Attorney Docket No. 40003010 USl
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicant:
`
`Elliot Ehrich
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`Application No.
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`11/083,167
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`Group No.
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`1627
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`Filed:
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`March [7, 2005
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`Examiner:
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`Kendra D. Carter
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`Confirmation N o.
`
`8002
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`For:
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`Naltrexone Long Acting Formulations and Methods for Use
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`AMENDMENT
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`Mail Stop Amendment
`Commissioner for Patents
`PO. Box 1450
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`Alexandria, VA 223 1 3- 1450
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`Sir:
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`This Amendment is in response to the Office action mailed from the US. Patent
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`and Trademark Office on January 6, 2010, in the above-identified application.
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`A Petition for Extension of Time for one month and the appropriate fees are being
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`filed concurrently.
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`Please amend the above-identified application as follows:
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`Amendments to the Claims are reflected in the listing of claims which begins on
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`page 2 ofthis paper.
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`Remarks/Arguments begin on page 5 of this paper.
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`Amendments to the Claims:
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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:
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`1.
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`_l\)
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`(Currently Amended) A method for treating an individual in need of naltrexone
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`comprising the step of parenterally administering a long acting formulation
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`comprising naltrexone and a biocompatible polymer to the individual wherein the
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`serum AUC of naltrexone is at least about three times greater than that achieved
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`by 50 mg/day oral administration.
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`(Previously Presented) The method of claim 1 comprising administering the long
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`acting formulation in a dose comprising between about 160 and 240 mg of
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`naltrexone or about 310 to about 480 mg of naltrexone.
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`(Withdrawn/Original) A method of treating an individual in need of naltrexone
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`comprising administering naltrexone, in the absence of co-administering alcohol,
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`to an individual who has not undergone alcohol abstinence within three days,
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`such as five days, prior to the naltrexone administration.
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`(Withdrawn/Original) The method of Claim 3 wherein the naltrexone is
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`administered in a long acting formulation comprising naltrexone.
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`(Withdrawn/Original) A method of increasing the days prior to occurrence of
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`alcohol consumption in an individual in need of naltrexone comprising
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`administering a long acting formulation comprising naltrexone, in the absence of
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`co-administering alcohol, to an individual who has not abstained from alcohol
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`within three days, such as five days, prior to the naltrexone administration.
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`(Previously Presented) The method of claim 1 comprising administering [[a]] the
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`long acting formulation comprising naltrexone in a dosage between about 160 mg
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`to about 480 mg naltrexone every four weeks for a period of about 24 weeks or
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`more wherein the individual has not used oral naltrexone within five or more days
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`before said administration.
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`(Original) The method of claim 1 wherein the long acting formulation releases
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`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
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`naltrexone for a period of about four weeks.
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`(Original) The method of claim 1 wherein the long acting formulation is
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`administered in a dose of at least about 160 mg of naltrexone.
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`(Original) The method of claim 1 wherein the long acting formulation is
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`administered in a dose between about 160 and 240 mg of naltrexone.
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`(Original) The method of claim 10 wherein the long acting formulation is
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`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
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`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
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`administered in a dose of about 380 mg ofnaltrexone.
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`10.
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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 1 wherein the long acting formulation is
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`administered over a period of about 24 week period or longer.
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`15.
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`(Previously Presented) The method of claim 1 further comprising a second
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`administration of a long acting formulation comprising naltrexone at least about 7
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`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
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`substantially similar to the first long acting formulation.
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`17.
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`18.
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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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`(Previously Presented) The method of claim 1 wherein the individual is an
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`individual afflicted by alcohol dependency.
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`19.
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`(Original) The method of claim 1 wherein the individual does not receive an
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`initial oral dose of naltrexone.
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`(Previously Presented) The method of claim 1 wherein naltrexone is administered
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`by injection.
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`(Original) The method of claim 1 wherein the long acting formulation comprises
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`a polylactidc polymer or a poly lactic acid polymer.
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`22.
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`(Previously Presented) The method of claim 1 wherein the long acting
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`formulation comprises a polylactide—co—glycolide polymer.
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`(Original) The method of claim 1 wherein the naltrexone is present in the long
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`acting formulation at a concentration of about 35 % by weight.
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`(Canceled)
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`(Previously Presented) A method for treating an individual in need of naltrexone
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`comprising the step of parenterally administering a long acting formulation
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`comprising naltrexone to the individual wherein the serum AUC ofnaltrexone is
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`at least about two times greater than that achieved by 50 mg/day oral
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`administration.
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`REMARKS
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`Claim 1 has been amended. Support for the amendment to claim 1 is
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`found on page 4, lines 19-21 and page 7, line 4. The term “biocompatible
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`polymer” is also defined in column 6, line 65 to column 7, line 58, of US. Pat.
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`No. 6,358,443, incorporated by reference on page 5, line 6 of the present
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`application. Claims 3-5 have been withdrawn. Claims 1-23 and 26 are pending
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`in the application. Reconsideration is respectfully requested.
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`
`Claim Re'ections 35 U.S.C.
`112 first ,ara rah
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`The Examiner has rejected claims 1, 2, 6-23 and 26 under 35 U.S.C. §112,
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`first paragraph, as failing to comply with the cnablcmcnt requirement. The
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`Examiner states that the instant claims are drawn to a method for treating an
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`individual in need of naltrexone comprising the step of parenterally administering
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`a long acting formulation wherein the serum AUC of naltrexone is at least about
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`three times greater than that achieved by 50 mg/day oral administration. The
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`Examiner asserts that the specification fails to provide information that would
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`allow the skilled artisan to fully practice the instant invention without undue
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`experimentation citing the Wands factors (In re Wands, 8 USPQ2d 1400, 1404
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`(CAFC 1988). Applicants respectfully disagree.
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`The Examiner argues that the predictability of every long acting
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`formulation providing an AUC of naltrexone at least about two or three times
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`greater than that achieved by 50 mg/day oral administration is relatively low. The
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`Examiner makes reference to Tice (US. Pat. No. 6,306,425) as the state of the art
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`and the Examiner asserts that Tice teaches that every long acting formulation of
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`naltrexone does not give an AUC of naltrexone of at least about two or three
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`times greater than that achieved by 50 mg/day oral administration. The Examiner
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`concludes that because there is a “potential” of reaching the claimed AUC serum
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`values, the actual long acting formulation that gives these results is unpredictable.
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`The Examiner further argues that the specification provides no working
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`examples. The Examiner also asserts that Applicants have failed to provide any
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`information sufficient to practice the claimed invention, absent undue
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`experimentation.
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`With regard to the Examiner’s position on unpredictability, the Examiner
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`uses the previously cited Tice patent as evidence that not every long acting
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`formulation results in the presently claimed AUC and the actual long acting
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`formulation that gives these results is unpredictable. However, Tice is not a
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`reasonable example of unpredictability. Tice did not attempt to achieve a
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`naltrexone formulation that provided an AUC that was at least 2 times greater
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`than the AUC for oral naltrexone (50 mg). Tice’s objective was to show that
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`naltrexone delivered intramuscularly was comparable to taking 50 mg oral tablets
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`of naltrexone for one month (column 14, lines 59-64). Applicants were the first
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`to discover that higher AUC could be achieved with an extended release
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`formulation.
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`Thus, it can not be concluded that Tice failed to achieve a formulation
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`having the presently claimed AUC. Ticc did not have the benefit of the presently
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`claimed invention which teaches that such AUC are possible. Applicants will
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`establish, once it is understood that the presently claimed AUC can be achieved, it
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`is well within the skill in the art to test any number of long acting formulations
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`without undue experimentation to determine which formulations provide the
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`claimed AUC.
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`It is also well established that the standard is whether a skilled person
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`could determine which embodiments that were conceived, but not yet made,
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`would be inoperative or operative with expenditure of no more effort than is
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`normally required in the art. Atlas Powder Co. v. E]. da Pont de Nemoars & C0.,
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`750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984) (MPEP 2164.08(b)).
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`Thus the Examiner’s assertion that every long acting formulation must predictably
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`provide the claimed AUC is not the standard. In order to expedite prosecution of
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`the present application, Applicants have amended claim 1 to recite long-acting
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`formulations that comprise biocompatible polymers. As Applicants will show
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`herein those formulations falling within the present claims are determined using
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`standard means without undue experimentation.
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`With regard to the Examiner’s statement that the application does not
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`include a working example, Applicant respectfully disagrees. There are five
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`working examples in the present specification. While Example 3 is not the head
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`to head comparison, it is a comparison of actual in viva data collected by
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`Applicants on the one hand and peer reviewed data and analysis on the other
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`hand. Such a semi quantitative comparison is a scientifically sound comparison
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`generally acceptable in research and is indeed a working example.
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`Using the materials and methods set forth in the Examples of the present
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`specification, a head to head comparison between oral naltrexone (50 mg) and a
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`long acting naltrexone formulation of the invention (i.e. MEDISORB®
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`Naltrexone 380 mg and 190 mg) was carried out and the data resulting from those
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`studies indicated that the claimed AUC was achieved. See the § 132 Declaration
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`of Dr. Elliot Ehrich submitted with the Response dated October 5, 2009. Note
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`that Table 8 of Exhibit A of the Ehrich Declaration shows that the 380 mg dose
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`has an AUC that is at least 3.3 times greater than the AUC of the per day dose of
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`oral regimen of 50 mg per day naltrexone. Based on the proportionality observed
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`between the 190 and 380 mg doses of MEDISORB® naltrexone, the 190 mg was
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`reasonably predicted to be about 2 fold higher than the AUC following oral
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`dosing of 50 mg per day for 28 days (page 2 of the Ehrich Declaration). In
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`accordance with MPEP 2164.05 an enablement rejection can be overcome by a
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`declaration after the filing date that demonstrates that the claimed invention
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`works using the patent application as a guide.
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`With regard to the Examiner’s statement that undue experimentation is
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`required, Applicants respectfully disagree. Numerous long acting biocompatible
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`formulations are known in the art. Several of these are mentioned on page 5, lines
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`2-12 of the present application and include the MEDISORB® biocompatible
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`polymer delivery system exemplified in the Examples and discussed in the Ehrich
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`declaration. The chemistry around these various biocompatible polymer delivery
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`systems is well established. Any number of variables including AUC is easily
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`tested using standard techniques in this highly studied art.
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`The art discussed on page 5, lines 2-12 of the present application confirms
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`this. For example, US Patent 6,264,987 (Exhibit A) cited on page 5, line 5 of the
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`present application discloses in Example 6, experiments correlating the effect of
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`temperature on the relationship between molecular weight of the long acting
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`biocompatible polymer formulation and the erosion rate of the polymer under
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`physiological conditions (column 10, lines 18-64). Figure 3 of US. Patent
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`6,264,987 (Exhibit A) depicts a graph of molecular weight as a function of
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`solution hold time at varying temperatures. The graph of FIG. 3 provides data
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`from which the skilled person can establish an algorithm for calculating sustained
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`release as a function of one or more variables of the particles. Obtaining this
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`information required standard procedures for establishing release of the active by
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`the polymer under physiological conditions.
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`Tice et al. cited by the Examiner (US. 6,306,425) discloses in vivo
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`experiments testing six different formulations of naltrexone long acting polymer
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`formulations to determine the response in humans to different protocols for
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`administration and the naltrexone release profile of a number of the six
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`formulations (column 13, beginning on line 1). From this data, Tice was able to
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`generally conclude that a long term supply of naltrexone at a physiologically
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`effective concentration can be provided in viva. Once again these tests are well
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`within the skill in the art.
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`Other evidence that shows the standard nature of testing of biocompatible
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`polymer delivery systems includes, but is not limited to the following. All patents and
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`applications referred to in the following section are provided herewith as exhibits
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`attached to this response.
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`In 1997, Cha er al. US 5,702,717 (Exhibit B), describes an injectable block
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`copolymer drug delivery system. The copolymer is made up of a hydrophobic block (A)
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`selected from the group consisting of poly (a-hydroxy acids) and poly (ethylene
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`carbonate), and a hydrophobic block (B) comprising polyethylene glycol. These
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`formulations were studied using standardized tests for the controlled release of human
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`calcitonin, platelet-derived
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`growth factor (PDGF-B), and insulin (Example 8). US. Patent No. 6,004,573 (Exhibit C)
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`describes the use of water soluble ABA or BAB type triblock polymers for drug delivery.
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`The polymer is made up of a major amount of a hydrophobic polymer (PLGA or PLA) as
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`the A block and a minor amount of a hydrophilic PEG block. Using standard testing, the
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`release rate of the drug may be altered by changing various parameters such as adjusting
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`hydrophobic/hydrophilic content, molecular weight, polymer concentration, and
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`polydispersity of the triblock copolymer (Examples 3, 4, and 5).
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`US. Publication No. 2002/0015737 (Exhibit D), discloses proteins deposited
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`onto sparingly soluble biocompatible particles for controlled protein release into a
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`biological environment from a polymer matrix. Example 8 discloses in viva
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`pharmacokinetic studies of hGH sustained release formulations in rats. These standard
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`studies were conducted in rats to verify the effect of hGH deposited on sparingly water
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`soluble zinc carbonate salt. Sprague-Dawley rats were given one of five different
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`formulations having various solution bascs.
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`Multiblock biodcgradablc macromcrs including at least four polymeric blocks arc
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`described U.S. Publication No. 2002/0151650 (Exhibit E). This application discloses
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`that at least two polymeric blocks are hydrophobic and at least one is hydrophilic, and the
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`macromer should include a crosslinkable group. The block copolymers may be linear,
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`star-shaped, or branched. The macromers include one or more regions that have thermo-
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`responsive properties such as poloxamers. Using standard in vitro testing, the
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`composition of the macromers can be altered to produce hydrogels with desired drug
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`delivery properties. Macromers were synthesized with a wide range of hydrophobicity
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`and tested for drug release properties using standard techniques (see, Examples 11—13).
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`It was shown that the certain formulations possessed a significant ability to retard water
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`permeation and drug release.
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`Thus, it is well within the ability of the skilled person to, for example,
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`adjust the various components of the polymer delivery systems such as excipients
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`that alter erosion rates and time of release and systematically test several of these
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`formulations to determine the effect on the desired feature. An algorithm for
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`calculation of each of the components can then be developed for each class of
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`biocompatible polymer and used to screen one or more types of compatible
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`biopolymers using standard techniques to determine which are capable of meeting
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`the AUC.
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`In Wands, the court noted that there was no disagreement as to the facts,
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`but merely a disagreement as to the interpretation of the data and the conclusion
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`to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-
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`07. The Court held that the specification was enabling with respect to the claims
`
`at issue and found that ”there was considerable direction and guidance" in the
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`specification; there was "a high level of skill in the art at the time the application
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`was filed," and "all of the methods needed to practice the invention were well
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`known," 858 F.2d at 740, 8 USPQ2d at 1406. In accordance with MPEP 2164.01,
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`it is well established that the fact that experimentation may be complex does not
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`necessarily make it undue, if the art typically engages in such experimentation. In
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`re Certain Limited-Charge Cell Culture iMicrocarriers, 221 USPQ 1165, 1174
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`(Int'l Trade Comm"n 1983), afl'd. sub nom., Massachusetts Institute of
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`Technology v. A.B. Fortia, 774 F.2d 1104, 227 USPQ 428 (Fed. Cir. 1985). See
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`also In re Wands, 858 F.2d at 737, 8 USPQZd at 1404. The test of enablement is
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`not whether any experimentation is necessary, but whether, if experimentation is
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`necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219
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`(CCPA 1976). Given that the Examiner agrees that the level of skill in the art is
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`high, and Applicants has shown that the methods needed to practice the invention
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`are disclosed in the application and are well known with regard to testing a
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`variety of long acting formulations comprising biocompatible polymers, it is clear
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`that undue experimentation is not required.
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`With regard the Examiner’s assertion that the amount of testing would be
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`“exhaustive”, according to MPEP 2164.06, the quantity of experimentation needed to be
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`performed by one skilled in the art is only one factor involved in determining whether
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`"undue experimentation" is required to make and use the invention. "[A]n extended
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`period of experimentation may not be undue if the skilled artisan is given sufficient
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`direction or guidance." In re Colianni, 561 F.2d 220, 224, 195 USPQ 150, 153 (CCPA
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`1977)." 'The test is not merely quantitative, since a considerable amount of
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`experimentation is permissible, if it is merely routine, or if the specification in question
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`provides a reasonable amount of guidance with respect to the direction in which the
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`experimentation should proceed.m In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400,
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`1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 489, 502-04, 190 USPQ 214, 217-
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`19 (CCPA 1976)).
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`In view of the above discussion, Applicants submit that the present claims are
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`fully enabled. Withdrawal of the rejection under this section is respectfully requested.
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`Allowable Subject Matter
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`Applicants thank the Examiner for the telephone call and the indication of
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`allowable subject matter upon amendment of claim 1 to include the subject matter of
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`claim 22. However, in view of the above discussion the Examiner can see that limiting
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`Applicants to a single polymer would deny Applicants the full scope of their invention.
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`Given the present application as a guide, highly skilled practitioners in this art can
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`rapidly screen, using standard techniques, any number of long acting formulations
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`comprising a variety of biocompatible polymers to determine which of those
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`formulations meets the presently claimed AUC. In In re Gaffe, 542 F.2d 564, 567,
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`191 USPQ 429, 431 (CCPA 1976), the court stated:
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`[T]o provide effective incentives, claims must adequately protect
`inventors. To demand that the first to disclose shall limit his claims to
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`what he has found will work or to materials which meet the guidelines
`specified for "preferred" materials in a process such as the one herein
`involved would not serve the constitutional purpose of promoting
`progress in the useful arts.
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`Therefore, Applicants respectfully request reconsideration of amended claim 1 and all
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`claims dependent thereon.
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`A general authorization is hereby granted to charge Deposit Account No.
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`502807 for any fees required under § 37 C.F.R. 1.16 and 1.17 in order to maintain
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`pendency of this application.
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`CONCLUSION
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`In view of the above amendments and remarks, it is believed that all claims are in
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`condition for allowance, and it is respectfully requested that the application be passed to
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`issue. If the Examiner feels that a telephone conference would expedite prosecution of
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`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, PC.
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`/Darlene A. Vanstone/
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`Darlene A. Vanstone
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`35,729
`Registration No.
`Telephone: (978) 251—3509
`Facsimile: (978) 251—3973
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`Dated: April 5, 2010
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