Ex Parte Park et al

Patent Trial and Appeal Board

Jan 5, 2017

13677738 (P.T.A.B. Jan. 5, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/677,738 11/15/2012 Eun Seok Park 042092.0009 2001
89980 7590
NSIP LAW
P.O. Box 65745
Washington, DC 20035
01/09/2017 EXAMINER
BROWN-PETTIGREW, ANGELA C
ART UNIT PAPER NUMBER
1621
NOTIFICATION DATE DELIVERY MODE
01/09/2017 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):
pto@nsiplaw.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte EUN SEOK PARK, YUN SEOK RHEE, CHUN WOONG PARK,
TACK OON OH, JU YOUNG KIM, JUNG MYTJNG HA, and JI HO SHIN1
Appeal 2015-003273
Application 13/677,738
Technology Center 1600
Before MELANIE L. MCCOLLUM, RICHARD J. SMITH, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
McCOLLUM, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a eutectic
mixture. The Examiner has rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
Claims 1—10 are on appeal (Br. 1). The claims subject to each
rejection have not been argued separately and therefore stand or fall
1 Appellants identify the real party in interest as RESEARCH & BUSINESS
FOUNDATION SUNGKYUNKWAN UNIVERSITY (Br. 2).
Appeal 2015-003273
Application 13/677,738
together. 37 C.F.R. § 41.37(c)(l)(iv). Claims 1 and 5 are representative and
read as follows:
1. A eutectic mixture comprising celecoxib or a pharmaceutically
acceptable salt thereof and poloxamer, wherein the eutectic mixture is
obtained by mixing the celecoxib or a pharmaceutically acceptable salt
thereof and the poloxamer, heating the mixture to form a homogenous
mixture and then cooling the homogenous mixture, and wherein the
celecoxib lacks a regular crystalline structure.
5. The eutectic mixture of claim 1, wherein the eutectic mixture
comprises a surfactant or an inclusion compound.
Claims 1—4, 7, 8, and 10 stand rejected under 35 U.S.C. § 103(a) as
obvious over Tawa2 in view of Sharma3 (Ans. 2).
Claims 5, 6, and 9 stand rejected under 35 U.S.C. § 103(a) as obvious
over Tawa in view of Sharma, Chowdary,4 and Rinaki5 (Ans. 5).
I
The Examiner relies on Tawa for teaching “a pharmaceutical
composition that comprises celecoxib, a poloxamer and hydroxypropyl-
cellulose” (Ans. 2). The Examiner relies on Sharma for teaching “methods
of improving drug solubility through solid dispersion” {id. at 3). In
particular, the Examiner finds that Sharma “teaches eutectic mixtures
2 Tawa et al., US 2006/0134198 Al, June 22, 2006.
3 Daisy Sharma et al., Solubility Enhancement — Eminent Role in Poorly
Soluble Drugs, 2 Research J. Pharm. & Tech. 220—24 (2009).
4 KPR Chowdary et al., A Factorial Study on the Effects of ft Cyclodextrin
and Poloxamer 407 on the Solubility and Dissolution Rate of Piroxicam, 1
International J. Res. Pharmacy & Chemistry 601—05 (2011).
5 Eleni Rinaki et al., Identification of Biowaivers Among Class II Drugs:
Theoretical Justification and Practical Examples, 21 Pharmaceutical Res.
1567-72 (2004).
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improve the bioavailability of poorly soluble compounds” (id.). The
Examiner concludes that “[o]ne of ordinary skill in the art would be
motivated to make a eutectic mixture comprising celecoxib and a poloxamer
in order to enhance the stability and bioavailability of the drug” (id. at 4).
With regard to the recitation in claim 1 that the “celecoxib lacks a regular
crystalline structure,” the Examiner finds that “[t]his an inherent property of
the celecoxib that will occur in eutectic mixtures” (id. at 6 (emphasis
omitted)).
Analysis
Tawa discloses “a pharmaceutical composition comprising . . .
(a) celecoxib; . . . (b) a poloxamer surfactant. . . ; and . . .
(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose
(HPMC)” (Tawa 46-49). Tawa also discloses that “celecoxib is a neutral
molecule that is essentially insoluble in water” (id. 1 6). Sharma discloses
that “[n]o review of solid dispersions would be complete without a brief
description of eutectic mixtures, which are the cornerstone of this approach
to improving bioavailability of poorly soluble compounds” (Sharma 220).
Sharma also discloses that “[sjolid eutectic mixtures are usually prepared by
rapid cooling of a comelt of the two compounds in order to obtain a physical
mixture of very fine crystals of the two components” (id. at 221). We
conclude that the Examiner has set forth a prima facie case that “one of
ordinary skill in the art would [have] be[en] motivated to make the
composition taught by Tawa as a eutectic mixture” (Ans. 7).
Appellants argue, however, that the “rejection should be reversed at
least because none of the cited references teaches or suggests a eutectic
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mixture comprising celecoxib” (Br. 10 (emphasis omitted)). We are not
persuaded.
The Examiner is not asserting that either Tawa or Sharma teaches a
eutectic mixture comprising celecoxib (Ans. 10—12). Instead, the Examiner
concludes that “one of ordinary skill in the art would modify the
pharmaceutical composition taught by Tawa into a eutectic mixture in order
to create a composition with enhanced dissolution and bioavailability” {id. at
12). We conclude that Appellants have not adequately explained why the
Examiner’s position is incorrect.
Appellants also argue “that there is no reasonable expectation of
achieving a eutectic mixture comprising celecoxib and poloxamer, based on
the references of record” (Br. 12). In particular, Appellants argue that “there
is no evidence in the record that any of the prior investigations into
formulations of celecoxib—whether using solid dispersion approaches or not—
achieved a eutectic mixture comprising celecoxib” {id. at 13 (emphasis
omitted)). In addition, Appellants argue that “there is a notable absence of
any guidance on how such a eutectic mixture might be achieved, as well as a
notable absence of any actual eutectic mixture comprising celecoxib despite
an express desire in the cited references to enhance solubility” {id. (emphasis
omitted)). Appellants also argue that “Sharma reports ‘poor predictability of
solid dispersion behavior due to a lack of understanding their material
properties’” {id. (emphasis omitted)). We are not persuaded.
First, we understand that the Examiner has not shown that either Tawa
or Sharma discloses a eutectic mixture comprising celecoxib. However, we
do not agree that the failure to disclose such a eutectic mixture is sufficient
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to demonstrate that one of ordinary skill in the art would not have had a
reasonable expectation of success in making one.
Second, we disagree with Appellants’ contention “there is a notable
absence of any guidance on how such a eutectic mixture might be achieved”
(id.). Instead, as noted by the Examiner (Ans. 9), Sharma discloses that
“[sjolid eutectic mixtures are usually prepared by rapid cooling of a comelt
of the two compounds in order to obtain a physical mixture of very fine
crystals of the two components” (Sharma 221). We conclude that
Appellants have not adequately explained why this guidance would have
been insufficient to one of ordinary skill in the art.
Third, we understand that Sharma teaches that, “[djespite extensive
expertise with solid dispersions, there are some problems which limit the
commercial application of solid dispersions” and that “[o]ne of the primary
reasons is the poor predictability of solid dispersion behaviour due to a lack
of a basic understanding of their material properties” (id. at 222). However,
we agree with the Examiner that commercial success is not the standard for a
reasonable expectation for success (Ans. 12—13).
In addition, Appellants argue that “none of the references of record
has been cited as teaching, either expressly or inherently, a eutectic mixture
‘wherein the celecoxib lacks a regular crystalline structure’” (Br. 6).
Appellants also argue “that any theory of inherency with respect to th[is]
limitation ... is improper because the Office has provided no basis in fact
and/or technical reasoning to reasonably support the determination that the
allegedly inherent characteristic necessarily flows from the teachings of the
applied prior art” (id. at 7). We are not persuaded.
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As noted by the Examiner (Ans. 6), the Specification states that “the
term ‘little or no crystallinity’ means particles lacking a regular crystalline
structure” (Spec. 8). Thus, the claim does not appear to exclude all
crystallinity. To support the inherency position, the Examiner cites Ali6 as
an evidentiary reference (Ans. 6). In particular, the Examiner finds that Ali
teaches that “[dissolution enhancement from solid dispersions prepared
with poloxamers has previously been attributed to a reduction in crystalline
drug particle size” and “the loss of ibuprofen crystalline diffraction peaks in
the 2:1 solid dispersion[, which is a eutectic mixture,] compared to the
presence of these features in the physical mix of the same mole ratio”
(Ans. 6—8 (citing Ali 165—166)). As also noted by the Examiner (Ans. 8),
Sharma discloses that “[s]olid eutectic mixtures are usually prepared by
rapid cooling of a comelt of the two compounds in order to obtain a physical
mixture of very fine crystals of the two components’ '' (Sharma 221 (emphasis
added)). Thus, we conclude that the Examiner has provided sufficient basis
to shift the burden to Appellants to demonstrate that a eutectic mixture
comprising Tawa’s compounds (Tawa ^fl[ 46-49) does not inherently lack a
regular crystalline structure, as the term is used in the present Specification
(Ans. 7). Appellants have not met this burden.
Appellants also argue “that ‘wherein the celecoxib lacks a regular
crystalline structure’ is not merely a process limitation” (Br. 8). Although
we agree, we conclude that the Examiner has clearly treated this limitation
6 W. Ali et al., Stochiometrically Governed Molecular Interactions in Drug:
Poloxamer Solid Dispersions, 391 International J. Pharmaceutics 162—68
(2010).
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as a structural limitation in the Examiner’s Answer (Ans. 6—9). In addition,
this limitation was not even in the claim at the time of the Final Rejection
(compare the claims filed 7/14/14 after the Final Rejection to the claims
filed 8/22/13).
In addition, Appellants argue:
[Wjith respect to the recitation of steps related to mixing,
heating, and cooling,... the Office has not sufficiently noted the
structure implied by process steps that should be considered
when assessing the patentability of product-by-process claims,
especially where the product can only be defined by the process
steps by which the product is made, or where the manufacturing
process steps would be expected to impart distinctive structural
characteristics to the final product.
(Br. 8—9.) We are not persuaded.
Claim 1 recites “mixing the celecoxib or a pharmaceutically
acceptable salt thereof and the poloxamer, heating the mixture to form a
homogenous mixture and then cooling the homogenous mixture” {id. at 18).
Claim 1 also recites that these steps are used to obtain a eutectic mixture.
However, the Examiner relies on Sharma for disclosing eutectic mixtures
(Ans. 3). Thus, we do not agree with Appellants that the Examiner has not
considered the structure implied by the process steps. In addition,
Appellants have not alleged, much less shown, that any structure other than
the formation of a eutectic mixture is implied by the claimed process steps.
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Appellants also argue “that [the] Office’s reliance on newly cited art[,
Law,7 in the Advisory Action] is contrary to principles of compact
prosecution” (Br. 9). We are not persuaded.
The Examiner states that the “reference used in the Advisory Action is
an evidentiary reference to show that increased dissolution rate of a drug is
an expected result in eutectic mixtures” (Ans. 10). Appellants have not
adequately explained why this reference was not properly used as an
evidentiary reference.
In addition, Appellants argue “that the evidence of record shows that
the claimed eutectic mixture achieves unexpectedly superior results
compared to examples that are even closer than the disclosure of Tawa”
(Br. 14). In particular, Appellants argue “that the dramatic increase in
dissolution rate of a preparation (Example 2) having exact correspondence
of component ingredients with another preparation (Comparative
Example 3) shows the unexpectedly superior results of the presently claimed
eutectic mixture” (id.). Appellants also argue:
[T]he Declaration evidence of record does not merely confirm
that a eutectic mixture, comprising celecoxib or a
pharmaceutically acceptable salt thereof and poloxamer, has the
expected properties of a eutectic mixture. Rather, the
Declaration evidence shows that, unexpectedly, Appellants]
ha[ve] been able to prepare a composition comprising celecoxib
in the form of a eutectic mixture.
(Id. at 15.) We are not persuaded.
7 Devalina Law et al., Properties of Rapidly Dissolving Eutectic Mixtures of
Polyethylene glycol) and Fenofibrate: The Eutectic Microstructure, 92 J.
Pharmaceutical Sciences 505—15 (2003).
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In support of their position, Appellants refer to two Declarations, the
2013 Declaration8 and the 2014 Declaration9 (id. at 14). Appellants’ 2013
Declaration does state that the simple mixture of “Comparative Example 3
showed a significantly lower dissolution rate as compared to that of [the
eutectic mixture of] Example 2 having the same composition” (2013
Decl. 5). However, Appellants have pointed to no evidence suggesting that
this would have been unexpected. “Attorney’s argument in a brief cannot
take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA
1974). In addition, as discussed above, Appellants have not provided
sufficient evidence that there would not have been a reasonable expectation
of success in achieving a eutectic mixture comprising celecoxib. Thus, we
do not agree with Appellants that they have provided sufficient evidence that
it was unexpected that they were able to achieve a eutectic mixture
comprising celecoxib.
Conclusion
The evidence supports the Examiner’s conclusion that Tawa and
Sharma suggest the product of claim 1. We therefore affirm the obviousness
rejection of claim 1. Claims 2-4, 7, 8, and 10 fall with claim 1.
II
In rejecting representative claim 5, the Examiner relies on Tawa and
Sharma as discussed above, but finds that they do “not teach an inclusion
compound and the poloxamer being poloxamer 407” (Ans. 5). The
Examiner relies on Chowdary for teaching “the individual and combined
8 Declaration of Eun-Seok Park dated 8/20/2013 (filed 8/22/13).
9 Declaration of Eun-Seok Park dated 2/4/2014 (filed 2/10/14).
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effects of P-cyclodextrin (PCD) and poloxamer 407 on piroxicam” (id. ). In
particular, the Examiner finds that Chowdary teaches that “PCD and
Poloxamer 407 alone gave an increase of 1.08 and 2.03 fold respectively in
the solubility of piroxicam and combined they gave 1.97 fold increase in the
solubility of piroxicam” (id.). The Examiner also finds that “[pjiroxicam,
like celecoxib, is a BCS class II drug and a non-steroidal anti-inflammatory
drug (NSAID) as taught by Rinaki. . . , meaning] that both drugs exhibit
low and variable oral bioavailability due to their poor aqueous solubility”
(id.). The Examiner concludes that it would have been obvious “to combine
the P-cyclodextrin and poloxamer 407 with the composition taught by Tawa
... in order to enhance the dissolution rate of celecoxib” (id. at 5—6).
Analysis
As discussed above, we conclude that the Examiner has set forth a
prima facie case that “one of ordinary skill in the art would [have] be[en]
motivated to make the composition taught by Tawa as a eutectic mixture”
(Ans. 7). Chowdary discloses that the “individual and combined effects of
PCD and Poloxamer 407 in enhancing the solubility of piroxicam were
highly significant” (Chowdary 605). We conclude that the Examiner has set
forth a prima facie case that it would have been obvious to include
Poloxamer 407, which is a surfactant (Chowdary 601: Abstract), and/or
PCD, which is an inclusion compound (see Appellants’ claim 6 (Br. 18)), in
the composition of Tawa (Ans. 5—6).
Appellants argue: “[According to Rinaki, Piroxicam is classified as a
Class I drug[] relative to solubility at pH 7.4. Accordingly, a person having
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ordinary skill in the art reading Chowdary and Rinaki would not have
modified Tawa and Sharma as alleged.” (Br. 15.) We are not persuaded.
As noted by Appellants {id.), Rinaki states that, “with the exception of
ibuprofen (no. 9), oxaprozin (no. 12), mefenamic acid (no. 13), and the two
nonacidic NSAIDs [celecoxib (no. 19) and rofecoxib (no. 20)], the
remaining compounds can be classified as Class I drugs relative to solubility
at pH 7.4”, suggesting that piroxicam, listed in Rinaki’s Table I, is a Class I
drug (Rinaki 1569-70). However, Chowdary specifically identifies
piroxicam as a BCS class II drug, which has poor aqueous solubility, and
relates to enhancing its dissolution rate (Chowdary 601). Moreover, as
noted by the Examiner (Ans. 16), Chowdary generally discloses the use of
cyclodextrins and/or Poloxmer 407 “for enhancing and solubility and
dissolution rate of poorly soluble drugs” (Chowdary 602). Thus, it is not
clear to us why the techniques described in Chowdary for enhancing
dissolution would not apply to celecoxib, which “is essentially insoluble in
water” (Tawa 1 6).
Conclusion
The evidence supports the Examiner’s conclusion that Tawa, Sharma,
Chowdary, and Rinaki suggest the product of claim 5. We therefore affirm
the obviousness rejection of claim 5. Claims 6 and 9 fall with claim 5.
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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