Attorney Docket No. 4000.3010 USI
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicant:
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`Elliot Ehrich
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`11/083,167
`Application No.
`March 17, 2005
`Filed:
`Confirmation No. 8002
`For:
`Naltrexone Long Acting Formulations and Methods for Use
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`1617
`Group No.
`Examiner: Kendra D. Carter
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`AMENDMENT
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`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Sir:
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`This Amendment is in response to the Office action mailed from the U.S. Patent
`and Trademark Office on May 5, 2009, in the above-identified application.
`A Petition for Extension of Time for two months and the appropriate fees are
`being filed concurrently.
`
`Please amend the above-identified application as follows:
`Amendments to the Claims are reflected in the listing of claims which begins on
`page 2 of this paper.
`Remarks/ Arguments begin on page 5 of this paper.
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`Amendments to the Claims:
`Please add new Claim 26.
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`The Claim Listing below will replace all prior versions of the claims in the application:
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`Claim Listing:
`(Currently Amended) A method for treating an individual in need of naltrexone
`1.
`comprising the step of parenterally administering a long acting formulation
`comprising naltrexone to the individual wherein the serum AUC of naltrexone is
`at least about t\vo times, preferably at least about three times, more preferably
`about 3.3 times greater than that achieved by 50 mg/day oral administration.
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`2.
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`3.
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`4.
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`5.
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`6.
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`(Currently Amended) The [[A]] method of claim 1 treating an individual in need
`ofnaltrmcone comprising administering [[a]] the long acting formulation in a dose
`comprising between about 160 and 240 mg of naltrexone or about 310 to about
`480 mg of naltrexone.
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`(Withdrawn/Original) A method of treating an individual in need ofnaltrexone
`comprising administering naltrexone, in the absence of co-administering alcohol,
`to an individual who has not undergone alcohol abstinence within three days,
`such as
`five days, prior to the naltrexone administration.
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`(Withdrawn/Original) The method of Claim 3 wherein the naltrexone is
`administered in a long acting formulation comprising naltrexone.
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`(Withdrawn/Original) A method of increasing the days prior to occurrence of
`alcohol consumption in an individual in need of naltrexone comprising
`administering a long acting formulation comprising naltrexone, in the absence of
`co-administering alcohol, to an individual who has not abstained from alcohol
`within three days, such as five days, prior to the naltrexone administration.
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`(Currently Amended) The [[A]] method of claim 1 treating an individual in need
`ofnaltrexone comprising administering [[a]] the long acting formulation
`comprising naltrexone in a dosage between about 160 mg to about 480 mg
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`naltrexone every four weeks for a period of about 24 weeks or more wherein the
`individual has not used oral naltrexone within five or more days, sueh as 'tvi-thiR
`teR days, before said administration.
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`(Original) The method of claim 1 wherein the long acting formulation releases
`naltrexone for a period of at least two weeks.
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`(Original) The method of claim 1 wherein the long acting formulation releases
`naltrexone for a period of about four weeks.
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`(Original) The method of claim 1 wherein the long acting formulation is
`administered in a dose of at least about 160 mg of naltrexone.
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`7.
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`8.
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`9.
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`10.
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`(Original) The method of claim 1 wherein the long acting formulation is
`administered in a dose between about 160 and 240 mg of naltrexone.
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`11.
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`12.
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`13.
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`14.
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`(Original) The method of Claim 10 wherein the long acting formulation is
`administered in a dose of about 190 mg of naltrexone.
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`(Original) The method of claim 1 wherein the long acting formulation is
`administered in a dose between about 310 and 480 mg of naltrexone.
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`(Original) The method of Claim 1 wherein the long acting formulation is
`administered in a dose of about 3 80 mg of naltrexone.
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`(Original) The method of claim 1 wherein the long acting formulation is
`administered over a period of about 24 week period or longer.
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`15.
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`(Currently Amended) The method of claim 1 further comprising a second
`administration of a long acting formulation comprising naltrexone at least about 7
`days, preferably at least about 14 days, more preferably at least about 21 days,
`sueh as about 28 days, after the first administration.
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`16.
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`(Original) The method of Claim 15 wherein the second long acting formulation is
`substantially similar to the first long acting formulation.
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`17.
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`(Original) The method of Claim 15 wherein the second long acting formulation is
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`the same as the first long acting formulation.
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`18.
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`19.
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`20.
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`21.
`a
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`(Currently Amended) The method of claim 1 wherein the individual is an
`individual afflicted by alcohol dependency, sueh as a heavy drinker.
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`(Original) The method of claim 1 wherein the individual does not receive an
`initial oral dose of naltrexone.
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`(Currently Amended) The method of claim 1 wherein naltrexone is administered
`by injection, sueh as iH-tram-useularly or subeutan:eously.
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`(Original) The method of claim 1 wherein the long acting formulation comprises
`polylactide polymer or a poly lactic acid polymer.
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`22.
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`(Currently Amended) The method of claim 1 wherein the long acting formulation
`comprises a polylactide-co-glycolide polymer, sueh as a ]90lymer 'tvhieh )90ssesses
`a moleeular weight of at least 100,000 daltons.
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`23.
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`(Original) The method of claim 1 wherein the naltrexone is present in the long
`acting formulation at a concentration of about 35 % by weight.
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`24-25. (Canceled)
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`26.
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`(New) A method for treating an individual in need ofnaltrexone comprising the
`step of parenterally administering a long acting formulation comprising
`naltrexone to the individual wherein the serum AUC of naltrexone is at least
`about two times greater than that achieved by 50 mg/day oral administration.
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`REMARKS
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`Claims 3-5 have been withdrawn. Claims 1, 2, 6, 15, 18, 20, and 22 have
`been amended. New claim 26 has been added. Support for claim 26 is found in
`claim 1 as originally filed and in the specification at page 3, line 12. Claims 1-23
`and 26 are pending in the application. Reconsideration is respectfully requested.
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`Claim Rejections- 35 USC §112
`The Examiner has rejected claims 6, 18, 20, and 22 on the grounds that the phrase
`"such as" renders the claim indefinite because it is unclear whether the limitations
`following the phrase are part of the claimed invention. Applicants have amended claims
`6, 18, 20, and 22 to remove the language objected to by the Examiner. Withdrawal of the
`rejection under this section is respectfully requested.
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`Claim Rejections- 35 USC §102
`Claims 1, 2, 6-21 and 23 are rejected under 35 U.S.C. §102(b) as being
`anticipated by Tice et al. (6,306,425 B1). The Examiner states that Tice teaches
`muscular injectable naltrexone microsphere compositions and their use in reducing
`consumption of alcohol. The Examiner also states that Tice discloses a composition
`comprising a matrix consisting of polymer poly-(D,L-lactide ). The Examiner further
`states that Tice discloses naltrexone being released in a controlled manner for greater
`than 28 or about 32 days. The Examiner states that Tice discloses that smaller doses may
`be administered after the first dose, because one continues to obtain release from the
`prior injected microspheres to which is added the release from the lately administered
`microspheres, or one can enjoy enhanced levels of the naltrexone without increasing the
`amount of the microspheres which are administered. The Examiner further states that
`Tice discloses microspheres that are formulated from about 150-350 mg ofnaltrexone
`such that the plasma concentration is in a therapeutic range of at least about 2 ng/ml. The
`Examiner asserts that the Tice microsphere formulation gave an AUC of more than 3.3
`times greater than that achieved by 50 mg/day oral administration based on the
`Examiner's interpretation of Tice at column 14, lines 40-55. With regard to claims 6 and
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`19, the Examiner asserts that Tice teaches that the primary application for the subject
`formulations in an intramuscular injection that is also designed to avoid oral
`administration so as to increase patient compliance. With regard to claim 13 the
`Examiner states that Tice teaches the limitation in which the amount of naltrexone is
`about 380 mg because the Examiner asserts that the 350 mg dosage taught by Tice reads
`on about 380 mg (emphasis original). Applicants respectfully submit that the Examiner
`is incorrect and that the presently claimed invention is not anticipated by Tice for the
`reasons discussed below.
`Turning first to amended claim 1 of the present invention, this claim requires that
`the serum AUC of a parenterally administered formulation of the invention be at least
`about three times greater than that achieved by 50 mg/day oral administration. Contrary
`to the Examiner's assertion, Tice does not disclose this AUC. The Examiner's
`interpretation of the data in column 14, lines 40-55, is incorrect. The column labeled
`"Ratio F-1/Tablets" as seen in column 14, lines 40-55, presents the mean AUC0_32d ratio
`between N altrexone in the injectable microsphere formulation ("F 1 ") and N altrexone in
`the oral 50 mg dose ("Tablets"). The Mean Ratio ofFl/Tablets is listed in column 14,
`lines 40-55, ofTice as 1.18, and is obtained by dividing 1051.6 by 888.01, as found in the
`"Ratio" column of the table in column 14. The mean AUC0_32d Fl/Tablets ratio ofTice is
`therefore not more than 3.3 as stated by the Examiner, but is in fact more than 60% lower
`than 3.3. In other words, the microsphere formulation of Tice gave an AUC that is
`merely 1.18 times greater than that achieved by the 50 mg/day oral administration- a
`value that is nearly identical to the 50 mg/day oral administration. The plain reading of
`Tice indicates that Tice admits that the AUC for the daily oral dose is similar to that of
`the AUC of Formulation F-1 '. For example, see column 14 lines 59-64, ofTice wherein
`it is states that:
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`The data indicate that the exposure to the active naltrexone moiety
`is likely to be comparable whether taking daily 50-mg tablets for one
`month or one 300 mg of microencapsulated naltrexone by intramuscular
`injection ifmicrosphere Formulation F-1' once monthly" [emphasis
`added].
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`Clearly, if the data in Tice showed that the injectable F-1' naltrexone formulation
`achieved a superior pharmacokinetic profile than the oral dose, such as three times
`greater, the inventors ofTice would have highlighted that result. Instead the inventors of
`Tice characterized the performance of the F-1' injectable formulation as merely similar to
`the daily oral dose. Indeed, none of the formulations made by Tice achieve even twice the
`AUC of the oral formulation over the same period of time. Thus, claim 1 and claim 26 do not
`embrace the formulations made in Tice. A reading of Tice as a whole establishes that the
`objective is to design formulations that are comparable to the oral dose, not at least twice or
`three times the oral dose. The AUC values between Tice and the presently claimed invention
`are not inherently the same and therefore, the claims do not embrace the formulation
`disclosed in Tice.
`Contrast Tice to the teachings of the present application at page 3, lines 15-20,
`which states:
`This invention arose from the unexpected discovery that substantially
`improved serum levels of naltrexone can be achieved by administering
`long acting formulations of naltrexone, such as the Alkermes, Inc.
`formulation, VIVITREX® injectable suspension, made employing its
`MEDISORB® delivery system. Indeed, it was not expected that serum
`levels of about 3.3 times that achieved by a 50 mg/day oral dose could be
`achieved by a single IM administration ofVIVITREX®.
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`Applicants are providing herewith a Declaration under § 1.132 by the inventor, Dr. Elliot
`Ehrich which discusses in more detail how this discovery came about and provides
`comparative data and information between Tice and the data and information upon which
`the present invention is based. It is clear from the Declaration and the Exhibits provided
`therewith that the AUC disclosed by Tice for the formulations tested therein are
`significantly below the presently claimed AUC for the long acting naltrexone
`formulations of the present invention. Therefore, claim 1 and claim 26 are not
`anticipated by Tice. Given that claims 2 and 6-23 have been amended to depend from
`claim 1 directly or indirectly claims 2 and 6-23 are also not anticipated by Tice.
`Withdrawal of the rejection under this section is respectfully requested.
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`Claim Rejections- 35 USC §103
`The Examiner has rejected claim 22 under U.S.C. 103(a) as being unpatentable
`over Tice et al. (6,306,425 B1) as applied to claims 1, 2, 6-21, and 23 above in further
`view of Chandrashekar et al. (6,143,314). The Examiner applies the teachings ofTice et
`al. as applied to claims 1, 2, 6-21, and 23 above. The Examiner states that Tice et al. do
`not teach a polylactide-co-glycolide polymer. The Examiner asserts that Chandrashekar
`et al. teach a controlled release liquid delivery compositions of active compounds such as
`naltrexone with polymers such as polylactides and poly(lactide-co-glycolide) as the
`controlled release additive (abstract; claims 1 and 2; column 7, line 15). The Examiner
`concludes that one of ordinary skill in the art at the time of the invention would have
`found it obvious and have been motivated to combine the method ofTice et al. and a
`polylactide-co-glycolide polymer because it is known in the art that these types of
`polymers are known to provide controlled release of active ingredients. The Applicants
`respectfully disagree.
`Claim 22 depends directly from claim 1. As discussed above, claim 1 is not
`anticipated by Tice as it does not disclose the presently claimed AUC of the trospium
`long-acting formulation of the invention as discussed in the § 1.132 Declaration filed
`herewith. Chandrashekar also does not disclose the presently claimed AUC of the long
`acting formulations of naltrexone of the invention. To establish a prima facie case of
`obvious, the prior art references when combined must teach or suggest all of the claim
`limitations (MPEP §2143). The cited combination ofTice and Chandrashekar do not
`disclose or suggest all of the presently claimed limitations.
`In addition, the Declaration further elaborates on the unexpected results reported
`on page 3, lines 15-20, of the present application. It is well settled that unexpected
`results can be established by factual evidence. In re Lindner, 173 USPQ 356 (CCPA
`1972). Applicants have provided this factual evidence in the specification and in the
`accompanying Declaration. It is also well settled that proof of unexpected properties
`may rebut a prima facie case of obviousness including differences based on longer
`lasting pharmacological activity where the actual increase was beyond reasonable
`expectations. See, In re Chupp, 2 USPQ2d 1437,1440 (CAFC 1987) citing In re Blonde!,
`499 F.2d 1311, 182 USPQ 294 (CCPA 1974) (reversing rejection of claims to
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`compounds which prior art suggested would have longer-lasting pharmacological
`activity, where actual increase was beyond reasonable expectations). Therefore, claim 22
`as well as claims 1 and all claims dependent thereon and claim 26 are not prima facie
`obvious in view of the cited combination of references. Withdrawal of the rejection is
`respectfully requested.
`A general authorization is hereby granted to charge Deposit Account No.
`502807 for any fees required under § 3 7 C.F .R. 1.16 and 1.17 in order to maintain
`pendency of this application.
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`CONCLUSION
`In view of the above amendments and remarks, it is believed that all claims are in
`condition for allowance, and it is respectfully requested that the application be passed to
`issue. If the Examiner feels that a telephone conference would expedite prosecution of
`this case, the Examiner is invited to call the undersigned at (978) 251-3509.
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`Respectfully submitted,
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`ELMORE PATENT LAW GROUP, P.C.
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`/Darlene A. Van stone/
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`35,729
`Registration No.
`Telephone: (978) 251-3509
`Facsimile: (978) 251-3973
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`Dated: October 5, 2009
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