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 RCE
`
`Filed:
`
`For:
`
`August 7, 2009
`
`Dated:
`
`April 30, 2013
`
`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: April 30, 2013
`
`Signature: Stephen J. Brown \Stephen J. Brown\
`
`AMENDMENT AND RESPONSE WITH
`RE UEST FOR CONTINUED EXAMINATION
`
`Madam:
`
`In response to the Final Office Action dated May 2, 2012, and Advisory Action dated
`
`November 2, 2012, Applications make the following amendments and remarks. This
`
`communication is filed concurrently with a Request for Continued Examination.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 5 of this paper.
`
`P8991
`
`BDSI EXHIBIT 1011
`
`Page 1
`
`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Page 2
`
`Amendments to the Claims:
`
`This listing of claims shall replace all previous listings in this application:
`
`1.
`
`(Currently 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
`
`is from about 3 [[2]] to about 3.5 in the presence of saliva.
`
`2.
`
`3.
`
`4.
`
`(Canceled).
`
`(Cancelled).
`
`(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.
`
`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.
`
`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
`
`Page 3
`
`11. (Cancelled).
`
`12. (Cancelled).
`
`13. (Cancelled).
`
`14. (Cancelled).
`
`15. (Cancelled).
`
`16. (Cancelled).
`
`17. (Currently 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 3 [[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. (Cancelled).
`
`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.
`
`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.
`
`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
`
`Page 4
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`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`(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.
`
`(Cancelled).
`
`(Cancelled).
`
`(Cancelled).
`
`(Original) An orally dissolving film formulation comprising buprenorphine and
`
`naloxone, wherein said formulation provides an in vivo plasma profile having a Cmax
`
`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.
`
`(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.
`
`(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.
`
`(Original) The formulation of claim 27, wherein said formulation comprises about 2
`
`to about 16 mg of buprenorphine or a salt thereof.
`
`(Original) The formulation of claim 27, wherein said formulation comprises about
`
`0.5 to about 4 mg of naloxone or a salt thereof.
`
`Page 4
`
`Page 4
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Page 5
`
`REMARKS
`
`Independent claims 1 and 17 have been amended to recite a local pH range of about 3
`
`to about 3.5. This limitation was previously claimed in claims 3 and 19, respectively.
`
`Accordingly, no new matter has been added.
`
`Claims 3, 11-16, 19, and 24-26 have been cancelled without prejudice.
`
`Claims 1, 4-10, 17-18, 20-23, and 27-31 are pending.
`
`Rejection 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. Patent
`
`Application Publication No. 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. Applicants respectfully traverse this rejection.
`
`Although believed unnecessary, claims 3, 11-17, 19, and 24-26 have been cancelled to
`
`further prosecution. The rejection of these claims has been rendered moot and withdrawal is
`
`respectfully requested.
`
`Claims 1, 4-10, 17-18, and 20-23:
`
`Independent claims 1 and 17 have been amended to recite a local pH range of about 3
`
`to about 3.5. Claims 4-10 and 18 and 20-23 depend from claims 1 and 17, respectively.
`
`As previously argued, the claimed pH range achieves the goals of optimizing the
`
`absorption of one component (buprenorphine) and minimizing the absorption of a second
`
`component (naloxone). The Applicants have repeatedly shown that Oksche is completely
`
`devoid of any recitation of any pH range. Thus, there is absolutely no direction in Oksche to
`
`allow one of ordinary skill in the art to come up with the claimed invention. And, assuming
`
`arguendo that Oksche disclosed a pH, there is simply no predictability in modifying that pH
`
`to the claimed level and expecting to achieve the significant results claimed.
`
`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
`
`Page 6
`
`Moreover, Applicants have repeated demonstrated that experimental results in the
`
`specification show that the claimed pH range has unexpected benefits. A detailed discussion
`
`of these results is presented below for completeness. To briefly summarize, , 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 3-3.5, the relative absorptions can be controlled effectively.
`
`In response, to these experimental results and argument, the Examiner has essentially
`
`conceded that they are sufficient to overcome the rejection over Oksche, but that the claims
`
`are not commensurate in scope to the data:
`
`Applicant’s argument that the Examples show significant benefits when a pH
`of about 3.5 is used is used as compared to a pH of 6.5 and 5.5, Example 8
`tested products at a pH of from 3.0-3.5 is not sufficient to provide evidence of
`unexpected or significant benefits associated with the full scope of the claimed
`invention, which recites a “local pH of about 2 to about 3.5 in the resence 0
`
`saliva.” Applicant showing is not commensurate in scope with the claimed
`invention.
`
`(Advisory Action at 2-3 (emphasis original).) Applicants note that the Examiner has not
`
`alleged that the experimental results are to be expected or otherwise rebutted the
`
`demonstration of unexpected results.
`
`Accordingly, although believed unnecessary and only to further prosecution,
`
`Applicants have amended independent claims 1 and 17 to recite the local pH range of about 3
`
`to about 3.5 to provide a scope that is fully and expressly supported by the experimental
`
`results. In view of the claims amendments, the Examiner’s comments, and the experimental
`
`results Applicants submit that the alleged prima facie obviousness has been rebutted. For this
`
`reason alone, reconsideration and withdrawal of the rejection are respectfully solicited for
`
`claims 1, 4-10, 17-18, and 20-23.
`
`As discussed above, previously described in the earlier responses, and as supported
`
`throughout the specification, the Applicant has surprisingly identified that the optimized
`
`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
`
`Page 7
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`adsorption of buprenorphine and the optimized limited adsorption of naloxone do not follow
`
`traditional or expected adsorption profiles. Both compounds are conjugate organic acids with
`
`pKa’s at approximately 8, and yet as the pH of the film for delivering the agents decreases,
`
`one compound undergoes a optimum adsorption, but the other compound surprisingly trends
`
`the opposite direction and is inhibited at the same lower pH levels. This divergence allows
`
`the Applicant to produce a film which delivers buprenorphine to the bloodstream and passes
`
`the naloxone to the gut where it is ineffective, thus providing a treatment regime for
`
`buprenorphine. At the same time, the film is protected from abuse, because if a patient
`
`diverts the dosage, the naloxone inhibits the opioid effect when injected, snorted or otherwise
`
`administered in a drug abuse attempt.
`
`To counter the experimental evidence and surprising results, the Examiner has offered
`
`only a single reference, 0ksche, in an obviousness rejection. 0ksche is completely silent
`
`regarding adjusting pH to optimize the adsorption of buprenorphine and minimize the
`
`adsorption of naloxone. The only evidence offered by the Examiner for such a conclusion is
`
`that 0ksche mentions pH modifiers such as “citric acid, tartaric acid, phosphoric acid,
`
`hydrochloric acid and maleic acid” in the context of “secondary components such as
`
`preservatives, anti-oxidants, surfactants, viscosity enhancers, colouring agents, flavouring
`
`agents, pH modifiers, sweeteners or taste-masking agents [that] may be incorporated into the
`
`composition.” 0ksche, [0072]. Thus, the Examiner concludes that optimizing the pH is
`
`obvious in view of 0ksche because pH modifiers are mentioned in passing. The Examiner
`
`relies on MPEP 2144.05 and asserts that “it would have been obvious to the ordinary skilled
`
`artisan... to modify their teachings so as to identify the optimal range of pH/dosage in an
`
`effort to identify formulations that would provide optimal adsorption of both agonist and
`
`antagonist. As per MPEP 2144.05,
`
`identification of the optimal pH/dosage appears to be a
`
`matter of routine experimentation.” Advisory Action dated November 6, 2012, p. 4.
`
`Applicant submits that the Examiner’s arguments are misplaced for at least two
`
`reasons. First, MPEP 2144.05 applies for “Obviousness of Ranges,” yet nothing within the
`
`disclosure of 0ksche describes any mge of pH. 0ksche is completely silent regarding any
`
`amounts of acids, bases, buffers or anything substantive beyond the passing mention of
`
`“secondary components.” Thus, the Examiner’s conclusion that it would be obvious to
`
`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
`
`Page 8
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`provide a specific range of pH for controlling adsorption of one active and inhibiting the
`
`adsorption of a similar active cannot be supported by that disclosure. Therefore, the
`
`Examiner is impermissibly relying on Applicant’s own discovery of the significance of pH
`
`ranges in optimizing adsorption.
`
`Second, even accepting for the sake of argument that MPEP 2144.05 applied because
`
`Oksche somehow provides some concept of pH, the instructions within that section of the
`
`MPEP again leads to the conclusion that reliance on Oksche is not proper. “A particular
`
`parameter must first be recognized as a result-effective variable i.e. a variable which
`
`achieves a recognized result, before the determination of the optimum or workable ranges of
`
`said variable might be characterized as routine experimentation.” MPEP 2144.05(II)(B)
`
`(citing In re Antonie, 559 F.2d 618 (CCPA 1977)) (emphasis added.) Here, Oksche is
`
`completely silent regarding the necessity of adding an acid or buffer. Oksche treats such
`
`components in the same manner as a flavoring agent, coloring agent, taste masking agent, or
`
`any number of other secondary components. Oksche does not indicate that the pH of 2-3.5
`
`would lead to an optimized buprenorphine adsorption AND a minimized naloxone
`
`adsorption. Oksche never identifies nor understands the criticality of pH, and therefore
`
`cannot be asserted for the conclusion that it’s merely a results effective variable that can be
`
`modified.
`
`Moreover, based on the disclosure of Oksche one of skill in the art would have had a
`
`no rationale to use pH to modify absorption. Significantly, Oksche actually discusses
`
`enhancing absorption of buprenorphine over the mucosa. However, this discussion has
`
`nothing to do with pH, but rather points to permeation enhancers:
`
`In order to allow absorption of buprenorphine over the mucosa of the
`mouth, and particularly sublingually, in one embodiment the dosage forms
`may additionally use agents that enhance absorption of the active agent,
`i.e. so-called permeation enhancers.
`
`Such permeation enhancers may be selected from the group comprising
`propandiol, dexpanthenol, and oleic acid. The permeation enhancers may also
`be selected from the group comprising saturated or unsaturated fatty acids,
`hydrocarbons, linear or branched fatty alcohols, dimethylsulfoxide, propylene
`glycol, decanol, dodecanol, 2-octyldodecanol, glycerine, ethanol or other
`alcohols.
`
`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
`
`Page 9
`
`(HI 0085-86 (emphasis added).) None of these would be considered to modify pH or act as
`
`buffers.
`
`Furthermore, this is but one of many variables and ingredients that could be
`
`considered to effect absorption of the active ingredients. Accordingly, one of skill in the art
`
`with knowledge of the absorption of the actives from a tablet at pH 6.5, would have had no
`
`rationale to turn to pH out of all parameters to optimize absorption, much less to drastically
`
`reduce the pH to 3 to 3.5 and expect optimum results.
`
`In sum, the rejection is completely devoid of any evidence or reasoning sufficient to
`
`demonstrate that one of skill in the art would have had any rationale to modify Oksche to
`
`arrive at the claimed invention.
`
`For these additional reasons, the rejection falls short of providing a prima facie case
`
`for the obviousness of the claims. Reconsideration and withdrawal are respectfully solicited.
`
`As noted above, the previous discussion of the experimental results is included here
`
`for completeness:
`
`Experimental Results
`
`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.
`
`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
`
`Page 10
`
`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 effect 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
`
`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.
`
`Page 10
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`Page 10
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`

`

`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Page 11
`
`Claims 27-31:
`
`Independent claim 27 recites that the “formulation provides an in vivo plasma profile
`
`having a Cmax 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.” Claims 28-31 depend from claim 27.
`
`These claims have not been addressed in any of the art rejections, except by number.
`
`Thus, the limitations of these claims have never been addressed by the Examiner.
`
`Accordingly, these claims have not been rejected on any grounds.
`
`Moreover, while Oksche does discuss the Cmax for buprenorphine, it is completely
`
`silent as to the Cmax for naloxone. Thus, even if the Examiner had applied the reference to
`
`the claims 27-31, Oksche would fall far short of supporting a rejection of claims 27-31 as
`
`obvious.
`
`For these reasons, the rejection does not present a primafacie case for the
`
`obviousness of claims 27-31. Reconsideration and withdrawal of the rejection as to these
`
`claims are respectfully solicited.
`
`Conclusion
`
`In view of the foregoing, it is submitted that rejection has been met and the claims are
`
`in condition for allowance. Prompt entry of the amendments and allowance of the application
`
`are respectfully solicited.
`
`The fees for a one 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.
`
`Page 11
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`Page 11
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`

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`Applicants: Myers et al.
`Serial No.: 12/537,571
`Docket No.: 1199-82
`
`Page 12
`
`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,
`
`/Stephen J. Brown/
`Stephen J. Brown
`Registration No.: 43,519
`Attorney for Applicants
`
`HOFFMANN & BARON, LLP
`
`6900 Jericho Turnpike
`Syosset, New York 11791
`(973) 331-1700
`
`Page 12
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`Page 12
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