Ex Parte Nutalapati

Patent Trials and Appeals Board

May 15, 2019

13971870 - (D) (P.T.A.B. May. 15, 2019)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/971,870 08/21/2013 Siva Rama K. Nutalapati ATP0008US2 6313
23413 7590 05/17/2019
TANTOR TOT RTTRN T T P
EXAMINER
20 Church Street NEAGU, IRINA
22nd Floor
Hartford, CT 06103 ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
05/17/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SIVA RAMA K. NUTALAPATI
Appeal 2018-001857
Application 13/971,8701
Technology Center 1600
Before RICHARD M. LEBOVITZ, ELIZABETH A. LaVIER, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
LaVIER, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant seeks review of the
Examiner’s rejections of claims 1-19, 23, and 24. We have jurisdiction
under 35 U.S.C. § 6(b).
For the reasons set forth below, we REVERSE.
1 Appellant identifies the real party in interest as APTAPHARMA INC. Br.
2.
Appeal 2018-001857
Application 13/971,870
BACKGROUND
The Specification describes liquid mucoadhesive intranasal dosage
formulations of methylnaltrexone, to address a need in the art for
formulations and methods of administering methylnaltrexone that require
lower doses compared to oral formulations, and better patient compliance
compared to subcutaneous and injectable formulations. Spec. 6-7.
Claim 1 is illustrative:
1. A liquid mucoadhesive intranasal dosage formulation,
comprising:
methylnaltrexone, a pharmaceutically acceptable salt of
methylnaltrexone, a pharmaceutically acceptable ester of
methylnaltrexone, or a combination thereof;
a mucoadhesive agent; and
a liquid carrier;
wherein the formulation does not substantially drip from the
intranasal cavity after administration of a single dose; and
the methylnaltrexone, a pharmaceutically acceptable salt of
methylnaltrexone, a pharmaceutically acceptable ester of
methylnaltrexone, or a combination thereof is dissolved in the
liquid carrier.
Br. 19 (Claims Appendix).
REJECTIONS MAINTAINED ON APPEAL
1. Claims 1, 5, 6, 9, 10, 16, and 17 stand rejected under pre-AIA
35 U.S.C. § 102(a) and (e) as anticipated by, or alternatively under
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Application 13/971,870
§ 103(a) as unpatentable over, Yuan2 as evidenced by Ugwoke.3 Ans.
3.
2. Claims 1-19 stand rejected under pre-AIA § 103(a) as
unpatentable over Yuan and Ugwoke. Ans. 4.
3. Claims 1-19, 23, and 24 stand rejected under pre-AIA § 103(a)
as unpatentable over Ilium,4 Yuan, and Ugwoke. Ans. 8.
DISCUSSION
Each of the pending rejections relies on Yuan as teaching aqueous
solutions comprising methylnaltrexone bromide and chitosan dissolved in a
carrier (distilled water), designed to be administered to nasal passages as
drops or sprays. Ans. 3 (Rejection 1 (citing Yuan]fl| 125, 139, 146)); see
also id. at 4 (Rejection 2), 9 (Rejection 3). Although Yuan does not describe
its nasally administered embodiments as mucoadhesive, the Examiner finds
that the mucoadhesive properties of chitosan are inherent and/or taught by
other cited references. See Ans. 3 (Rejection 1); see also Ans. 6-7
(Rejection 2), 11-12 (Rejection 3).
We find that the record lacks adequate support for the conclusion that
Yuan’s nasal solutions are mucoadhesive. To the contrary, Yuan states,
“[njasal solutions are prepared so that they are similar in many respects to
2 Yuan, US 2011/0250278 Al, published Oct. 13, 2011.
3 Michael I. Ugwoke et al., Nasal Mucoadhesive Drug Delivery:
Background, Applications, Trends and Future Perspectives, 57 Adv. Drug
Delivery Rev. 1640-1665 (2005).
4 L. Ilium et al., Intranasal Delivery of Morphine, 301 J. Pharm. & Exp.
Therapeutics 391^400 (2002).
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Appeal 2018-001857
Application 13/971,870
nasal secretions, so that normal ciliary action is maintained.'’'’ Yuan ^ 125
(emphasis added). As Dr. Williams explains in a declaration provided by
Appellants, “normal ciliary action is to clear (or wash) the nasal cavity of
matter, both particulate and dissolved, so this example does not contemplate
mucoadhesion or any extended residence time of administered formulation
in the nasal cavity.” Williams Decl. ^ 5.5 The Specification also
distinguishes normal “Nasal Mucociliary Clearance” from the claimed
mucoadhesive property, in which the formulation attaches and localizes to
the nasal cavity, enhancing the drug concentration gradient across the
epithelium. Spec. ^ 21. In other words, by describing its nasal solutions as
formulated to maintain normal ciliary action, Yuan implies that its nasal
solutions are not mucoadhesive.
Nor do we discern that Yuan indicates its particular formulations have
mucoadhesive characteristics. The Examiner’s rejections focus on the
preparations described in Examples 1 and 4 of Yuan. See, e.g., Ans. 3
(citing Yuan^flf 139 (Example 1), 146 (Example 4)). Example 1 teaches
incorporating dissolved methylnaltrexone into an aqueous solution of
pentasodium tripolyphosphate (TPP) to form nanoparticles. Yuan 139. As
Appellant argues (see Br. 6 (citing Williams Decl. 7-8)) and the
Examiner does not dispute (see Ans. 16-17), the addition of TPP causes
crosslinking of the chitosan, which results in the formation of the
nanoparticles. Appellant maintains that “extensive crosslinking” reduces or,
in the case of Yuan eliminates, the mucoadhesive characteristics of the
5 Declaration Pursuant to 37 C.F.R. § 1.132 of Michael G. Williams, dated
Jan. 12, 2016.
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Application 13/971,870
resulting particles. Br. 6 (citing Williams Decl. 7-9, Ugwoke 1646). The
Examiner responds by pointing to evidence that it was known that
“crosslinking of chitosan with TPP results in excellent mucoadhesive
properties for the resulting drug nanoparticles.” Ans. 17 (citing Femandez-
Urrusuno6). Ultimately, we find that Appellant has the better position.
Although Femandez-Urrusuno does indeed teach improved mucoadhesion
when TPP is used to crosslink chitosan in insulin-loaded nanoparticles (see
Femandez-Urrusuno Abstract, 1580), Ugwoke explains “[tjhere is a critical
polymer molecular mass and cross-linking density below or above which
there is reduced adhesive power, and this varies with the type of polymer.
Mucoadhesion requires an adequate free chain length for interpenetration to
occur. Reducing the free chain length by extensive cross-linking therefore
reduces mucoadhesion” (Ugwoke 1646). Thus, the Examiner’s position
oversimplifies the relationship between crosslinking and mucoadhesion.
Degree matters, and we discern no finding in the record that Yuan’s
nanoparticles are crosslinked at a level at which the chitosan confers
mucoadhesive properties for nasal formulations. To the contrary, as noted
above, Yuan’s description of its nasal solutions as formulated to maintain
“normal ciliary action” (Yuan 125) indicates they are not mucoadhesive.
In addition to the nanoparticles described in Example 1 of Yuan, the
Examiner also relies on the aqueous methylnaltrexone solution of Example 4
of Yuan as teaching an “aqueous solution comprising methylnaltrexone (in
non-particulate form) dissolved in distilled water.” Ans. 4 (citing Yuan
6 Rocio Femandez-Urrusuno et al., Enhancement of Nasal Absorption of
Insulin Using Chitosan Nanoparticles, 16 Pharmaceutical Res. 1576-
1581 (1999).
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Appeal 2018-001857
Application 13/971,870
Tf 146 (Rejection 2)), 12 (Rejection 3); see also Ans. 3 (Rejection 1)).
However, the aqueous formulation of Example 4 of Yuan is for oral
administration (Yuan 146), and Yuan offers no guidance on how to modify
the formulation of Example 4 for nasal administration. Yuan 146. We
agree with Appellant (see Br. 10, 14-17) that this distinction is significant,
and cannot be remedied by citation to references such as Ugwoke and Ilium,
which relate to delivery of other drugs, such as morphine. As Dr. Williams
explains, for example, morphine’s major site of action is in pain receptors in
the brain, whereas methylnaltrexone’s is in receptors in the gut. Williams
Decl. T| 11. Thus, “[njasal absorption is not inherently a route from which to
achieve targeted sites throughout the gut.” Id. Further, Dr. Williams opines
that, in general, methylnaltrexone is poorly absorbed due to its
hydrophilicity and low lipophilicity, and so presents a “conundrum” to
formulate effectively. Id. at 9. The Examiner “acknowledges the
difference between the properties of morphine and [methylnaltrexone],” but
refers back to Yuan as “clearly teaching] nasal solutions of
methylnaltrexone” and Ugwoke as teaching nasal mucoadhesive drug
formulations. Ans. 23. Because we find, as described above, that Yuan
indicates its nasal formulations of methylnaltrexone are not mucoadhesive,
reliance on other references relating to other drugs having markedly
different properties cannot bridge this gap.
Accordingly, the record before us is not adequate to support any of the
three rejections, all of which rely on Yuan.
CONCLUSION
We reverse Rejections 1, 2, and 3.
REVERSED
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