Attorney Docket No. COLG—001/16US
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`PATENT
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In Re Application of:
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`Roman V. Rariy, et al. Confirmation No.:
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`4089
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`Serial No.:
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`14/946,275
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`Group Art Unit:
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`1611
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`Filed:
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`November 19, 2015
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`Examiner:
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`CHANNAVAJJALA. L. S.
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`FOR:
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`ABUSE-DETERRENT PHARMACEUTICAL COMPOSITIONS OF OPIOIDS
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`AND OTHER DRUGS
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`Mail Stop Amendment
`Commissioner for Patents
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`PO. Box 1450
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`Alexandria, VA 22313-1450
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`RESPONSE AND AMENDMENT UNDER 37 CFR§ 1.111
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`This paper is in response to the Office Action issued on February 2, 2016. A three-
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`month extension is hereby requested making this paper timely filed by August 2, 2016.
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`Amendments to the Claims begin on page 2 of this paper.
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`Remarks/Arguments begin on page 5 of this paper.
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`Attorney Docket No. COLG—OOl/l6US
`Serial No. 14/946,275
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`THE CLAIMS:
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`Setforth below in ascending order, with status identifiers, is a complete listing ofall
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`claims currently under examination. Changes to any amended claims are indicated by
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`strikethrough and underlining. This listing also reflects any cancellation and/or addition of
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`claims
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`1-56. Canceled
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`57.
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`(New)
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`An abuse-deterrent oral dosage form comprising a plurality of microparticles,
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`wherein each microparticle comprises a homogenous single phase comprising:
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`(a)
`
`(b)
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`oxycodone, and
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`one or more fatty acids;
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`wherein the molar ratio of fatty acid to oxycodone is in excess of about 7:1 and the
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`oxycodone is in the form of a fatty acid salt.
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`58. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the one or more fatty
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`acids is linoleic acid, octanoic acid, lauric acid, stearic acid, palmitic acid, myristic acid, or oleic
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`acid.
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`59. (New)
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`The abuse-deterrent oral dosage form of claim 58, wherein the one or more fatty
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`acids is stearic acid, palmitic acid, or myristic acid.
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`60. (New)
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`The abuse-deterrent oral dosage form of claim 59, wherein the fatty acid is
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`myristic acid.
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`61. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the microparticles
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`further comprise one or more carrier materials.
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`62. (New)
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`The abuse-deterrent oral dosage form of claim 61, wherein the one or more carrier
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`materials comprise fats, fatty substances, waxes, wax-like substances or mixtures thereof.
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`63. (New)
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`The abuse-deterrent oral dosage form of claim 62, wherein the one or more carrier
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`materials comprise beeswax, carnauba wax, hydrogenated oil or mixtures thereof.
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`64. (New)
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`The abuse-deterrent oral dosage form of claim 63, wherein the one or more carrier
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`materials comprise beeswax, carnauba wax, or mixtures thereof.
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`65. (New)
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`The abuse-deterrent oral dosage form of claim 64, wherein the fatty acid is
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`myristic acid.
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`66. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the oral dosage form is
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`a capsule or a tablet.
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`67. (New)
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`The abuse-deterrent oral dosage form of claim 66, wherein the oral dosage form is
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`a capsule.
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`68. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the oral dosage form
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`further comprises an antioxidant.
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`69. (New)
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`The abuse-deterrent oral dosage form of claim 68, wherein the antioxidant
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`comprises butylated hydroxy toluene (BHT), ascorbic acid, its salts and esters, Vitamin E,
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`tocopherol and its salts, sodium metabisulphite, cysteine, citric acid, propyl gallate, butylated
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`hydroxyanisole (BHA), or combinations thereof.
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`70. (New)
`
`The abuse-deterrent oral dosage form of claim 57, wherein each microparticle
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`further comprises an enteric coat.
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`71. (New) The abuse-deterrent oral dosage form of claim 57, wherein the oral dosage form is a
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`controlled-release oral dosage form.
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`72. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein each microparticle
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`further comprises a pharmaceutically acceptable surfactant.
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`73. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the microparticles are
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`spherical.
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`74. (New)
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`The abuse-deterrent oral dosage form of claim 57, wherein the oral dosage form
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`retards the release of the one or more drugs prone to abuse, even if the physical integrity of the
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`dosage form is compromised and the compromised dosage form is placed in water.
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`75. (New)
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`A method of making the abuse-deterrent oral dosage form of claim 57, wherein
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`the oxycodone, in the form of a free base, is dissolved in a hot melt solution comprising the one
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`or more fatty acids and wherein the molar ratio of fatty acid to oxycodone is in excess of about
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`7:1.
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`76. (New)
`
`The method of claim 75 wherein the one or more fatty acids is linoleic acid,
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`octanoic acid, lauric acid, stearic acid, palmitic acid, myristic acid, or oleic acid.
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`77. (New)
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`The method of claim 76, wherein the one or more fatty acids is stearic acid,
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`palmitic acid, or myristic acid.
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`78. (New)
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`The method of claim 77, wherein the fatty acid is myristic acid.
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`1.
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`Claim Amendments
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`REMARKS
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`Claims 57-7 8 are pending. Claims 57-78 are new. Support for these claims can be
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`found throughout the specification, specifically at page 16, lines 24-26 of the as-filed
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`specification. Claims 30-56 have been canceled without prejudice, Applicants reserve the right
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`to prosecute canceled subject mater in the present or subsequent applications. No new matter is
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`believed to have been entered by way of these amendments. Entry and consideration of these
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`amendments is respectfully requested.
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`II.
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`Rejections
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`A.
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`Double Patenting Rejections
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`The Examiner has rejected the pending claims as being unpatentable due to nonstatutory
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`double patenting over US. Patent Nos. 8,840,928, 7,771,707, 8,557,291, and 9,044,398, and
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`US. Application No. 14/054,513 (now US. 9,248,195) in view of US. 6,692,767 to Burnside et
`
`a1. (herein after Burnside) and US. 5,965,161 to Oshlack et a1. (herein after Oshlack). Without
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`addressing the propriety of these rejections and solely in the interest of advancing prosecution,
`
`Applicants submit Terminal Disclaimers to US. Patent Nos. 8,840,928, 7,771,707, 8,557,291,
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`9,044,398, and 9,248,195.
`
`The Examiner has provisionally rejected the pending claims as being unpatentable due to
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`nonstatutory double patenting over co-pending US. Application No. 14/321,125. Applicants
`
`request that the Examiner defer this provisional rejection until allowable subject matter is
`
`indicated.
`
`B.
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`35 USC 103(a)
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`The Examiner has rejected the pending claims as obvious over US. 6,692,767 to
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`Burnside et a1. (herein after Burnside) and US. 5,965,161 to Oshlack et a1. (herein after Oshlack.
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`Applicants respectfully disagree, as not only has the Examiner failed to support a primafacie
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`Attorney Docket No. COLG—OOl/16US
`Serial No. 14/946,275
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`case of obviousness, one of skill in the art, looking to these references, would not be motivated to
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`combine the cited references in order to provide the presently claimed formulation.
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`The present invention is directed to an abuse-deterrent composition comprising a
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`plurality of microparticles, wherein each microparticle comprises a homogenous single phase
`
`comprising oxycodone and one or more fatty acids, wherein the molar ratio of fatty acid to
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`oxycodone is in excess of about 7:1 and the oxycodone is in the form of a fatty acid salt.
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`Without being bound by a particular mechanism, it is believed that the abuse-deterrence of the
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`composition is due, in part, to the fatty acid salt of oxycodone. As discussed in the
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`specif1cation1, modifying a drug to produce a more lipophilic derivative, such as a fatty acid salt,
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`reduces the water solubility of the drug, and thus reduces the aqueous extractability of the drug,
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`thereby reducing its potential for abuse. Furthermore, such a lipophilic derivative can be
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`solubilized in a molten fatty substance or wax like mixture in order to create an intimately
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`dispersed composition from which it is harder to extract the drug. As the references fail to teach
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`or suggest either an abuse-deterrent composition or microparticles comprising a homogenous
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`single phase comprising oxycodone and a fatty acid, wherein the molar ratio of fatty acid to
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`oxycodone is in excess of about 7:1 and the oxycodone is in the form of a fatty acid salt, the
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`references fail to create a primafacie case of obviousness.
`
`1.
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`The
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`references
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`fail
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`to teach or
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`suggest
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`an abuse-deterrent
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`composition.
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`As discussed in the specification, sustained release formulations of abuse-prone drugs,
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`such as opioid analgesics like oxycodone, contain relatively large amounts of drug that are meant
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`to be released from the formulation over an extended time period. These formulations are
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`particularly attractive to potential abusers as the sustained release action can typically be
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`destroyed by crushing or grinding the formulation. Abusers can then (1) snort the material, (2)
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`swallow the material or
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`(3) dissolve the material
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`in water and subsequently inject
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`it
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`intravenously. The abuse-deterrent compositions of the present invention reduce the potential for
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`such misuse as the release of the drug is minimized even if the dosage form is compromised.
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`‘
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`1 As filed specification, page 12, line 4 to page 13, line 13.
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`Attorney Docket No. COLG—OOl/16US
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`As discussed in the Declaration filed herewith, Oshlack fails to teach an abuse-deterrent
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`composition. As shown in paragraphs 7-14 of the Declaration, the compositions of Oshlack
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`allow for the rapid release of the abuse prone drug, thereby allowing for dose dumping. As such,
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`Oshlack fails to teach or suggest abuse-deterrent compositions.
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`Burnside expressly discloses that its compositions are n_ot abuse-deterrent, unlike the
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`claimed compositions. Applicants direct the Examiner’s attention to abstract of the as filed
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`application. As discussed therein, an “abuse-deterrent composition retards the release of drug,
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`even if the physical integrity of the formulation is compromised (for example, by chopping with
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`a blade or crushing) and the resulting material
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`is placed in water, snorted, or swallowed.”
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`Burnside, as stated in the specification, is directed to compositions that provide gm release of a
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`drug.2 This rapid release is shown in the dissolution profiles of Burnside compositions. For
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`example, as shown in Figure 2, the formulations of Example 1 release 80-100% of the drug
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`within less than 30 minutes in an aqueous solution, which would be considered an immediate
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`release formulation by one of skill in the art. As the Burnside formulations rapidly release the
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`drug when placed in water, they would not be considered abuse-deterrent. This release occurs
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`without crushing or chopping the dosage forms, and one of skill would assume that doing so
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`would increase the release rate. Therefore, Burnside fails to teach or suggest abuse-deterrent
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`compositions.
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`As the cited references fail to teach, either expressly or inherently, an abuse-deterrent
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`composition, the Examiner has failed to create a case of prima facie obViousness. As such,
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`applicants respectfully request that this rejection be withdrawn.
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`The references fail to teach or suggest the formation of an fatty acid
`2.
`salt of oxycodone or a molar ratio of fatty acid to oxycodone in excess of about 7:1
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`Applicants note that Claim 1 requires microparticles comprising a homogenous single
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`phase comprising oxycodone and a fatty acid, wherein the molar ratio of fatty acid to oxycodone
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`is in excess of about 7:1 and the oxycodone is in the form of a fatty acid salt. The references,
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`alone or in combination, fail to teach this limitation. As discussed in the specification, the ratio
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`of fatty acid to oxycodone is critical in order to manufacture microparticles in which the drug is
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`intimately dispersed in the microparticles. Such microparticles are manufactured, for example,
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`from a hot melt process in which the drug is solubilized in a molten fatty substance or wax
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`mixture, rather than physically dispersed in a particulate form. For oxycodone, it has been found
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`that a molar ratio in excess of about 7:1 (fatty acid to oxycodone) results in a homogeneous melt
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`using this technique.
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`In the examples of Oshlack, the fatty acid to drug molar ratio is significantly less than
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`7: 1, while the present claims require a fatty acid to oxycodone molar ratio in excess of 7:1. The
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`examples of Oshlack have molar ratios of fatty acid to drug from 1:4.8 to 4.8:1, far below the
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`molar ratio in excess of 7:1 required by the present claims. Moreover, the examples comprising
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`oxycodone hydrochloride have a molar ratio of fatty acid to drug of 1.1:1. Outside of the
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`Examples, there is no teaching or suggestion that the fatty acid and drug have a particular molar
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`ratio. Therefore Oshlack fails to teach or suggest a pharmaceutical composition having a molar
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`ratio of fatty acid to oxycodone is in excess of about 7:1. Additionally, as Oshlack fails to teach
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`or suggest the formation of a fatty acid salt of oxycodone, one of skill in the art would not be
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`motivated to modify the molar ratios taught by Oshlack in order to arrive at the claimed molar
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`ratio.
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`Furthermore, Oshlack fails to teach or suggest a fatty acid salt of oxycodone. Oshlack
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`teaches two compositions comprising oxycodone, and in both compositions, the oxycodone is in
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`the form of oxycodone hydrochloride. Applicants respectfully direct the Examiner’s attention to
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`paragraphs 15 and 16 of the Declaration, which demonstrates that oxycodone hydrochloride,
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`which is taught in Oshlack, cannot form a homogenous single phase when combined with a fatty
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`acid in a hot melt composition. As discussed in the specification,
`
`in order to create a
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`composition that protects the drug from exposure, and therefore extraction, upon mechanical
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`disruption (e.g., grinding or chopping) the drug should be intimately dispersed within the
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`microparticle.
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`In order to do this, the components of the microparticle, including the drug and
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`fatty acids, must form a homogenous single phase. As shown in the Declaration, combining
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`2 Burnside, ‘H [0002] and ‘H [0037]
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`oxycodone base with myristic acid and waxy excipients in the melt phase forms a fatty acid salt
`
`of oxycodone and creates a homogenous single phase.
`
`In contrast, combining myristic acid and
`
`waxy excipients with the oxycodone hydrochloride (oxycodone HCl) taught by Osnlack fails to
`
`produce a fatty acid salt of oxycodone, and therefore fails to produce a homogeneous, single
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`phase. Thus, Osnlack discloses compositions that necessarily cannot comprise a fatty acid salt of
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`oxycodone.
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`This definicincy is not remedied by Burnside. Applicants maintain that Burnside
`
`provides no teaching or suggestion as to how to obtain the presently claimed microparticles
`
`comprising a homogenous single phase comprising oxycodone and a fatty acid wherein the
`
`molar ratio of fatty acid and oxycodone is in excess of about 7:1 and the oxycodone is in the
`
`form of a fatty acid salt. As discussed above, without being bound by a particular mechanism,
`
`the oxycodone fatty acid salt provides, at least in part, abuse-deterrence as it provides a less-
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`water soluble, lipophilic derivative of oxycodone that is capable of forming a homogenous single
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`phase during the melt manufacture of microparticles.
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`Burnside, however, fails to teach or suggest fatty acid salts of oxycodone. Burnside fails
`
`to teach oxycodone in any form, much less as a fatty acid salt.
`
`The Examiner alleges that
`
`Burnside teaches a fatty acid. Applicants respectfully note that the reference teaches the dosage
`
`forms may comprise a hydrophobic long chain fatty acid or ester material, and in fact are the
`
`most preferred hydrophobic material is glyceryl behenate, a mixture of various esters of behenic
`
`acid and glycerol. One of skill in the art would be aware that fatty acid esters are incapable of
`
`forming a salt. Therefore as Burnside teaches that fatty acid esters are preferable over fatty
`
`acids, Burnside not only fails to teach or suggest the formation of an oxycodone fatty acid salt as
`
`required by the claimed invention, the reference fails to contemplate or appreciate the formation
`
`of a salt between oxycodone and a fatty acid.
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`Even if, assuming in arguendo, Burnside taught a formulation comprising oxycodone and
`
`a fatty acid, the reference fails to recognize the criticality of the molar ratio of fatty acid to
`
`oxycodone. While Burnside teaches a broad range for percentages of the fatty acid or ester and
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`drug, the only example of a formulation comprising a fatty acid, Example 8, has a ratio of about
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`l.6:l fatty acid to drug. As discussed above, the present invention requires a fatty acid to
`
`oxycodone molar ratio in excess of 7:1. Burnside fails to not only teach or suggest this ratio,
`
`but, as Burnside fails recognize the importance of forming a fatty acid salt, the reference fails to
`
`teach or suggest that one of skill would need to optimize the ratio of fatty acid to oxycodone in
`
`order to form a salt that will be homogenously dispersed in the melt solution. Furthermore,
`
`Burnside does not
`
`teach or suggest, either expressly or through the Examples,
`
`that
`
`the
`
`optimization or criticality of the ratio of any component to drug is necessary for the formation of
`
`homogeneous single phase.
`
`As discussed in the MPEP, “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
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`the optimum or workable ranges of said variable might be characterized as
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`routine
`
`experimentation.”3 Burnside, however, fails to recognize that the molar ratio of fatty acid to
`
`oxycodone is critical in forming a homogeneous single phase, and therefore one of skill in the
`
`art, looking to the teachings of Burnside would have no motivation to optimize the ratios of any
`
`component, let alone the fatty acid component as presently claimed. As such, Burnside fails to
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`teach or suggest either a molar ratio of fatty acid to oxycodone in excess of about 7:1 or an
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`oxycodone fatty acid salt.
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`As the references, alone or in combination, fail to teach or suggest an abuse-deterrent
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`composition, a molar ratio of fatty acid to oxycodone in excess of about 7: l, or an oxycodone
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`fatty acid salt, the Examiner has failed to establish a proper case ofprime facie obviousness. It is
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`only with improper hindsight reasoning that the Examiner is arriving at the claimed invention.
`
`Given the teachings of both references as discussed above, a skilled artisan, looking to make an
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`abuse-deterrent composition, would not arrive at the presently claimed invention. Therefore, the
`
`references fail to support a case of obviousness and the Applicants respectfully request that this
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`rejection be withdrawn.
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`3 MPEP 2144.05 1103)
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`Attorney Docket No. COLG—001/16US
`Serial No. 14/946,275
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`CONCLUSION
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`In view of the foregoing, Applicant respectfully submits that no further impediments
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`eXist to the allowance of this application, and therefore, requests an indication of allowability,
`
`However, if any outstanding issues remain, the Examiner is invited to phone the undersigned.
`
`The Director is hereby authorized to charge any appropriate fees under 37 C.F.R. §§1.16,
`
`1.17, and 1.21 that may be required by this paper, and to credit any overpayment, to Deposit
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`Account No. 50-1283.
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`Dated: August 2, 2016
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`COOLEY LLP
`
`ATTN: Patent Group
`1299 Pennsylvania Avenue NW, Suite 700
`Washington, DC 20004
`
`(202) 962-8375
`Tel:
`Fax: (202) 842-7899
`
`Respectfully submitted,
`COOLEY LLP
`
`By:
`
`/_Sandhya Deo/
`Sandhya Deo
`Reg. No. 65,841
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