light of the teachings of Keller, Weber, and Yu. (Ans. 4--5, 8-9.)
As we noted above, the cited references need not teach every point
within a claimed range in order to render the claims prima facie obvious. In
re Peterson, 315 F.3d at 1329-30; In re Geisler, 116 F.3d at 1469. Keller's
disclosed pH range includes several pH log units within both claims 33 and
34 (see note 7 above), as the Examiner indicated. (Final Action 7; Ans. 7.)
And thus, the prima facie case of obviousness is not defeated, even if Lowry
teaches one should "avoid[] very low (2.6) or very high (10.6) pH
formulations," which are pH values included in the pH range embraced by
claims 33 and 34 (Appeal Br. 17), or that "virtually all the formulations of
Keller et al. are excluded" (Appeal Br. 19-20). Nor does it matter that the
prior art cited by Appellants may "teach away from low and high pH
formulations." (Appeal Br. 10-12.) The question is whether the prior art
teaches one or more values in the claimed pH range would have been
obvious; we agree with the Examiner's conclusion that pH values between
4.1--4.7 or 4.1--4.4 would have been. In light of Keller and Lowry's teaching
regarding tolerable pH being above 4 and up to 8, and Weber's teaching that
pH as low as 3 .98--4.10 is a threshold of where an adverse cough reaction
may occur but that a pH of 5.5 would cause ciprofloxacin to precipitate
(Weber 259; Ans. 8), we agree with the Examiner that one of ordinary skill
in the art would have been motivated to provide a pH of a commercial
ciprofloxacin formulation between 4.1and4.7 (or 4.1--4.4) with a reasonable
expectation of succeeding in obtaining a formulation having ciprofloxacin
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solubilized in an aerosol for delivery to a patient, where that formulation
would not cause a cough response. (Ans. 8-9.)
In general, a prima facie case of obviousness with respect to claimed
ranges may be overcome by establishing "that the [claimed] range is critical,
generally by showing that the claimed range achieves unexpected results
relative to the prior art range." In re Geisler, 116 F.3d at 1469-70,
(alterations in original). But "[t]o be particularly probative, evidence of
unexpected results must establish that there is a difference between the
results obtained and those of the closest prior art, and that the difference
would not have been expected by one of ordinary skill in the art at the time
of the invention." Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752
F.3d 967, 977 (Fed. Cir. 2014). Appellants have not provided sufficient
evidence of unexpected results, particularly in light of Yu's teaching that it
was known that ciprofloxacin is much more soluble at pH below 6 than at
neutral pH. (Yu (Fig. 3); Final Action 4; Ans. 3.)
Appellants also contend that because Lowry excludes formulations
included within the claimed range and includes formulations excluded by the
claimed range Lowry ( 1) does not understand that "very high and very low
pH formulations can be used; (2) ... do[ es] not understand that the pH needs
to be moved away from 7.4 by a significant amount to obtain the desired
drug concentration; and (3) . . . [has] no appreciation of the relationship
between volume, pH and drug concentration as used to treat an infection."
(Appeal Br. 15.) This argument does not persuade us that the Examiner's
rejection is in error. Even setting aside that the prior art does not need to
teach every value in the range to render the claims obvious, the claims do
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not recite a particular drug concentration. And in any event, Yu clearly
teaches the relationship between ciprofloxacin solubility and pH was well
known. (Yu (Fig. 3); Final Action 4; Ans. 3.)
Reduction in antibiotic solubility upon administration
Appellants also contend the Examiner's obviousness rejection is in
error because the prior art "does not show the composition [having] the
inherent property [of precipitating the antibiotic out of solution upon
administration]." (Appeal Br. 18-19.) Appellants concede that precipitation
of the antibiotic upon administration as recited by the claims is simply a
property of the claimed formulation having a pH value anywhere within the
claimed range. (Appeal Br. 18-19). We agree with the Examiner, that the
composition suggested by Lowry, Keller, Weber, and Yu having a pH value
between 4.1--4.7 (or 4.1--4.4) would precipitate upon administration as
recited in the claims. (Ans. 4, 11.) Whether the art shows that property is
inherent is immaterial to the question of obviousness. The recitation of an
additional advantage associated with doing what the prior art suggests does
not lend patentability to an otherwise unpatentable invention. Ex
parte Obiaya, 227 USPQ 58, 60 (BP AI 1985). It is sufficient that the
reference "suggests doing what appellants have done." In re Kronig, 539
F.2d 1300, 1304 (CCPA 1976).
concentration
Appellants further argue the Examiner's obviousness rejection is
improper because "there is no teaching or suggestion [of] why a higher
concentration of [a drug such as ciprofloxacin] within an aerosolized
formulation might provide beneficial effects." (Appeal Br. 18.) This
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argument is not persuasive in light of Weber's disclosure that there was
interest in testing higher concentrations of ciprofloxacin but such could not
be done in light of the solubility problems in water and normal saline with
the commercial formulation with which it was testing aerosolization.
(Weber 253.)
Accordingly we, we affirm the Examiner's obviousness rejection of
claims 33 and 34.
SUMMARY
For the reasons discussed, we affirm the Examiner's rejection of
claims 33 and 34 under 35 U.S.C. § 103(a) for obviousness over Lowry, Yu,
Keller, and Weber.
TIME PERIOD FOR RESPONSE
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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