Docket No.:
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`I 17744- I 2902
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`(PATENT)
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re Patent Application of:
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`Andrew FINN el al.
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`Application No.: 13/590,094
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`Confirmation No.2 5975
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`Filed: August 20, 2012
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`Art Unit: 1619
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`For: ABUSE-RESISTANT MUCOADHESIVE
`DEVICES FOR DELIVERY OF
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`Examiner: ALAWADI, SARAH
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`WBUPRENORPHINE
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`Mail Stop Amendment
`Commissioner for Patents
`PO. Box 1450
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`Alexandria, VA 223l3—l450
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`DECLARATION OF NIRAJ VASISHT PH.D. UNDER 37 CFR 1.132
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`I, Niraj Vasisht declare:
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`l.
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`I am the Senior Vice President of Product Development and Chief Technical
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`Officer ofBioDelivery Sciences International, Inc, the owner ofthe instant application.
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`I am
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`also an inventor of the instant application.
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`2.
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`I have over 20 years of experience in pharmaceutical product development and
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`have played a significant role in the development and regulatory approval ofthree products.
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`I
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`am responsible for the development ofa portfolio ofproducts that include the innovative
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`features claimed in the instant application, including BEMA Buprenorphine for chronic pain and
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`BEMA Buprenorphine with Naloxone for opioid dependence. My responsibilities include
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`pharmaceutical development and manufacturing, nonclinical and clinical development,
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`regulatory affairs and quality assurance for these products.
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`I received a Bachelor of Science in
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`Chemical Engineering from the Indian Institute ofTechnology, Kanpur, a Master’s Degree in
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`Chemical Engineering from the University ofNew Hampshire and a Doctorate in Chemical
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`Engineering from Rensselaer Polytechnic Institute. My curriculum vitae is attached.
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`_.
`eral 15091027vi
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`RB EX. 2003
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`BDSI v. RB
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`PHARMACEUTICALS LTD.
`IPR2014—00998
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`Page 1
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`Page 1
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`RB Ex. 2003
`BDSI v. RB
`PHARMACEUTICALS LTD.
`IPR2014-00998
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`Docket No.
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`I 17744—12902
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`Application No. 13/590,094
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`3.
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`1 have read and understand the Office Action dated November 23, 2013 issued in
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`connection with the instant application.
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`1 am also an inventor of both US 1 1/639,408 and
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`PCT/US2007/016634 that correspond to, respectively, US 2007/0148097 (Finn el al.) and WO
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`2008/01 1 194 (Vasisht el al.) and that were cited in the Office Action.
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`4.
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`WO 2008/01 1 194 describes transmucosal drug delivery devices comprising a
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`mucoadhesive polymeric diffusion environment (i.e., a mucoadhesive layer) and a backing layer.
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`A drug, such as buprenorphine, is present in the mucoadhesive layer, and enhanced uptake ofthe
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`drug is achieved by adjusting the pH ofthe mucoadhesive layer. As a result of experiments
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`described in WO 2008/01 1 194, we determined that enhanced buccal absorption of
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`buprenorphine can be achieved when pH of the mucoadhesive layer is adjusted to between about
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`4.0 and about 6.0.
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`In these experiments, we did not adjust the pH of the backing layer.
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`5.
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`Since naloxone exhibits two pKa values — 7.3 and 10.6 — it was initially believed
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`that when naloxone is present in the backing layer of the mucoadhesive device, it should be
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`buffered at a very low pH, i.€., 2.75, in order to minimize its absorption through the buccal route.
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`At this pH, the drug should be completely ionized, thus reducing the transport of ionized drug
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`through the buccal muscosa.
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`6.
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`To test the effect of adjusting pH in the backing layer, we prepared and measured
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`buccal absorption ofbuprenorphine and naloxone from mucoadhesive devices that contained
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`buprenorphine in the mucoadhesive layer buffered at pH 4.75, and naloxone in the backing layer
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`buffered at pH of 2.75. We expected the buprenorphine Cmax of buprenorpl’iine for our devices
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`to be similar to that from the control Suboxone® tablets. We found that the buprenorphine CW1X
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`ofour devices containing 0.75 mg buprenorphine/0.1875 mg naloxone was far lower than the
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`buprenorphine Cmax of the control Suboxone® tablet (Cmax of 0.564 mg/mL vs. 1.28 ng/mL for
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`the Suboxone® tablet, see Table 4, pages 22-23 ofthe instant application). Indeed, it was less
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`than halfof what was expected. These results demonstrated that, unexpectedly, buccal
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`absorption ofbuprenorphine from the mucoadhesive layer of our devices is influenced by the pH
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`in the backing layer.
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`7.
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`With the discovery that the pH ofthe backing layer dramatically effects
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`absorption ofthe drug in the mucoadhesive layer, through extensive experimentation we were
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`M131 15091027v.1
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`Page 2 of3
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`Docket No.
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`1 17 74442902
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`Appliezitii’n‘i No.
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`l3/59ti,00=¢l
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`able to determine the pH ol’tlie backing layer that allowed H.810 achieve the 'apeutie levels of
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`buprenm'pliine, while still impeding the absorption tii'l‘naloxone We fli‘l‘lVCd at a device having
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`naloxone in the backing layer buttered at pH ol’between 4.0 and 4.8. The devices containing,
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`8.3., 0.75 mg blipl‘ellfil‘lfil'iint) (ell Alf/5M1 l 875 mg RalOXORC (pH 4.25), Cnm was HO log/ml, vs.
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`0.853 ng/ml. for the control Subomnefi’ tablet, and for the device ooi-naining 0.3 mg
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`buprenorphine (pH Al.75)/O.'75 mg, naloxone (le 4.25)., Cola); was 3.4-4 mg/mli ‘5' 3-33 “lg/”IL
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`for the control Suboxone‘m tablet. See Tables 6 and 75 pages 24~25 ol‘tlie instant application.
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`8.
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`The devices o'l‘tlie claimed invention provide a therapeutic amount of
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`Suboxonel" tablet (which is currently the standard ol’eare). Not only is less than l‘iaill’the
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`therapeutic drug needed to obtain therapeutic levels but the patient is no longer exposed to the
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`excess l‘iuyn‘enorphine. This is significant because exposure to opioid, such as l'iui‘irenorphinew in
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`the GI tract is associated with side effects such as constipation. Finally, the claimed devices
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`provide enough buprenorphine for effective pain relie‘l‘and treatment oi’opioid dependence,
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`while retaining the almsemdeterrent effect oi’naloxoi'le, should the devices be used almsively
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`(egg, {.lissoliition and injection).
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`I hereby glee-late. tliat all staten'ients made herein oi‘my own knowledge are true and that
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`all statements made on information and beliel‘ai'e believed to be true; and further that these
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`staten'ients are made with the lo'iowledge that willful false statements and the like so made may
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`be punishable by line or imprisonment:”‘ or bottln and that such willt‘iil false statements may
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`Dated: aflyuuflma
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`jeopardize the validity ol’this Amalie-atlas: for ’zitent or any patent issuing thereon.«I
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