PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s)
`
`Myers et al.
`
`Examiner:
`
`Janet L. Epps-Smith
`
`Serial No.:
`
`12/537,571
`
`Group Art Unit:
`
`1633
`
`Confirmation No. :
`
`5630
`
`Docket:
`
`1199-82
`
`Filed:
`
`For:
`
`August 7, 2009
`
`Dated:
`
`October 22, 2012
`
`Sublingual and Buccal Film
`Compositions
`
`Mall Stop AF
`.
`.
`COHIIIIISSIOI’ICI' fOI' Patents
`P.O. BOX 1450
`
`Alexandria, Virginia 22313-1450
`
`Certificate of EFS-Web Transmission
`Ihereby certify that this correspondence is being transmitted to the US.
`Patent and Trademark Office Via the Office's electronic filing system.
`
`Dated: October 22, 2012
`
`Signature:
`
`/Jane Callahan/Jane Callahan
`
`AMENDMENT AND RESPONSE
`AFTER FINAL OFFICE ACTION
`
`Madam:
`
`In response to the Final Office Action dated May 2, 2012, a response to which is due
`
`by August 2, 2012, please amend the application as follows:
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 7 of this paper.
`
`Page 1
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`BDSI EXHIBIT 1009
`
`Page 1
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 2
`
`Amendments to the Claims:
`
`This listing of claims shall replace all previous listings in this application:
`
`1.
`
`(Previously Amended) A film dosage composition comprising:
`
`a. A polymeric carrier matrix;
`
`b. A therapeutically effective amount of buprenorphine or a pharmaceutically
`
`acceptable salt thereof;
`
`c. A therapeutically effective amount of naloxone or a pharmaceutically
`
`acceptable salt thereof; and
`
`d. A buffer in an amount to provide a local pH for said composition of a value
`
`sufficient to optimize absorption of said buprenorphine, wherein said local pH
`
`2.
`
`3.
`
`is from about 2 to about 3.5 in the presence of saliva.
`
`(Canceled).
`
`(Previously Amended) The composition of claim 1, wherein the local pH of said
`
`composition is from about 3 to about 3.5.
`
`4.
`
`(Original) The composition of claim 1, wherein said film dosage composition
`
`provides a bioequivalent absorption of buprenorphine to that of a tablet having an
`
`equivalent amount of buprenorphine or a pharmaceutically acceptable salt thereof.
`
`5.
`
`(Original) The composition of claim 1, wherein said polymeric carrier matrix
`
`comprises at least one polymer in an amount of at least 25% by weight of said
`
`composition.
`
`6.
`
`(Original) The composition of claim 1, wherein said buffer is present in an amount of
`
`from about 2:1 to about 1:5 by weight of buffer to buprenorphine.
`
`7.
`
`(Original) The composition of claim 1, wherein said polymeric carrier matrix
`
`comprises at least one self-supporting film forming polymer.
`
`8.
`
`(Original) The film dosage composition of claim 1, wherein said buprenorphine is
`
`present in an amount of from about 2 mg to about 16 mg per dosage.
`
`Page 2
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`Page 2
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 3
`
`9.
`
`(Original) The film dosage composition of claim 1, wherein said buffer comprises
`
`sodium citrate, citric acid, and combinations thereof.
`
`10. (Original) The film dosage composition of claim 1, wherein said buffer comprises
`
`acetic acid, sodium acetate, and combinations thereof.
`
`11. (Previously Amended) A film dosage composition comprising:
`
`a. A polymeric carrier matrix;
`
`b. A therapeutically effective amount of buprenorphine or a pharmaceutically
`
`acceptable salt thereof;
`
`c. A therapeutically effective amount of naloxone or a pharmaceutically
`
`acceptable salt thereof; and
`
`d. A buffer in an amount sufficient to inhibit the absorption of said naloxone,
`
`while also optimizing absorption of said buprenorphine when administered
`
`orally.
`
`12. (Previously Amended) The composition of claim 11, wherein said composition has a
`
`local pH of about 2 to about 3.5.
`
`13. (Previously Amended) The composition of claim 11, wherein said composition has a
`
`local pH of about 3 to about 3.5.
`
`14. (Previously Amended) The composition of claim 13, wherein said buffer is present in
`
`an amount sufficient to provide—a bioequivalent level of absorption of buprenorphine
`
`as a tablet having an equivalent amount of buprenorphine or a pharmaceutically
`
`acceptable salt thereof.
`
`15. (Previously Amended) A film dosage composition comprising:
`
`a. A polymeric carrier matrix;
`
`b. A therapeutically effective amount of buprenorphine or a pharmaceutically
`
`acceptable salt thereof;
`
`c. A therapeutically effective amount of naloxone or a pharmaceutically
`
`acceptable salt thereof; and
`
`d. A buffering system;
`
`Page 3
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`Page 3
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 4
`
`wherein said buffering system comprises a buffer capacity sufficient to maintain
`
`the ionization of naloxone during the time which said composition is in the oral
`
`cavity of a user, and also sufficient to optimize the absorption of said
`
`buprenorphine.
`
`16. (Previously Amended) The composition of claim 15, wherein said composition has a
`
`local pH of about 2 to about 3.5.
`
`17. (Previously Amended) A method of treating narcotic dependence of a user,
`
`comprising the steps of:
`
`a. providing a composition comprising:
`
`i. A polymeric carrier matrix;
`
`ii. A therapeutically effective amount of buprenorphine or a
`
`pharmaceutically acceptable salt thereof;
`
`iii. A therapeutically effective amount of naloxone or a pharmaceutically
`
`acceptable salt thereof; and
`
`iv. A buffer in an amount to provide a local pH of about 2 to about 3.5 for
`
`said composition of a value sufficient to optimize absorption of said
`
`buprenorphine and also sufficient to inhibit absorption of said
`
`naloxone; and
`
`b. administering said composition to the oral cavity of a user.
`
`18. (Original) The composition of claim 17, wherein said method provides a
`
`bioequivalent absorption of buprenorphine to that of a tablet having an equivalent
`
`amount of buprenorphine or a pharmaceutically acceptable salt thereof.
`
`19. (Previously Amended) The method of claim 17, wherein said composition has a local
`
`pH of about 3 to about 3.5.
`
`20. (Original) The method of claim 17, wherein said film dosage composition is
`
`administered to the user through buccal administration, sublingual administration, and
`
`combinations thereof.
`
`21. (Original) The method of claim 17, wherein said film dosage composition remains in
`
`the oral cavity of the user for a period of at least 1 minute.
`
`Page 4
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`Page 4
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`e5
`Pag
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`22. (Original) The method of claim 17, wherein said film dosage composition remains in
`
`the oral cavity of the user for a period of between about 1 and 1.5 minutes.
`
`23. (Original) The method of claim 17, wherein said film dosage composition remains in
`
`the oral cavity of the user for a period of up to 3 minutes.
`
`24. (Previously Amended) A process of forming a film dosage composition comprising
`
`the steps of:
`
`a.
`
`casting a film-forming composition, said film-forming composition
`
`comprising:
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`A polymeric carrier matrix;
`
`A therapeutically effective amount of buprenorphine or a
`
`pharmaceutically acceptable salt thereof;
`
`A therapeutically effective amount of naloxone or a pharmaceutically
`
`acceptable salt thereof; and
`
`A buffer in an amount to provide a local pH of said composition of a
`
`value sufficient to optimize absorption of said buprenorphine and also
`
`sufficient to inhibit absorption of said naloxone; and
`
`b. drying said film-forming composition to form a self-supporting film dosage
`
`composition.
`
`25. (Previously Amended) The process of claim 24, wherein said composition has a local
`
`pH of about 2 to about 3.5.
`
`26. (Previously Amended) A film dosage composition comprising a therapeutically
`
`sufficient amount of buprenorphine or a pharmaceutically acceptable salt thereof and
`
`a therapeutically sufficient amount of naloxone or a pharmaceutically acceptable salt
`
`thereof, said film dosage composition having a bioequivalent release profile as a
`
`tablet containing about 2 times the amount of buprenorphine or a pharmaceutically
`
`acceptable salt thereof, and wherein said composition provides a local pH of from
`
`about 2 to about 3.5.
`
`27. (Original) An orally dissolving film formulation comprising buprenorphine and
`
`naloxone, wherein said formulation provides an in vivo plasma profile having a Cmax
`
`Page 5
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`Page 5
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 6
`
`of between about 0.624 ng/ml and about 5.638 ng/ml for buprenorphine and an in
`
`vivo plasma profile having a CmaX of between about 41.04 pg/ml to about 323.75
`
`pg/ml for naloxone.
`
`28. (Original) The formulation of claim 27, wherein said formulation provides a mean
`
`AUC of between about 5.431 hr.ng/ml to about 56.238 hr.ng/ml for buprenorphine.
`
`29. (Original) The formulation of claim 27, wherein said formulation provides a mean
`
`AUC of between about 102.88 hr.pg/ml to about 812.00 hr.pg/ml for naloxone.
`
`30. (Original) The formulation of claim 27, wherein said formulation comprises about 2
`
`to about 16 mg of buprenorphine or a salt thereof.
`
`31. (Original) The formulation of claim 27, wherein said formulation comprises about
`
`0.5 to about 4 mg of naloxone or a salt thereof.
`
`Page 6
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`Page 6
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 7
`
`REMARKS
`
`Claims 1 and 3-31 are pending in this office action.
`
`
`Rejection Under 35 U.S.C. §112
`
`In the Office Action, the Examiner rejected claims 1-3, 13-14, 16-23, and 25-26 under
`
`35 U.S.C. §112, first paragraph, as allegedly containing new matter. The Examiner stated
`
`that the amendments to the pH from about 2 to about 3.5 for buprenorphine was not in the
`
`specification. The Examiner pointed to paragraph [0016] which discusses the pH that inhibits
`
`naloxone, but alleged that there was no support in the specification for the pH with regard to
`
`buprenorphine.
`
`The Applicant respectfully traverses this rejection and directs the Examiner to
`
`paragraph [0064], for example. This paragraph states, in relevant part:
`
`it has
`In such combination films [including buprenorphine and naloxone],
`been discovered that the local pH of the film composition should preferably be
`in the range of about 2 to about 4, and more preferably about 3 to about 4...
`Most preferably the local pH of the film composition is about 3.5. At this
`local pH level, absorption of the buprenorphine is optimized while absorption
`of the naloxone is inhibited.
`
`There is clear and literal support in the application as filed for the local pH of a
`
`combination film (e. g., including buprenorphine and naloxone) being from about 2 to about
`
`3.5. Additional support for the pH being about 3.5 may be found in additional paragraphs,
`
`including, for example, paragraphs [0067] and [0087], as well as Example 8, which is directly
`
`related to an Analysis of In Vivo Absorption of a Film Having a Ph of From 3-3.5 (paragraphs
`
`[0097]-[0101].
`
`In view of the significant literal support for this pH range in the application as filed,
`
`the Applicant respectfully traverses the rejection. There is ample support in the application
`
`for the claimed limitations, and thus the rejection should be withdrawn.
`
`Page 7
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`Page 7
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`

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`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 8
`
`Re'ection under 35 U.S.C.
`
`103
`
`In the Office Action, the Examiner rejected claims 1 and 3-31 under 35 U.S.C.
`
`§103(a) as allegedly obvious over Oksche (WO 2008/025791, counterpart US
`
`2010/0087470). The Examiner stated that, although Oksche fails to disclose pH values, the
`
`determination of a suitable pH range would have been obvious and routine experimentation.
`
`The Examiner stated that Oksche discloses a Suboxone tablet, and thus it would have been
`
`obvious to modify Oksche accordingly. Finally, the Examiner stated that the “open range” of
`
`the pH in the claims (i.e., using the term “about”) further demonstrates its obviousness.
`
`Applicant’s Response
`
`The Applicant respectfully traverses the instant rejection, noting that the reference
`
`cited would simply not direct one of ordinary skill in the art to using a pH range that is
`
`clearly claimed. In fact, there is no direction in Oksche that one of ordinary skill in the art
`
`could follow and come up with the claimed invention. Finally, the Applicant has
`
`demonstrated through the examples shown in the application that the presently claimed range
`
`demonstrates unexpected and significant improvements, particularly when compared to that
`
`of the prior art and when compared to what one of ordinary skill in the art would have been
`
`led to believe (i.e., through partition theory, as explained in the application as filed at
`
`paragraph [0100]).
`
`In addition, the Applicant traverses the Examiner’s opinion that the term “optimize” is
`
`not limiting. The Examiner stated that limitations from the specification are not read into the
`
`claims, which is correct, however, the term “optimize” is expressly and unequivocally
`
`defined in the specification. The Applicant is permitted to be its own lexicographer, and
`
`terms that are given definition in the specification are defined as such in the claims. (CITE).
`
`The claims specifically identify a particular pH range, which is sufficient to achieve
`
`the goals of optimizing the absorption of one component (buprenorphine) and minimizing the
`
`absorption of a second component (naloxone). There is absolutely no identified pH range in
`
`Oksche, and thus no direction whatsoever to allow one of ordinary skill in the art to come up
`
`Page 8
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`Page 8
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`

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`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 9
`
`with the claimed invention. There is simply no predictability in modifying the pH of Oksche
`
`to the claimed level and expecting to achieve the significant results claimed.
`
`Even further, as explained in detail in the application as filed and in the previous
`
`response, one of ordinary skill in the art would have expected that a product would follow pH
`
`partition theory. According to pH partition theory, one would expect that saliva (which has a
`
`pH of about 6.5) would maximize the absorption of both actives. However, it has been
`
`surprisingly discovered by the Applicant that by buffering the dosage to a particular pH level,
`
`the optimum levels of absorption of the buprenorphine and the naloxone may be achieved. It
`
`has been discovered that the desirable local pH of a composition including buprenorphine and
`
`naloxone is between about 2 to about 3.5. At this local pH level, the desired absorption of the
`
`buprenorphine and the naloxone is achieved. As described in the application as filed and in
`
`the Examples (discussed below), controlling the local pH of the film compositions of the
`
`present invention provides a system in which the desired release and/or absorption of the
`
`components is achieved.
`
`As such, if one of ordinary skill in the art was to simply modify the pH, that person
`
`would have followed pH partition theory and used a pH of about 6.5. This is E outside the
`
`claimed range.
`
`Experimental Results
`
`The present inventors have undertaken significant experimentation to determine the
`
`conditions to effectively and efficiently deliver a suitable dosage of buprenorphine and, in
`
`appropriate circumstances, to effectively and efficiently inhibit the absorption of naloxone.
`
`The inventors have determined that the buffer selected and the buffer capacity used in the
`
`film has a significant and dramatic affect on the absorption of actives. However, the arrival
`
`at this invention is not simply limited to mere selection of pH ranges, and must take into
`
`account the Cmax and AUC values for the product.
`
`The Examples are set forth in the application as filed, and as can be seen, the
`
`Applicant discovered that optimized values can be achieved when the pH of the film falls
`
`within the claimed range. These results are surprising, particularly in view of pH partition
`
`Page 9
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`Page 9
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 10
`
`theory, which would be understood that a pH of about 6.5 would be successful in achieving
`
`the desired balance between drug solubility and ionization.
`
`The tests conducted by the Applicant demonstrate surprising and very effective results
`
`at the claimed pH levels. Again, these levels are certainly not obvious over Oksche’s general
`
`disclosure (including lack of any pH range) and the present examples demonstrate the
`
`surprising effect that is achieved.
`
`In particular, the Examples show the significant benefits when a pH of about 3.5 is
`
`used as compared to a pH of 6.5 and 5.5. See, for example, Example 8, which tested products
`
`at a pH of from 3.0-3.5.
`
`As has previously been explained, the present applicants have discovered that the
`
`suitable buffer capacity actually differs from that which would be expected from pH partition
`
`theory. For example, the buffer capacity for a product including both the buprenorphine and
`
`naloxone would be one that minimizes the absorption of the naloxone but optimizes the
`
`absorption of the buprenorphine — a concept not disclosed nor considered by Oksche. For
`
`example, the present inventors have discovered that at a pH of about 2-3.5, the relative
`
`absorptions can be controlled effectively.
`
`Conclusion
`
`The fees for a three month extension of time is also due with this submission, to be
`
`charged to Deposit Account No. 08-2461. If any additional fees are due, the Commissioner is
`
`hereby authorized to charge payment any fees associated with this communication, or credit
`
`any overpayment, to Deposit Account No. 08-2461. Such authorization includes
`
`authorization to charge fees for extensions of time, if any, under 37 CPR § 1.17 and also
`
`should be treated as a constructive petition for an extension of time in this reply or any future
`
`reply pursuant to 37 C.F.R. § 1.136.
`
`If there are any questions or if additional information is required, the Examiner is
`
`respectfully requested to contact Applicant’s attorney at the number listed below.
`
`Respectfully submitted,
`
`Page 10
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`Page 10
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`Applicants: Myers et a1.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Amendment and Response dated October 22, 2012
`Page 11
`
`HOFFMANN & BARON, LLP
`
`6900 Jericho Turnpike
`Syosset, New York 11791
`(973) 331-1700
`
`/Stephen J. Brown /
`Stephen J. Brown
`Registration No.: 43,519
`Attorney for Applicant(s)
`
`Page 11
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`Page 11
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`