Ex Parte Srinivasan et al

Patent Trial and Appeal Board

Jun 21, 2016

10939351 (P.T.A.B. Jun. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/939,351 09/14/2004
13897 7590 06/23/2016
Abel Law Group, LLP
8911 N. Capital of Texas Hwy
Bldg 4, Suite 4200
Austin, TX 78759
FIRST NAMED INVENTOR
Viswanathan Srinivasan
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.
3205-P25091 4378
EXAMINER
WORSHAM, JESSICA N
ART UNIT PAPER NUMBER
1615
NOTIFICATION DATE DELIVERY MODE
06/23/2016 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):
mail@Abel-IP.com
hmuensterer@abel-ip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte VISWANATHAN SRINIVASAN, RAPH BROWN,
DAVID BROWN, JUAN CARLOS MENENDEZ,
VENKATESH BALASUBRAMANIAN,
and SOMPHET PETER SUPHASA WUD 1
Appeal2013-009326
Application 10/939,351
Technology Center 1600
Before ULRIKE W. JENKS, JACQUELINE T. HARLOW,
and TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to dosage
forms ofphenylephrine, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We affirm-in-part.
1 Appellants identify the Real Party in Interest as Sovereign
Pharmaceuticals, LLC. (Appeal Br. 3.)
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Application 10/939,351
STATEMENT OF THE CASE
"Phenylepherine, when taken orally by human subjects in adequate
dosages ... relieves swelling of the mucous membranes of the nose and
contiguous respiratory mucosa when this swelling is caused by viral or
allergic conditions." (Spec. i-f 3.) "The present invention relates to a
pharmaceutical dosage form which contains phenylepherine and/or a
pharmaceutically acceptable salt thereof in combination with at least one
additional active ingredient." (Id. i-f 1.)
Claims 129-256 are on appeal. Claim 129 is illustrative:
129. A pharmaceutical dosage form which comprises (a) a first
drug which is selected from phenylepherine and
pharmaceutically acceptable salts thereof and (b) at least one
second drug, wherein the dosage form provides a plasma
concentration within a therapeutic range of the at least one
second drug over a period which is coextensive with at least
about 70 % of a period over which the dosage form provides a
plasma concentration \'l1ithin a therapeutic range of
phenylepherine.
(Appeal Br. 40 (Claims App'x).) Certain other claims (e.g., claim 233)
require only phenylephrine without a second active drug. (Id. at 58.)
The claims stand rejected as follows:
Claims 129-131, 133-137, 140-142, 147-164, 167, 169, 170, 176-
205, and 214--256 as unpatentable under 35 U.S.C. § 103(a) over Fanara et
al. (US 6,699,502 Bl, Mar. 2, 2004) ("Fanara") in view of Findlay et al. (US
4,650,807, Mar. 17, 1987) ("Findlay").
Claim 132 as unpatentable under 35 U.S.C. § 103(a) over Fanara in
view of Findlay and Dang et al. (US 6,462,094 B 1, Oct. 8, 2002) ("Dang").
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Claims 206-213 as unpatentable under 35 U.S.C. § 103(a) over
Fanara in view of Findlay and Wen et al. (US 6,001,392, Dec. 14, 1999)
("Wen").
Claims 138, 143, 168, and 175 as unpatentable under 35 U.S.C.
§ 103(a) over Fanara in view of Findlay and Mayer et al. (US 5,840,731,
Nov. 24, 1998) ("Mayer").
Claims 139, 166, and 172 as unpatentable under 35 U.S.C. § 103(a)
over Fanara in view of Findlay and Shtohryn et al. (US 4,820,523, Apr. 11,
1989) ("Shtohryn").
Claims 139, 166, and 172 as unpatentable under 35 U.S.C. § 103(a)
over Fanara in view of Findlay and Sunshine et al. (US 4,839,354, June 13,
1989) ("Sunshine").
Claims 129-131, 133-137, 140-142, 144--165, 167, 169-171, 173,
174, 176-205, and 214--256 as unpatentable under 35 U.S.C. § 103(a) over
Fanara in view of Paradissis et al. (US 5,445,829, Aug. 29, 1995)
("Paradis sis").
On appeal, we determine whether the Examiner established by a
preponderance of the evidence that the claims would have been obvious
under each of the rejections listed above.
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Findings of Fact2
DISCUSSION
1. Fanara teaches pharmaceutical compositions "allowing for the
controlled release of at least one active substance." (Fanara Abstract.)
Fanara teaches "multi-layered pharmaceutical compositions, including at
least one layer of the inventive composition." (Id.) Fanara also teaches the
"release of active substances during oral administration can be controlled by
means of matrix-type pharmaceutical compositions" (id. at col. 1, 11. 14--16),
such as by "hydrophilic matrices [that] comprise gelling excipients" (id. at
col. 1, 11. 30-31 ). Moreover, Fanara teaches these compositions may be
"provided in the form of tablets, granules, micro granules and the like, these
forms being coated or otherwise." (Id. at col. 5, 11. 19-22.)
2. According to Fanara, it is desirable "to control the release of
pharmaceutically active substances so that they can be administered in a few
daily doses, ideally in a single dose." (Id. at col. 1, 11. 11-13.) Fanara
teaches that its compositions "allow[] the controlled release of
pharmaceutically active substances such that a satisfactory therapeutic effect
is observed over fairly long periods, for example in only one or two daily
doses ... and allow regular and continuous release of active substances over
periods of at least 12 hours." (Id. at col. 3, 11. 24--32.) Fanara also teaches
2 We adopt the Examiner's other findings that are uncontested on appeal.
For example, the Examiner cites Dang, Mayer, Wen, Sunshine, Shtohryn,
and Paradissis as disclosing certain elements of the dependent claims. (See,
e.g., Final Act. 7 (citing Dang's teaching of phenylephrine tannate); id. at 14
(citing bropheniramine maleate and other agents taught in Paradissis).)
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it is increasingly therapeutically advantageous to be able to
simultaneously administer by the oral route an active substance
released immediately after administration, and the same or a
second active substance released gradually and regularly after
administration. In the case where the same active substance is
simultaneously administered for immediate release and for
prolonged release, this makes it possible to rapidly release a
sufficient dose of active substance to trigger the desired effect
and to maintain this effect by a gradual and prolonged release
of the same active substance. In the case where an active
substance is released immediately and another active substance
is released gradually, this makes it possible to obtain combined
therapeutic effects by means of two active substances having
very different pharmacokinetic profiles.
(Id. at col. 2, 11. 36-50.)
3. Fanara teaches the active substances may include
"vasoconstrictors, antihistamines, analgesics, antitussives and the like." (Id.
at col. 4, 11. 57-58.) More specifically, Fanara identifies
[ n ]onlimiting examples of such active substances are
pseudoephedrine, ephedrine, phenylephrine,
phenylpropanolamine, trapidil, hydrocodone, cetirizine,
efletirizine, hydroxyzine, meclizine, buclizine, pentoxyverine,
codeine, morphine, their optical isomers or their
pharmaceutically acceptable salts.
As regards the dose of active substance used, it depends
on the effective dose and may therefore vary within very wide
limits depending on the said active substance.
(Id. at col. 4, 11. 62 through col. 5, 1. 3 (emphasis added).) Fanara identifies
working examples with combinations of active substances, such as
pseudoephedrine/cetirizine and immediate release hydrocodone/prolonged
release hydrocodone. (Id. at col. 6, 11. 20-29; id. col. 9-10, Example 4; id. at
col. 12-13, Example 7.)
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4. Findlay discloses antihistamines for human use and teaches that
such compounds may be used with other therapeutic agents, including "a
sympathomimetic agent such as the decongestants pseudoephedrine or
phenylpropanolamine, an antitussive such as codeine, an analgesic such as
acetaminophen ... or an expectorant such as guaifenesin." (Findlay col. 5,
11. 1-15.) Finlay also teaches its formulations "may be presented as discrete
units such as capsules, cachets, tablets or lozenges ... as a powder or
granules; or a suspension in an aqueous liquid or non-aqueous liquid such as
a syrup, an elixir, an emulsion or a draught." (Id. at col. 5, 11. 34--40.)
5. Wen discloses antitussive drugs delivered by ion exchange resins.
(Wen Abstract.) Wen teaches "a controlled release syrup suspension for oral
administration, preferably containing dextromethorphan polystyrene
sulfonate resin. The composition provides up to 12 hours of symptomatic
relief from dry coughing." (Id. at col. 1, 11. 5-9.) Wen teaches formulations
may include "at least one of an antihistamine, sympathomimetic drug (nasal
decongestant, bronchodilator) analgesic, anti-inflammatory, cough
suppressant and/or expectorant." (Id. at col. 4, 11. 40-46.)
Analysis
1) Rejection of Claims 129-131, 133-137, 140-142, 147-164, 167,
169, 170, 176-205, and 214--256 over Fanara and Findlay
Claim 129 is representative. 3
3 We address the rejections in the order presented in the Appeal Brief. To
the extent Appellants argue a claim or group of claims separately, we will
address in tum. When, however, multiple claims are subject to the same
ground of rejection and have been argued together, we may select a single
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According to the Examiner, Fanara teaches "oral pharmaceutical
compositions for controlled release of active substances, whereby the
compositions include multi-layered formulations." (Final Act. 3.) The
Examiner finds that Fanara's compositions "can be administered in a few
daily doses, ideally in a single daily dose" and "allow [for] regular and
continuous release of active substances over periods of at least 12 hours."
(Id. at 3--4.) The Examiner also finds that Fanara teaches compositions with
a single active substance, for instance, in immediate and sustained release
formulations, as well as multiple active substances in controlled release
formulations. (Id.) Where different active substances are used, the
Examiner finds Fanara teaches that "this makes it possible to obtain
combined therapeutic effects by means of two active substances having very
different pharmacokinetic profiles." (Id. at 4.)
The Examiner finds that Fanara teaches the active substances may
include "antihistamines, analgesics, ... decongestants, such as
pseudoephedrine, phenylepherine, ... and antitussives such as hydrocodone
... [and their] pharmaceutically acceptable salts." (Id.) According to the
Examiner, "Examples at columns 6-18 [of Fanara] demonstrate various
layered controlled release pharmaceutical compositions of the invention.
For instance, Example 7 at column 12 demonstrates a double-layered tablet
comprising hydrocodone bitartrate." (Id.) The Examiner also cites Example
4 of Fanara as teaching a formulation that "combines a pseudoephedrine
claim from the group and decide the appeal as to the ground of rejection for
that group on the basis of the selected claim alone. 47 C.F.R.
§ 41.37(c)(l)(iv).
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controlled release layer with a cetirizine immediate release layer" along with
data the Examiner contends shows "Fanara specifically exemplifies a bi-
layer tablet with an overlap in period of pharmaceutical activity." (Ans. 7.)
Moreover, the Examiner finds "the active agents are not limited to
pseudoephedrine and cetirizine, but can also be selected from ephedrine,
phenylephrine, phenylpropanolamine, hydrocodone, etc .... [and] [t]hus it
would have been obvious that phenylephrine could be selected as one active
ingredient and formulated in combination with another active ingredient,
including itself, in either controlled or immediate release form." (Id. at 7-8.)
The Examiner finds that the claim language about overlapping
therapeutic periods is known and would have been obvious over Fanara:
[w]ith respect to the instant claim limitation of the "dosage
form providing a plasma concentration within a therapeutic
range of the at least one second drug over a period which is
coextensive with at least about 70% of a period over which the
dosage form provides a plasma concentration \'l1ithin a
therapeutic range of the first drug (phenylepherine )" as well as
"at least about 95%", it is the position of the Examiner that the
Fanara reference meets these claim limitations. The Fanara
reference explicitly recognizes and teaches simultaneous
administration of multiple active agents whereby it is possible
to combine therapeutic effects of active substances having very
different pharmacokinetic profiles. Thus, the Fanara reference
teaches an objective similar to that being claimed by Applicant.
(Final Act. 5.) Also, according to the Examiner,
[t]he percent of coextension or overlap (about 70%) of one drug
with another does not distinguish over the teachings of the art
... since one of ordinary skill in the art would clearly desire
overlap of therapeutic activity so as to form a continuum of
beneficial effects without interruption or discontinuity in the
therapeutic activity.
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(Ans. 4.) Moreover, the Examiner finds that Appellants' arguments about
therapeutic overlap "are directed to functional data without any structural
limitations resulting in the claimed function ... [and] without any other
structural details limiting the claims, similar ingredients will behave in a
similar manner, with similar functional properties." (Adv. Act. 2; see also
Final Act. 16.)
The Examiner finds that Fanara does not recite certain antihistamines
and other active substances appearing in some of the dependent claims, and
so turns to Findlay. For example, the Examiner states that "Fanara does not
teach the antihistamines promethazine and/or chlorpheniramine ... and
do[ es] not teach the antitussive/expectorant- guaifenesin." (Final Act. 5.)
After identifying those substances in Findlay, the Examiner finds "[i]t would
have been obvious to one of ordinary skill in the art at the time the invention
was made to incorporate the suitable antihistamines and expectorants taught
by Findlay[] within the formulations of Fanara[]." (Id. at 6.) The reason,
according to the Examiner, is Findlay teaches such compounds are "useful
for their histamine-blocking and cough suppressing properties" and thus the
"expected result[ s] would be an improved formulation for the treatment of
cough suppression and allergic conditions." (Id.)
Appellants' arguments focus on the claim phrase concerning the
extent of overlap between the periods of therapeutic activity of the first and
second drugs. According to Appellants, it is not enough to show in the art
an overlap (even 70, 80, or 90 percent or more) in plasma concentrations
between the first and second drugs because one or the other drug may be
therapeutically inactive during the period of overlap. (Appeal Br. 9-10.)
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What is decisive, Appellants contend, is whether the second drug is
therapeutically active during "at least about 70%" of the time that the first
drug is therapeutically active. (Id.) Appellants assert that Fanara "is
concerned primarily with pharmaceutical compositions for controlled release
of active substances ... not with the administration of different active
substances in a single dosage form." (Id. at 10; Reply Br. 2.) And,
Appellants' argument goes, "there is not a single passage in FANARA
wherein the period of therapeutic activity of any active substance in relation
to the period of therapeutic activity of another active substance is
addressed." (Appeal Br. 15.)
Appellants' arguments are unpersuasive. We agree claim 129 requires
more than mere overlap in a measurable plasma concentration of two drugs,
but we are not persuaded that Fanara's disclosure and the reasoning provided
by the Examiner fail to establish a prima facie case that claim 129 would
have been obvious.
In arguing that Fanara is "primarily" concerned with controlled
release of active substances and not administration of different active
substances in a single dosage form (id. at 10), Appellants dismiss Fanara's
other material teachings. Merck & Co., Inc. v. Biocraft Labs., Inc., 87 4 F .2d
804, 807 (Fed. Cir. 1989) ("But in a section 103 inquiry, the fact that a
specific [embodiment] is taught to be preferred is not controlling, since all
disclosures of the prior art, including unpreferred embodiments, must be
considered." (citation and internal quotation marks omitted)). Throughout,
Fanara teaches the administration of different active substances in a single
dosage form. (FF 2.) Fanara teaches compositions "allowing for the
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controlled release of at least one active substance" such as, for example, in
a "multi-layered pharmaceutical compositions including at least one layer of
the inventive composition." (FF 1 (emphasis added).) Fanara teaches that,
when different active substances are simultaneously included, Fanara's
compositions "make[] it possible to obtain combined therapeutic effects by
means of two active substances having very different pharmacokinetic
profiles." (Ans. 10; FF 2.) Fanara further teaches that controlled release
formulations are desirable in order to limit administration to "a few daily
doses, ideally in a single daily dose." (FF 2.) Similarly, Fanara teaches
compositions that exhibit a "satisfactory therapeutic effect ... over fairly
long periods ... [and] allow regular and continuous release of active
substances over periods of at least 12 hours." (FF 2.)
Based on Fanara's full disclosure, the skilled artisan would have
reason to limit the number of doses to improve patient compliance while
maintaining therapeutic activity over a longer period of time. That is true
whether one or multiple drugs are administered in a single dosage. Indeed,
we find it illogical that a skilled artisan would control the release of only one
drug when the control of multiple drugs, such as the decongestants,
antihistamines, antitussives, and analgesics described in Fanara, is needed to
limit daily doses of a multi-drug formulation. As the Examiner finds, "one
of ordinary skill in the art would clearly desire overlap of therapeutic
activity so as to form a continuum of beneficial effects without interruption
or discontinuity in the therapeutic activity." (Ans. 4.) To illustrate in the
context relevant here, it would be desirable that a patient taking a single-
dose formulation that includes a decongestant and antitussive not have the
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therapeutic benefit of the antitussive end within a few hours while the other
drug remains therapeutically active for 12 hours. Otherwise the patient
would require a separate dose of antitussive alone within a few hours to
remedy their persistent cough, yet no additional decongestant would be
needed because it is still fully active in the patient's system. Instead, the
skilled artisan would predictably design a controlled formulation that
provides substantial overlap in the various drugs' therapeutic activity over
the desired period (e.g., 12 hours) so that, at the end of the period, another
single-dose with both drugs could be taken by the patient as necessary.
As for Appellants' argument that Fanara is completely silent in
addressing the period of therapeutic activity of any one drug in relation to
another, we disagree. For the reasons above, we find that a person of
ordinary skill in the art would have understood Fanara to teach that the
therapeutic activity of multiple drugs in a single-dosage form should
substantially overlap within the desired period of time. Appellants have
offered no other persuasive interpretation of Fanara' s teachings, including its
disclosure that the inventive compositions "make[] it possible to obtain
combined therapeutic effects by means of two active substances having very
different pharmacokinetic profiles." (FF 2 (emphasis added); see also
Appeal Br. 12-14.)4 And, although Fanara does not expressly state, on a
4 Appellants describe hypothetical scenarios they contend show overlap
between therapeutic periods would serve no useful purpose. (Appeal Br.
12-14.) These scenarios, however, are inconsistent with Fanara's examples.
Example 4 shows the combination of a controlled-release decongestant
(pseudoephedrine) and immediate-release antihistamine ( cetirizine - an
antihistamine that the skilled artisan would know has a respectively longer
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percentage basis, the degree to which the drugs' therapeutic activity should
overlap, absent factual evidence to the contrary, we find it likely those
percentages would have been derived through predictable optimization. In
re Aller, 220 F.2d 454, 456 (CCPA 1955) ("[W]here the general conditions
of a claim are disclosed in the prior art, it is not inventive to discover the
optimum or workable ranges by routine experimentation.").
Appellants also challenge the Examiner's citation to working
examples in Fanara, but this challenge fails to persuade us that the claims
would have been nonobvious. (Reply Br. 5---6.) The Examiner cites
Example 4, a tablet combining pseudoephedrine in a controlled-release layer
with cetirizine in an immediate-release layer, along with "[t]he data in Table
10 [that] show that within 10 hours over 100% of each active agent is
released." (Ans. 7.) The Examiner finds Example 4 of Fanara "exemplifies
a bi-layer tablet with an overlap in period of pharmaceutical activity." (Id.)
Appellants counter that "this allegation appears to be an indication that the
Examiner fails to appreciate the difference between the length of the period
of release of a drug (inside the body) and the length of the period over which
the drug is therapeutically active." (Reply Br. 6.) Appellants do not,
window of therapeutic activity (Adv. Act. 2)). (See Fanara col. 9-10.) By
using controlled- rather than immediate-release pseudoephedrine, its
therapeutic activity is prolonged within the therapeutic window of cetirizine.
(Fanara Fig. 1 (comparing plasma concentration curves of controlled- vs.
immediate-release pseudoephedrine ).) In other words, the formulation in
Example 4 with controlled-release pseudoephedrine appears to increase the
extent of overlap between the periods of therapeutic activity.
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however, provide any persuasive argument or evidence to show that the
therapeutic activity of the drugs in Example 4 do not, in fact, overlap.
On the other hand, the Examiner's finding that the therapeutic activity
of the drugs in this example would overlap is reasonable. Fanara discloses
the plasma concentrations of immediate-release and controlled-release
formulations of pseudoephedrine at the same dosage and with similar
excipients as in Example 4, which exhibited maximum concentration at
around 4.5 to 5 hours. (Fanara Fig. 1; col. 7, Table 3.) Fanara does not
expressly recite the plasma concentration of cetirizine, but it is a well-
known, long-acting antihistamine (Adv. Act. 2 ("Cetirizine, a drug taught by
Fanara is known in the art to have a half-life of 8 hours"); and the dose of
cetirizine provided in Fanara is the same as a preferred dose of cetirizine
identified in the Specification.5 It is thus reasonable to think that the periods
of therapeutic activity of the drugs in this example would substantially
overlap. And, because the Patent Office lacks the ability to confirm through
experimentation, it is appropriate to require Appellants to show that the
periods do not overlap in the manner claimed. See In re Best, 562 F.2d
1252, 1255 (CCPA 1977) ("Where ... the claimed and prior art products are
identical or substantially identical ... the PTO can require an applicant to
prove that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product. Whether the rejection is based on
5 The Specification discloses preferred antihistamines, including cetirizine
hydrochloride, to combine with the decongestant phenylephrine, and notes
that the "Preferred Amount" of cetirizine is 5-10 mg. (Spec. i-f 154.) As the
Examiner finds, Fanara identifies phenylepherine as an alternative
decongestant. (Final Act. 4; Ans. 7-8, 10; FF 3.)
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'inherency' under 35 U.S.C. § 102, on 'prima facie obviousness' under
35 U.S.C. § 103,jointly or alternatively, the burden of proof is the same, and
its fairness is evidenced by the PTO' s inability to manufacture products or to
obtain and compare prior art products." (citations and footnote omitted)).
Finally, in response to the Examiner's determination that overlap in
therapeutic activity is a functional parameter and the Examiner's suggestion
that additional structure be included to distinguish claim 129 over the prior
art, Appellants contend the genus they claim is so "huge" that it "is
impossible to recite all of these combinations in a single claim (or even a
limited number of claims)" that would exhibit the functional characteristics.
(Appeal Br. 18-19; see also Final Act. 16 and Adv. Act. 2.) The breadth
Appellants attribute to claim 129 underscores why Appellants must do more
to show nonobviousness over the Examiner's findings and reasoning drawn
from Fanara. Specifically, more is required to counter the Examiner's
finding that it would have been obvious to design single-dose formulations
having overlap in therapeutic activity in the manner claimed - and that the
formulations described in Fanara do, in fact, exhibit such overlap. See In re
Best, 562 F.2d at 1254--55 ("[W]here the Patent Office has reason to believe
that a functional limitation asserted to be critical for establishing novelty in
the claimed subject matter may, in fact, be an inherent characteristic of the
prior art, it possesses the authority to require the applicant prove that the
subject matter shown to be in the prior art does not possess the characteristic
relied on." (quoting Jn re Swinehart, 439 F.2d 210, 212-13 (CCPA 1971))).
For all these reasons, we conclude the Examiner established by a
preponderance of the evidence that claim 129 would have been obvious over
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Fanara and Findlay. Except as addressed below, the other claims subject to
this rejection have not been argued separately and therefore fall with claim
129. 37 C.F.R. § 41.37(c)(l)(iv).
2) Rejection of Claims 182, 187, 191, and 195 over Fanara and
Findlay
Claim 182 depends from claim 160 and is representative. Appellants
separately argue claim 182 on the basis that neither Fanara nor Findlay
suggests a "bi-layered tablet with two controlled release layers." (Appeal
Br. 20.) We are not persuaded. As the Examiner correctly points out,
"Fanara suggests more than one controlled release layer" may be used.
(Ans. 11.) Fanara teaches pharmaceutical compositions "allowing for the
controlled release of at least one active substance ... [and] multi-layered
pharmaceutical compositions, including at least one layer of the inventive
composition." (FF l (emphasis added).) Although working examples in
Fanara include a bi-layer tablet with one immediate release layer and one
controlled release layer, Fanara's teaching is not limited to such
embodiments. If prolonged activity of multiple active drugs within a desired
period (e.g., 12 hours) was required, it would be well within the skilled
artisan's ability, applying Fanara's teachings, to predictably form a bi-layer
tablet with each drug in a separate controlled-release layer.
For these reasons, as well as those described above regarding claim
129, we conclude the Examiner established by a preponderance of the
evidence that claim 182 would have been obvious over Fanara and Findlay.
Claims 187, 191, and 195 have not been argued separately and therefore fall
with claim 182. 37 C.F.R. § 41.37(c)(l)(iv).
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3) Rejection of Claim 159 over Fanara and Findlay
Appellants separately argue this dependent claim on the basis that
neither Fanara nor Findlay suggests "a dosage form which is liquid."
(Appeal Br. 21-22.) The Examiner finds it would be "obvious to one of
ordinary skill in the art to formulate the composition in any suitable dosage
form, including those of liquids (i.e., suspensions)." (Ans. 9.) Moreover,
the Examiner explains:
[p ]harmaceutical formulations treat various patient populations,
of which certain dosage forms are more easily administered
than others. For example, in pediatrics, liquid dosage forms are
more easily administered than solid forms. Therefore it is well
within the purview of the skilled artisan to modify the dosage
form for easier compliance dependent on the target patient
population.
(Ans. 9.) The Examiner also cites Findlay's teaching that liquid dosage
forms of the types of drugs relevant here are known in the art. (Id.; FF 4.)
The Examiner has the better position. The Examiner has provided a
reason with rational underpinning (e.g., ease of administering drugs to
children) why the person of ordinary skill in the art would modify Fanara's
compositions to provide in liquid form. Appellants have provided
insufficient persuasive evidence or argument to the contrary.
For these reasons, as well as those described above regarding claim
129, we conclude the Examiner established by a preponderance of the
evidence that claim 159 would have been obvious over Fanara and Findlay.
4) Rejection of Claims 200-204 over Fanara and Findlay
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Claim 200 is representative. Appellants separately argue claim 200
on the basis that neither Fanara nor Findlay suggests a multi-layer tablet that
comprises phenylephrine in one of its layers and, in another layer, a second
drug having a plasma half-life that differs from the plasma half-life of
phenylephrine by at least about 2 hours. (Appeal Br. 21-22.)
The Examiner finds that "the Fanara reference teaches similar active
ingredients as claimed and thus, the plasma half-lives would be expected to
be the same as that claimed." (Final Act. 5.) To illustrate, the Examiner
notes that the plasma half-life of phenylephrine is 2.5 hours and other drugs
taught in Fanara and Findlay that would be obvious to combine with
phenylephrine such as cetirizine and promethazine have half-lives of 8 hours
and 9 hours respectively. (Adv. Act. 2.) Moreover, the Examiner finds "co-
administration of Fanara's active substances, such as antihistamine (i.e.,
cetirizine) in combination with a decongestant (i.e., phenylepherine) would
yield the same drug plasma parameters sought by applicant and would yield
the same plasma curve." (Final Act. 15-16.)
Appellants' arguments are unpersuasive. (Appeal Br. 21-22.) Fanara
discloses multi-layer tablets that may include one or more active drugs in
layers. (FF 1, 3.) And Appellants' arguments do not address the proposed
combinations, much less show why such combinations do not meet the claim
limitations.
For these reasons and those described above regarding claims 129 and
182, we conclude the Examiner established by a preponderance of the
evidence that claim 200 would have been obvious over Fanara and Findlay.
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Claims 201-203 have not been argued separately and therefore fall with
claim 200. 37 C.F.R. § 41.37(c)(l)(iv). 6
5) Rejection of Claims 220-232 over Fanara and Findlay
Claim 220 is representative. Claim 220 is a "dosage form which
comprises phenylepherine and/or a pharmaceutically acceptable salt thereof
in two different forms or layers which release the phenylepherine and/or a
pharmaceutically acceptable salt thereof over a different period and at a
different rate." (Appeal Br. 24.) In other words, claim 220 does not require
an additional drug beyond phenylephrine. Appellants argue that Fanara and
Findlay do not teach such a composition. (Id.)
The Examiner finds that "Fanara teaches the therapeutic advantages of
simultaneously administering by the oral route an active substance released
immediately after administration, and the same or a second active substance,
released gradually and regularly after administration." (Final Act. 20
(emphasis omitted).) According to the Examiner, Fanara also teaches
various active substances may be used, including for instance phenylephrine,
hydrocodone, etc. (Id.) Thus, "it would have been obvious to one of
ordinary skill in the art ... to formulate phenylephrine as an immediate
release/ controlled release dosage form." (Id. at 21.)
6 Independent claim 204 appears to have been inadvertently grouped with
claims 200-203, and was not otherwise separately argued. (Appeal Br. 23.)
We thus sustain the Examiner's rejection of claim 204 for the reasons
provided regarding claims 129 and 159.
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On this record, we are persuaded that claim 220 would have been
obvious. Fanara teaches multi-layer formulations where the active
ingredient may be the same in each layer. (Id. at 20; FF 1-2.) Fanara
provides a specific example of such a formulation in Example 7 with
double-layer hydrocodone tablets for immediate and sustained release of the
drug. (Final Act. 13; FF 3.) Without countervailing factual evidence, we
agree with the Examiner that it would have been obvious to substitute
phenylephrine (a preferred active substance in Fanara) in a formulation such
as described in Example 7. (FF 3.)
For these reasons and those provided above regarding claim 129, we
conclude the Examiner established by a preponderance of the evidence that
claim 220 would have been obvious over Fanara and Findlay. Claims 221,
231, and 232 have not been argued separately and therefore fall with claim
220. 37 C.F.R. § 41.37(c)(l)(iv).
6) Rejection of Claim 222 over Fanara and Findlay
Claim 222 depends from claim 220, but requires that the first and
second forms or layers of the phenylephrine comprise "a controlled release
form or layer" - and Appellants argue nothing in Fanara or Findlay teaches
or suggests "two controlled phenylephrine containing forms or layers."
(Appeal Br. 25.)
The Examiner did not adequately address this claim or argument, and
thus we are not persuaded on this record that claim 222 would have been
obvious over Fanara and Findlay. Example 7 of Fanara, for example, shows
hydrocodone double-layer tablets with an "immediate-release layer" and
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"controlled-release layer" where the hydrocodone content in the immediate-
release layer was entirely released within 1 hour and the controlled-release
layer continued releasing hydrocodone for up to 12 hours. (Fanara col. 13.)
But the Examiner has provided no rationale why a formulation with two
controlled phenylephrine forms or layers would have been obvious in view
of these (or other) teachings of Fanara. We thus reverse this rejection.
7) Rejection of Claims 223-226 over Fanara and Findlay
Claim 223 is representative. It depends from claim 220 and adds that
at least one of the two forms or layers include "an additional drug."
Appellants argue that neither Fanara nor Findlay teaches or suggests a
tablet with immediate-release and controlled-release layers that each include
phenylephrine "and that at least one of these two layers comprises an
additional drug." (Appeal Br. 26.)
This argument is unpersuasive. Fanara discloses multi-layer tablets
"allowing the controlled release of at least one active substance." (Fanara
col. 3, 11. 37--40 (emphasis added); FF 1.) As the Examiner notes, this
"allow[ s] for the addition of multiple active ingredients in each layer."
(Ans. 12.)
For these reasons and those above related to claims 129 and 220, we
conclude the Examiner established by a preponderance of the evidence that
claim 223 would have been obvious over Fanara and Findlay. Claims 224--
226 have not been argued separately and therefore fall with claim 223.
37 C.F.R. § 41.37(c)(l)(iv).
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8) Rejection of Claim 227 over Fanara and Findlay
This claim depends from claim 220 and requires two different
controlled release layers, each of which includes phenylephrine (or a
pharmaceutically acceptable salt) and wherein at least one of the layers
comprises an additional drug. We reverse the rejection of this claim for the
reasons stated above with respect to claim 222. The Examiner has not
explained adequately why, based on Fanara, it would have been obvious to
design a bi-layered tablet with two controlled-release layers that each
include phenylephrine.
9) Rejection of Claims 228-230 over Fanara and Findlay
Claim 228 depends from claim 220 and is representative. Appellants
argue neither Fanara nor Findlay suggests a dosage form which is a liquid,
let alone a liquid that includes a complexing agent. (Appeal Br. 27 .)
The Examiner restates the findings and rationales with respect to
claim 159 concerning liquid dosage forms. (Ans. 12-13.) We agree with
the Examiner that those findings and rationales are equally applicable to
claim 228. Absent evidence to the contrary, it would have been obvious for
the skilled artisan to provide liquid dosage forms as claimed. As noted
above with respect to claim 159, liquid dosage forms are easier to administer
to some patient populations, such as pediatrics. (Id.)
For these reasons and those provided above regarding claims 129 and
220, we conclude the Examiner established by a preponderance of the
evidence that claim 228 would have been obvious over Fanara and Findlay.
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Claims 229 and 230 have not been argued separately and therefore fall with
claim 228. 37 C.F.R. § 41.37(c)(l)(iv).
10) Rejection of Claims 233-246 over Fanara and Findlay
Claim 233 is representative and recites "a pharmaceutical dosage form
which comprises at least about 3 7 mg of phenylepherine or an equivalent
amount of a pharmaceutically acceptable salt thereof." (Appeal Br. 28.)
Appellants argue "the Examiner has not cited any document which
teaches a dosage form comprising at least about 37 mg of phenylepherine
... or identifies the amount of phenylepherine that is contained in a dosage
form as a result-effective variable." (Id. at 29 (emphasis omitted).)
Moreover, Appellants argue the Examiner has cited nothing in the art that
provides a reason "to increase the amount of phenylepherine in a dosage
form according to FANARA beyond the conventionally employed levels and
in particular, to at least about 37 mg." (Id. (emphasis omitted).)
This is unpersuasive. As the Examiner correctly points out, the use of
the decongestant phenylephrine was well known based at least on Fanara
and "it would be within the level of the skilled artisan to determine suitable
or effective amounts of active agent, based on manipulative experimentation
to yield the best outcome." (Ans. 13.) Indeed, Fanara teaches "the dose of
active substance used [] depends on the effective dose and may therefore
vary within very wide limits depending on[] said active substance." (FF 3;
Ans. 14.) Thus, contrary to Appellants' arguments, a variable to be
optimized is the amount of the active substance as taught in Fanara.
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Moreover, Appellants' argument that there is no reason to increase the dose
"beyond the conventionally employed levels" lacks evidentiary support.
For these reasons and those provided above regarding claims 129 and
220, we conclude the Examiner established by a preponderance of the
evidence that claim 233 would have been obvious over Fanara and Findlay.
Claims 234--238 and 241-243 have not been argued separately and therefore
fall with claim 233. 37 C.F.R. § 41.37(c)(l)(iv).
11) Rejection of Claims 239 and 240 over Fanara and Findlay
These claims depend from claim 233 and add an "additional drug" to
the dosage form. Claim 239 is representative. We are not persuaded it
would have been nonobvious to add another drug to the formulation when
Fanara and the other cited art teaches multi-drug combinations like claimed.
For these reasons and those provided above regarding claims 129,
220, 223-226, and 233, we conclude the Examiner established by a
preponderance of the evidence that claim 239 would have been obvious over
Fanara and Findlay. Claim 240 has not been argued separately and therefore
falls with claim 239. 37 C.F.R. § 41.37(c)(l)(iv).
12) Rejection of Claim 244 over Fanara and Findlay
Claim 244 depends indirectly from claim 233 and adds that the
formulation is "a bi-layered tablet that comprises two controlled
phenylepherine containing forms or layers." (Appeal Br. 29-30.) For the
reasons discussed above with respect to claims 222 and 227, we reverse the
Examiner's rejection of claim 244.
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13) Rejection of Claims 245 and 246 over Fanara and Findlay
Claims 245 and 246 depend directly or indirectly from claim 233 and
are drawn generally to providing the active substance in a liquid dosage
form. (Appeal Br. 31.) Claim 245 is representative. Appellants and the
Examiner essentially repeat their positions with respect to other claims to
liquid dosage forms as discussed above.
For the reasons provided above regarding claims 129, 159, 220, 228-
230, and 233, we conclude the Examiner established by a preponderance of
the evidence that claim 245 would have been obvious over Fanara and
Findlay. Claim 246 has not been argued separately and therefore falls with
claim 245. 37 C.F.R. § 41.37(c)(l)(iv).
14) Rejection of Claims 247-256 over Fanara and Findlay
Claim 24 7 is representative and recites a dosage form with "at least
one controlled release form or layer of phenylepherine ... wherein the
dosage form is associated with instructions to administer the dosage form
... every x hours and wherein the resultant amount of phenylepherine ...
administered every x hours divided by xis at least 5 mg." (Appeal Br. 60-
61 (Claims App'x).)
According to the Examiner, "the only difference between the prior art
product and the claimed product is the printed matter that is not functionally
related to the product. The dosage form is the same whether the printed
matter is there or not." (Ans. 14.) Such printed matter thus does not, the
Examiner finds, distinguish over the prior art. (Id. (citing In re Ngai, 367
F.3d 1336, 1339 (Fed. Cir. 2004)).) In any event, the Examiner finds "it is
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known ... that pharmaceutical dosage forms are provided with an insert and
label so as to guide the user and provide information on proper
administration of the dosage forms." (Final Act. 22.) Also, "it would have
been obvious to one of ordinary skill in the art at the time the invention was
made to determine suitable ranges, percentages or ratios through routine or
manipulative experimentation, to obtain the best possible results, as these are
indeed variable parameters attainable within the art." (Id.)
Appellants argue the claim is not merely a dosage form with
instructions, but recites the result of following these instructions ("the
(average) administration of at least 5 mg of phenylepherine ... per hour").
(Appeal Br. 33.) Moreover, Appellants contend, Fanara and Findlay "appear
to be silent with respect to the administration of a specific amount per time
unit of any drug, and neither has the Examiner cited any other document
which mentions a specific amount per time unit of phenylepherine (or any
other drug)." (Id.)
Appellants' arguments are unpersuasive. Claim 247 is directed to a
dosage form ofphenylepherine (e.g., at least 20 mg administered every 4
hours, etc.), with instructions reflecting the same. Fanara teaches the
administration of phenylephrine and that "the dose of active substance used
[] depends on the effective dose and may therefore vary within very wide
limits." (FF 3.) Fanara also teaches that irregular or zero-order release
kinetics may be desired. (See, e.g., Fanara col. 2, 11. 29-35 ("A zero order
kinetics of release corresponds to regular and constant release over time and
is highly desirable in order to ensure regular and long-lasting therapeutic
effect.").) As the Examiner finds, determining the optimal dosages of
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phenylepherine is well within the capabilities of the skilled artisan through
routine experimentation. (Final Act. 22.) We have been presented with no
persuasive evidence to the contrary.
Moreover, even considering the instructions, they merely provide
administration of an obvious dosage form. Instructions like a
pharmaceutical package insert were well known and would be obvious to
include. (Final Act. 22.) And we find no nonobvious functional relationship
between the content of the instructions and the dosage form. See Ngai, 367
F.3d at 1338 (printed matter must create a "new and unobvious functional
relationship" in order to patentably distinguish the claims from the prior art
(quoting Jn re Gulack, 703 F.2d. 1381, 1386 (Fed. Cir. 1983))).
For these reasons as well as those provided above regarding claims
129, 220, and 233, we conclude the Examiner established by a
preponderance of the evidence that claim 24 7 would have been obvious over
Fanara and Findlay. Claims 248-256 have not been argued separately and
therefore fall with claim 247. 37 C.F.R. § 41.37(c)(l)(iv).
15) Rejection of Claim 132 over Fanara, Findlay, and Dang
Appellants incorporate their argument related to claim 129 and
contend only that Dang "apparently is unable to cure the noted deficiencies
of FANARA and FINDLAY." (Appeal Br. 34.) For the reasons provided
above regarding claim 129, we conclude the Examiner established by a
preponderance of the evidence that claim 132 would have been obvious over
Fanara, Findlay, and Dang.
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16) Rejection of Claims 206-213 over Fanara, Findlay, and Wen
Claim 209, which depends indirectly from claim 204, is representative
and requires, inter alia, a liquid dosage form that comprises an ion-exchange
resin. The Examiner finds Wen teaches ion-exchange resins used with
sustained-release pharmaceuticals. (Final Act. 7-8.) The Examiner further
finds it would have been obvious to use sodium polystyrene sulfonate as an
ion-exchange resin to control the active release of active agent as taught by
Wen, and particularly to achieve "a pharmaceutically effective activity [e.g.,
of the antitussive dextrommethorphan] over a twelve hour period of time."
(Id. at 8.) Further, the Examiner finds, "it would be obvious that using
phenylepherine, a commonly known sympathomimetic drug, in combination
with the antitussive agent and ion exchange resin would also be stable and
effective." (Id.)
ii~ppellants argue claim 209 is nonobvious based on the same reasons
argued with respect to claim 129. (Appeal Br. 34.) Appellants further
essentially restate their arguments regarding liquid dosage forms, such as
noted above with respect to claims 159 and 228-230. (Id. at 35; see also id.
at 22.) We find these arguments unpersuasive for the same reasons stated
above for these other claims concerning liquid formulations. Also, the
Examiner has provided further reasoning with rational underpinning for the
inclusion of a complexing agent that includes an ion-exchange resin in the
formulation. (Final Act. 8; FF 5.)
For these reasons as well as those provided above regarding claims
129, 159, and 228-230, we conclude the Examiner established by a
preponderance of the evidence that claim 209 would have been obvious over
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Fanara, Findlay, and Wen. Claims 206-208, and 210-213 have not been
argued separately and therefore fall with claim 209. 37 C.F.R.
§ 41.37(c)(l)(iv).
17) Rejection of Claims 138, 143, 168, and 175 over Fanara,
Findlay, and Mayer
Appellants incorporate their argument related to claims 129 and 160
(which was not argued separately from claim 129) and contend only that
Mayer "apparently is unable to cure the noted deficiencies of FANARA and
FINDLAY." (Appeal Br. 36.) For the reasons provided above regarding
claim 129, we conclude the Examiner established by a preponderance of the
evidence that claims 138, 143, 168, and 175 would have been obvious over
Fanara, Findlay, and Mayer.
18) Rejection of Claims 139, 166, and 172 over Fanara, Findlay,
and Shtohryn
Appellants incorporate their argument related to claims 129 and 160
(which was not argued separately from claim 129) and contend only that
Shtohryn "apparently is unable to cure the noted deficiencies of FANARA
and FINDLAY." (Id. at 36.) For the reasons provided above regarding
claim 129, we conclude the Examiner established by a preponderance of the
evidence that claims 139, 166, and 172 would have been obvious over
Fanara, Findlay, and Shtohryn.
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19) Rejection of Claims 139, 166, and 172 over Fanara, Findlay,
and Sunshine
Appellants incorporate their argument related to claims 129 and 160
(which was not argued separately from claim 129) and contend only that
Sunshine "apparently is unable to cure the noted deficiencies of FANARA
and FINDLAY." (Id. at 37.) For the reasons provided above regarding
claim 129, we conclude the Examiner established by a preponderance of the
evidence that claims 139, 166, and 172 would have been obvious over
Fanara, Findlay, and Sunshine.
20) Rejection of Claims 129-131, 133-137, 140-142, 144--165,
167, 169-171, 173, 174, 176-205, and 214--256 over Fanara
and Paradissis
According to the Appellants, the rejections based on Fanara and
Paradis sis
essentially differs from the [rejections based on Fanara and
Findlay] only in that PARADIS SIS instead of FINDLAY is
relied upon for supporting the Examiner's assertion that it
would have been obvious to one of ordinary skill in the art to
incorporate certain (second) drugs recited in the instant claims
into a dosage form according to FAN ARA. Also dependent
claims 165 and 171 are rejected over FANARA in view of
P ARADISSIS but not over FANARA in view of FINDLAY. 7
(Id. at 38-39.) As such, Appellants merely incorporate their remarks as to
the other rejections. (Id.)
7 It appears that, in addition to claims 165 and 171, claims 144--146 are also
rejected based on Fanara and Paradissis, but not Fanara and Findlay.
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The Examiner does likewise: "[t]o avoid repetition, the rejections of
Fanara in view of Paradissis are sustained for the same reasons as discussed
above with regards to the rejections of Fanara in view of Findlay." (Ans.
16.)
Because Appellants and the Examiner treat these rejections as rising
or falling with the above arguments, we take that approach as well. So, with
the exception of claims 222, 227, and 244, we affirm the rejections based on
Fanara and Paradissis for the reasons above concerning the rejections based
on Fanara and Findlay. We reverse the rejections of claims 222, 227, and
244 over Fanara and Paradissis also for the reasons provided above.
SUMMARY
We affirm rejection of claims 129-131, 133-137, 140-142, 147-164,
167, 169, 170, 176-205, 214--221, 223-226, 228-243, and 245-256 as
unpatentable under 35 U.S.C. § 103(a) over Fanara in view of Findlay. We
reverse the rejection of claims 222, 227, and 244 over Fanara and Findlay.
We affirm the rejection of claim 132 as unpatentable under 35 U.S.C.
§ 103(a) over Fanara in view of Findlay and Dang.
We affirm the rejection of claims 206-213 as unpatentable under
35 U.S.C. § 103(a) over Fanara in view of Findlay and Wen.
We affirm the rejection of claims 138, 143, 168, and 175 as
unpatentable under 35 U.S.C. § 103(a) over Fanara in view of Findlay and
Mayer.
We affirm the rejection of claims 139, 166, and 172 as unpatentable
under 35 U.S.C. § 103(a) over Fanara in view of Findlay and Shtohryn.
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We affirm the rejection of claims 139, 166, and 172 as unpatentable
under 35 U.S.C. § 103(a) over Fanara in view of Findlay and Sunshine.
We affirm the rejection of claims 129-131, 133-137, 140-142, 144--
165, 167, 169-171, 173, 174, 176-205,214--221,223-226,228-243,and
245-256 as unpatentable under 35 U.S.C. § 103(a) over Fanara in view of
Paradissis. We reverse the rejection of claims 222, 227, and 244 over
Fanara and Paradissis.
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-IN-PART
32