`Patent No. 7,919,499
`Supplemental Declaration of Kinam Park, Ph.D.
`Attorney Docket No. AMNEAL 7.1R-005
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALKERMES PHARMA IRELAND LIMITED,
`
`Patent Owner.
`
`Patent No. 7,919,499 to Elliot Ehrich
`Issue Date: May 19, 2015
`Title: NALTREXONE LONG ACTING
`FORMULATIONS AND METHODS OF USE
`____________________________
`
`Inter Partes Review No. IPR2018-00943
`__________________________________________________________________
`
`(Exhibit 1061)
`
`SUPPLEMENTAL DECLARATION OF
`KINAM PARK, Ph.D. IN SUPPORT OF
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`TABLE OF CONTENTS
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`Page
`
`INTRODUCTION ........................................................................................... 1
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`I.
`
`II.
`
`SUMMARY OF OPINIONS ........................................................................... 1
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`III. A PERSON OF ORDINARY SKILL IN THE ART ...................................... 2
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`IV. CLAIM CONSTRUCTION ............................................................................ 3
`
`A. “the serum AUC of naltrexone…than that
`achieved by 50 mg/day oral administration” ............................................ 3
`
`B. “the step of parentally administering a long acting formulation
`comprising about 310 mg to about 480 mg of naltrexone” ...................... 5
`
`C. “initial oral dose of naltrexone” ..............................................................10
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`V.
`
`TECHNICAL BACKGROUND AND STATE OF THE ART ....................12
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`A. The Area Under The Curve (AUC) ........................................................12
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`B. AUC Calculations And Time Zero .........................................................13
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`C. AUC And Plasma Level .........................................................................19
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`D. AUC And Sample Frequency .................................................................22
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`E. AUC And Prior Administration ..............................................................24
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`F. The Claimed AUC Differential Is
`Known Or Would Be Apparent ..............................................................29
`
`VI. THE CHALLENGED CLAIMS WERE
`TAUGHT BY COMER AND NUWAYSER................................................33
`
`A. Comer And Nuwayser Each Disclose
`The Subject Matter Of Claims 1, 3-5, And 10-12 ..................................33
`
`VII. THE CHALLENGED CLAIMS WERE
`READILY APPARENT TO A POSA ..........................................................41
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`Supplemental Declaration of Kinam Park, Ph.D.
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`A. Comer In View Of Nuwayser And/Or Nuwayser In
`View Of Comer And Either In View Of Wright And Rubio .................41
`
`B. Nuwayser In View Of Kranzler, Wright, And Rubio .............................52
`
`C. Alkermes’ 10-K In View Of The
`Vivitrex Specimen, Wright, And Rubio .................................................57
`
`1. Alkermes’ 10-K ................................................................................57
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`2. Vivitrex Specimen ............................................................................58
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`3. Wright ..............................................................................................59
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`ii
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`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`I, KINAM PARK, declare and state as follows:
`
`I.
`
`INTRODUCTION
`I am the same Kinam Park, Ph.D., who submitted a declaration in
`1.
`
`support of Petitioner’s Petition for Inter Partes Review (“Prior Declaration,”
`
`Ex. 1030) on April 19, 2018.
`
`2. My background, education, training, compensation, and professional
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`experiences are set forth in my Prior Declaration and are incorporated herein by
`
`reference.
`
`3.
`
`I have reviewed the Declarations of Cory J. Berkland, Ph.D., and
`
`Charles P. O’Brien, M.D., Ph.D. submitted by Alkermes in support of its Response
`
`as well as the Patent Owner’s Response (“Response”), Patent Owner’s Preliminary
`
`Response, and the various exhibits submitted to date and those cited herein.
`
`II.
`
`SUMMARY OF OPINIONS
`I have been asked to provide my opinions on the ’499 Patent and state
`4.
`
`of the art around April 2004, which is the priority date of the ’499 Patent. In
`
`addition, I have been asked to respond to the opinions set forth in Dr. Berkland’s
`
`and Dr. O’Brien’s declarations.
`
`5.
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`Here, I address issues raised in the Patent Owner’s Preliminary
`
`Response (Paper No. 7), by the Board’s Institution Decision (Paper No. 8), and the
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`Patent Owner’s Response
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`(“Response”)
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`(Paper No. 14), and
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`I provide
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`supplemental evidence in support of my opinions that the claims of the ’499 Patent
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`are anticipated and obvious to a person of ordinary skill in the art at the time of the
`
`invention.
`
`6.
`
`I maintain my opinions that claims 1, 3-5, and 10-12 were taught by
`
`Comer and Nuwayser and that all of the challenged claims would be readily
`
`apparent to a person of skill in the art for the reasons explained in the various
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`grounds identified in the Petition. I disagree with many of the opinions expressed
`
`by Dr. Berkland and Dr. O’Brien, and I will address some of these herein. My
`
`silence on a particular opinion does not mean I agree with that opinion.
`
`III. A PERSON OF ORDINARY SKILL IN THE ART
`I understand Dr. Berkland’s definition of POSA is someone with a
`7.
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`Master’s degree and two or three years’ experience, or a Ph.D. or M.D. with at
`
`least one or two years’ experience. As I stated in my Prior Declaration, I believe
`
`the treatment steps of the claimed method are very well known and should not be
`
`the central focus of the discussion of patentability. Most of the central issues are
`
`formulation related, and medical doctors often do not have sufficient formulation
`
`knowledge and experience. However, my opinions do not change if Dr. Berkland’s
`
`definition is adopted.
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`Supplemental Declaration of Kinam Park, Ph.D.
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`IV. CLAIM CONSTRUCTION
`I understand that it is often desirable to construe the meaning of claim
`8.
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`terms to eliminate ambiguity when possible. I also understand from counsel that
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`the claims in this IPR are to be given their broadest reasonable interpretation
`
`(“BRI”) unless they are specifically defined otherwise. My understanding of
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`broadest reasonable interpretation is that the definition must be consistent with the
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`understanding of a POSA in the field and with the patent specification and the
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`patentee’s statements made during prosecution. Terms are not necessarily limited
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`to only those examples recited in the specification. Under the BRI standard, terms
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`can be given a more inclusive meaning.
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`A. “the serum AUC of naltrexone…than that
`achieved by 50 mg/day oral administration”
`
`9.
`
`Claim 1 recites “the serum AUC of naltrexone is about three [or 3.3]
`
`times greater than that achieved by 50 mg/day oral administration.” I understand
`
`that Alkermes and Dr. Berkland interpret this limitation to mean “the serum AUC
`
`of naltrexone…achieved by 50 mg/day oral administration” to mean a serum AUC
`
`of oral naltrexone of about 30 µg∙h/L, or 30 ng∙h/mL, or 1.25 ng∙day/mL.
`
`10. As I stated in my Prior Declaration, the ’499 Patent does not define
`
`the AUC of the claimed formulation or claimed oral dosing. And I believe that a
`
`POSA would look to the art and find that there is no single accepted data set for the
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`AUC resulting from administering 50 mg/day orally.
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`Supplemental Declaration of Kinam Park, Ph.D.
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`11. As stated in my Prior Declaration, the claim reflects a broad dosing
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`range of 310 to 480 mg. The AUC for each of these doses will necessarily be
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`different. As the ’499 Patent did not provide a consistent set of data points to use
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`for the comparative oral dosing, it is almost impossible to know if the resulting
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`differential is accurate or meaningful.
`
`12. Alkermes and Dr. Berkland rely on the Ehrich Declaration as the sole
`
`support for claim construction of this term. I also note that the Ehrich Declaration
`
`is not reflected in the patent. As Alkermes did not provide a data set in either the
`
`patent or the claims, I maintain that a POSA would conclude that Alkermes
`
`intended to allow a POSA to use any available data set. In other words, a POSA
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`could use any published data for the AUC of a 50 mg/day oral dose oral to
`
`compare with the AUC of the claimed depot method. I understand, however, that
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`the Board, at least preliminarily, concluded that since the Ehrich Declaration was
`
`part of the record made during patent prosecution, a POSA would look to the data
`
`in that document.
`
`13. The Ehrich Declaration actually provided and relied upon two data
`
`points for a serum AUC of oral naltrexone: 27.8 µg∙h/L, as reported by Tice and
`
`used by Dr. Ehrich in Exhibit C of his declaration, and 1.270 ng∙day/mL (or
`
`30.5 µg∙h/L) as reported for Cohort A in Table 8 and Exhibit C. In its Institution
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`Decision, the Board also accepted the Cohort B value of 35.2 µg∙h/L (or
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`1.468 ng∙day/mL) in Table 8, although this value is less appropriate considering
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`that it is based on repeat doses. Based on this, Alkermes and Dr. Berkland suggest
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`this term be construed to mean “a serum AUC of oral naltrexone of about
`
`30.0 µg∙h/L.” If the Board accepts this construction, then the use of “about” should
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`necessarily encompass at least 27.8 µg∙h/L (to cover Tice) to 30.5 µg∙h/L (to cover
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`Cohort A).
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`14. Regardless of how this term is construed, the prior art clearly shows a
`
`serum AUC of naltrexone that is three times greater than the serum AUC of oral
`
`naltrexone that is “about 30.0 µg h/L,” whether defined as 27.8 µg h/L, 30.5 µg
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`h/L, or any of the values provided in my Prior Declaration.
`
`B. “the step of parentally administering
`a long acting formulation comprising
`about 310 mg to about 480 mg of naltrexone”
`
`15. Claim 1 recites “a long acting formulation,” which I discussed in my
`
`Prior
`
`Declaration
`
`as meaning
`
`a
`
`formulation
`
`that
`
`provides
`
`controlled/sustained/extended release of at least one week to a POSA.
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`16.
`
`I understand Alkermes has taken the position that “administering a
`
`long acting formulation” means administering “a single injection of a long acting
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`formulation” to a POSA. I struggle with this opinion as I do not understand how
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`the broadest reasonable construction of the general term “administering” could be
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`so narrow as to be limited to only a single injection.
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`17. None of the claims of the ’499 Patent indicates “a single injection.”
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`And nothing in the specification requires a single injection. Alkermes seems to be
`
`arguing that because using a single injection is taught in the examples, the claim
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`must be limited to this one specific way of administering naltrexone. I think that is
`
`inconsistent with the BRI standard. In fact, I think it is inconsistent with a plain
`
`reading of the Patent. I also think that in the context of the claims, even if one were
`
`to import a requirement of a “single injection,” that term must be understood to
`
`require a temporal component—administering the entire dose at one time, not that
`
`it is given in one injection.
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`18. A POSA understands that the goal of the claimed method is
`
`administering a long acting formulation that provides a dose of drug that is
`
`effective to achieve a necessary pharmacological effect, and doing so on one
`
`occasion—one office visit, or once a month as opposed to more frequently. A
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`POSA looking at this term in the context of the claimed method, and the
`
`specification, would not think that it referenced the number of injections used to
`
`deliver that dose during that single visit or on that one day of that month.
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`19. The purpose of the invention was to provide a protocol where a
`
`patient does not have to take more medication every day. It is in that context that
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`the terms of the claim should be interpreted. It does not matter if the oral dose
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`referenced in the claims was one 50 mg tablet, or two 25 mg tablets, or five 10 mg
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`Supplemental Declaration of Kinam Park, Ph.D.
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`tablets, the swallowing of each tablet separated by a brief moment. Indeed using
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`multiple dosage forms to achieve a single dose of naltrexone was already known in
`
`the art. (See Bertoletti 1997 (Ex. 1064) (100 mg dose of naltrexone by
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`administered two 50 mg capsules).) In the same way, it does not matter whether
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`the claimed depot injection comprises one 380 mg injection in the right buttock or
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`two 190 mg injections, given within moments of each other, one in each buttock or
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`even both in the same buttock. In any event, the individual is administered 380 mg
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`of depot naltrexone.
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`20. And this is consistent with the general understanding and common
`
`experiences of a POSA. Different doses of aspirin may be used to treat different
`
`conditions because a dose is keyed to desired effect. A dose of 75-325 mg of
`
`aspirin is recommended for prevention of heart attack, while a dose of 160-
`
`162.5 mg is recommended for suspected heart attack, 80 mg/daily to 650/mg twice
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`daily for carotid endarterectomy, and up to 3 grams/day for certain arthritis. (See
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`Ex. 1065, at 3053.) Ecotrin enteric-coated aspirin is supplied in tablets of three
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`different strengths: 81 mg, 325 mg, and 500 mg. (Id.) A POSA knows, however,
`
`that a dose of 160-162.5 can only be achieved by taking two 81 mg tablets, a dose
`
`of 650 mg by taking two 325 mg tablets of aspirin, and a dose of 3 grams by taking
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`six 500 mg tablets. The same is true for other well-known drugs. (See id. at 2663
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`(Pepto Bismol label indicating that 2 tablets or caplets are one adult dose, 1 tablet
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`or caplet is a dose for children 9-12 years, and 2/3 of a tablet/caplet is a dose for
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`children 6-9 years).)
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`21. Further, the word “single” is used in the ’499 Patent four times.
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`a. Column 2, lines 34-36. “Indeed, it was not expected that serum
`
`levels of about 3.3 times that achieved by a 50 mg/day oral dose
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`could be achieved by a single IM administration of Vivitrex®.”
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`b. Column 4, lines 56-58. “The therapy can end after a single dose
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`or can be maintained for longer periods of time.”
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`c. Column 5, lines 28-33. “In one embodiment, the increase in
`
`days prior to occurrence of alcohol consumption can include the
`
`consumption of a single alcoholic beverage or it can include
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`consumption of four or five alcoholic beverages, such as the
`
`number of drinks characterizing an episode of "heavy
`
`drinking,"
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`d. Column 6, lines 54-56. “The ambient polymer and drug
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`solutions were mixed together until a single homogeneous
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`solution (organic phase) was produced.
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`22. While “single IM administration” used in (a) above might suggest to a
`
`POSA using a single dosage form, it certainly does not suggest that this is the only
`
`way that naltrexone can be delivered in the context of the invention. And
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`(b) above, where therapy can end after a single dose, strongly suggests to a POSA
`
`the number of administrations rather than the number of injections. And surely the
`
`consumption of a single alcoholic beverage in (c) above is not limited to
`
`consuming the whole alcoholic beverage in one shot or one swallow. Whether the
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`standard used is BRI or some other standard, I don’t think limiting the claim to
`
`using a single injection is a fair reading, and I don’t think a POSA would reach that
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`conclusion. The fact that the specification may describe using one injection in one
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`instance would not suggest to a POSA that the claimed method could only be
`
`practiced using a single injection.
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`23. Alkermes also points to the Ehrich Declaration, to support its
`
`assertion that this term is limited to a single injection. The Ehrich Declaration
`
`stated: “The present invention is directed to the unexpected discovery that a single
`
`injection of a naltrexone-containing long-acting formulation provides systemic
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`exposure to naltrexone (AUC) which is at least 2 fold higher over a 28 day period
`
`than the AUC of an oral regimen of 50 mg per day over a 28 day period.”
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`(Ex. 1003, at 1.) In my opinion, Alkermes is off base. This study was not directed
`
`at comparing 380 mg of naltrexone given in a single injection versus 380 mg of
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`naltrexone given as two 190 mg injections, which is the only data that would be
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`relevant to PO’s proposed construction. And, as noted above, if anything, the
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`Ehrich Declaration supports my position that the claim is actually referencing a
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`Supplemental Declaration of Kinam Park, Ph.D.
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`temporal component. Indeed, in the study reflected in the declaration—which is the
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`same study reference in the ’499 Patent—a single 380 mg dose, given on day one
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`of a month, is compared to smaller doses given once a day for the entire month;
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`one “single” administration as opposed to 28 or 32 separate administrations.
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`C. “initial oral dose of naltrexone”
`24. Claim 11 requires the individual not receive an “initial oral dose” of
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`naltrexone. The ’499 Patent does not define this term, and the only instance of the
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`phase “initial oral dose” is in the claims. Alkermes and Dr. Berkland have taken
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`the position that “initial” should mean “first” and point to a dictionary definition
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`(Ex. 2055), which defines “initial” as “1: of or relating to the beginning…2: placed
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`at the beginning: FIRST.”
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`25. But by only construing the word “initial,” rather than the phrase
`
`“initial oral dose of naltrexone,” Alkermes fails to provide proper context. The
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`term in question is “initial oral dose.” As I previously stated, a POSA would
`
`understand a “dose” to be a specific amount of medication to be taken at one time
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`to achieve a specific therapeutic effect. The only reference to “dosing” in the
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`’499 Patent is to the administration of naltrexone to treat a patient’s addiction long
`
`term. This disclosure would suggest to a POSA that the intended therapeutic effect
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`of the recited “dose” is long term addiction treatment. Accordingly, the “dose” of
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`this claim would lead a POSA to the conclusion that the claim intended to exclude
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`a method in which an initial amount of oral naltrexone is provided orally as part of
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`a long-term treatment.
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`26. The art, however, makes clear that there are other therapeutic goals
`
`aside from long term treatment, such as Comer’s teaching of administering oral
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`naltrexone as part of a detoxification process. (Ex. 1010, at 353.) Comer provided a
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`two day break between administering the oral for detoxification purposes and
`
`administering the depot injection for treatment purposes. (Id.)
`
`27. Similarly, a small percentage of the patient population may have
`
`serious adverse reactions to naltrexone. Thus, naltrexone may have been given
`
`orally to test for adverse reactions prior to committing to a long term depot
`
`injection for treatment. (Exs. 1015, 5:65-6:6, 6:13-17; 1011, at 1074.) It would be
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`difficult enough to the health and safety of a patient to give them a single oral dose
`
`of 50 mgs of naltrexone only to find out that they are allergic. But it would be far
`
`more serious if a 380 mg dose were delivered in a nonreversible way that would
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`expose the patient to naltrexone continuously over 30 days. Testing a patient by
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`giving a single smaller amount orally would be a responsible way of confirming
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`that the patient is a candidate for the intended treatment. But a POSA would not
`
`consider such an oral dose to be part of the claimed treatment. Clearly the art
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`distinguishes initial “treatment doses” from prior doses given for other purposes,
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`11
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`and I don’t think a POSA would read claim 1 as excluding such earlier doses for
`
`other purposes.
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`28. There is one final point that suggests to me that a POSA would not
`
`read the claimed term as Alkermes and its experts suggest. The claim as they
`
`propose it be read would exclude giving their depot injection to a patient who had,
`
`at any prior time, been treated with oral naltrexone. Claim 11, as Alkermes
`
`interprets it, requires that the patient never have received oral naltrexone before. In
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`that case, a patient who was previously treated with naltrexone, at any time in
`
`his/her life, and at some later time—even months or years later—given a depot
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`injection according to the invention, would fall outside of the claims. This is an
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`irrational result, and I cannot believe that a POSA would accept such an
`
`interpretation.
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`V. TECHNICAL BACKGROUND AND STATE OF THE ART
`I understand Dr. Berkland’s Declaration provided various opinions
`29.
`
`that disagreed with those given in my Prior Declaration. I address each below.
`
`A. The Area Under The Curve (AUC)
`30. As I discussed in my Prior Declaration, any POSA knows how to
`
`calculate AUC. An AUC is a property of a pharmacokinetic (PK) profile plotting
`
`plasma concentration of a drug over time, and this PK profile is all that is needed
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`to calculate AUC. It can be determined in any of the conventional ways that area is
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`determined, and AUC has been calculated for decades.
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`31. Regardless of the oral naltrexone data used for comparison, the
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`calculations I provided in my Prior Declaration for Comer and Nuwayser are the
`
`same. I understand Alkermes thinks the oral AUC should be about 30 µg h/L. In
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`my Prior Declaration, I used 1.278 ng∙days/mL (30.7 µg h/L) as the oral AUC
`
`value, which is slightly higher than PO’s 30 µg.h/L. If, instead, one used PO’s
`
`number, the result would only increase the AUC differential between Comer and
`
`oral naltrexone from 2.9 to 2.96. But it would still be “about 3 times greater than
`
`that achieved by oral dosing as claimed.
`
`B. AUC Calculations And Time Zero
`32. Dr. Berkland states that “[a] s a POSA would know, quantification of
`
`AUC must begin at time zero.” (Ex. 2055 ¶ 59.) And that “a POSA would have
`
`recognized the data in Fig. 1 as incomplete and unacceptable for determining
`
`pharmacokinetic variables like AUC.” (Id.) In forming this opinion, Dr. Berkland
`
`cites to references that have no relevance to the present inquiry.
`
`33. A POSA knows that the plasma concentration for a depot injection at
`
`time zero would be zero because the drug must first be released from a long-acting
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`formulation and then it must diffuse through the musculature or connective tissue
`
`before it even reaches the blood stream. In fact, intramuscular and subcutaneous
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`13
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`routes are used when an immediate drug effect is not required, unlike an
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`intravenous injection which results in blood levels rising virtually as rapidly as the
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`time necessary to empty the syringe. (Ex. 1066, at 1110.) The same is true for oral
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`administration of naltrexone. The drug concentration in the blood after oral
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`administration at time zero is clearly zero because no drug is absorbed. (Ex. 1067,
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`at 353.) Thus, for all AUC calculations, the drug concentration at time zero is zero,
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`and the only exception is when a drug is administered directly to the bloodstream,
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`i.e., by an intravenous injection. A time zero measurement may be taken to ensure
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`that any prior dose of naltrexone will not meaningfully impact the data. This is
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`discussed more below, but was not necessary in a study like in Comer, where the
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`workup for each patient before they were given the depot injection was well
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`controlled and well monitored. It included a small dose (50 mg) of naltrexone but
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`provided a two day wash out period, which was more than enough given the short
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`half-life (approximately four hours) of naltrexone to ensure that any remaining
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`naltrexone would not impact the study. Indeed, even the reference cited by
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`Dr. Berkland (Ex. 2028) concludes that the mean half-life of naltrexone is
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`3.57±2.62, as described in Table 3. He, however, relied on an outlier as discussed
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`herein.
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`34. Dr. Berkland’s cites a draft guidance published by FDA in 2013
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`(Ex. 2026) entitled Bioequivalence Studies with Pharmacokinetic Endpoints for
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`14
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`Drugs Submitted Under an ANDA. This draft guidance was intended mainly for
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`oral formulations and some non-orally administered drug products, such as
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`transdermal delivery systems and certain rectal and nasal drug products. To
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`compare the bioequivalence of two different formulations, area under the
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`plasma/serum/blood concentration-time curve (i.e., AUC) from time zero to time t
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`is used as an indicator for extent of absorption. As described above in
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`paragraph 33, at time zero, the blood concentration from a depot injection is zero.
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`35. Furthermore, a POSA would appreciate that any missing data between
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`time zero and the initial sample taken by Comer would have a negligible effect on
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`the total AUC, which in this case is measured over 28 days or more. AUC is a
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`measurement of area, including a “height” component provided by the plasma
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`concentration on the y-axis of a pharmacokinetic profile graph and a “length”
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`component provided by a time interval on the x-axis of the same graph. The first
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`blood draw of Comer is taken at two hours, followed by 1, 2, 3, 4, 5, 6, 8, 11, 15,
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`18, 22, 25, 29, 32, 36, and 39 days after administration. The drug concentration in
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`the blood at time zero is clearly zero, as the depot formulation was administered
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`subcutaneously at time zero. Even where that two-hour data point represented Cmax,
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`the maximum “length” component for any missing plasma concentration data
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`between time zero and Comer’s first sample is two hours, or .08 days, in relation to
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`the 28 days over which the total AUC is measured. Because that component is so
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`15
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
`
`small, any area provided by missing “height” data prior to Comer’s first sampling
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`will be negligible in relation to the total AUC over 28 days.
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`36. Comer measured the first naltrexone concentration at two hours,
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`which is 8.80 ng/mL. Using the pharmacokinetic profile of Comer showing the
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`naltrexone concentration ranging from time 0 to day 39, I calculated the AUC0-28d
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`using the manual trapezoidal method, as shown below. The calculated AUC is
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`103.12 ng∙day/mL, which is basically the same value as 103.7 ng∙day/mL, which I
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`calculated through the use of Photoshop in my Prior Declaration. (Ex. 1030.)
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`For the 28-day depot formulation, measuring the first data point at two hours
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`provides a complete pharmacokinetic profile to calculate accurate AUC values. If
`
`one considers a hypothetical measurement at 10 min after administration, then the
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`16
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`following calculation can be made. Assuming that the naltrexone plasma
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`concentration at 10 min is 12 ng/mL, the area from time zero to two hours as
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`indicated in red in the figure below can be calculated to be 12 ng∙h/mL, or
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`0.5 ng∙day/mL. This accounts for only 0.5% of
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`the
`
`total AUC0-28d of
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`103.12 ng∙day/mL, and clearly, it does not affect the calculated AUC values from
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`Comer’s pharmacokinetic profile.
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`
`
`
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`And even if the hypothetical concentration at 10 min were assumed to be
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`30 ng/mL, the area from time zero to two hours is 1.25 ng∙day/mL, which accounts
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`for only 1.2% of the total AUC0-28d and still has no significant effect on the
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`calculated AUC.
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`37.
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`I acknowledge that during my deposition I testified that “if you do not
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`include
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`time zero…you’re not going
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`to have a whole picture of
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`the
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`17
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
`
`pharmacokinetic profile.” (Ex. 2025, at 66-67.) And I stand by that statement. But
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`the Patent Owner misconstrues my testimony in its papers. My answer was given
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`to a question that was specific to oral formulations, as Exhibit 1044, described
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`calculating AUC of oral formulations which maintain the drug concentration in the
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`blood for only 24 hours. In that situation, measuring the first time point much later
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`than time zero, e.g., start measuring AUC from at 12 hours later will not provide a
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`whole picture of the pharmacokinetic profile for oral formulations. Dr. Berkland
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`confuses this with not including the drug concentration at time zero. For oral and
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`depot administration, the drug concentration at time zero is zero, and thus, in the
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`AUC calculation, time zero with the zero drug concentration is automatically
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`added.
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`38.
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`I note that neither the study reported in the ’499 Patent nor the study
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`described in the Ehrich Declaration report pharmacokinetic profiles for accurate
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`AUC calculation, as presented in Comer. It is not clear whether the first time point
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`in the Ehrich Declaration report was 12 hours or 24 hours, as there is no
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`information on the pharmacokinetic profile. Thus, if Dr. Berkland and Alkermes
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`have issues with the first time point at two hours (since the drug concentration at
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`time zero is zero) measured in Comer, then their concern should apply similarly to
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`the Ehrich Declaration report itself. In fact, Dr. Berkland and Alkermes are
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`implying that the AUC claimed in the Ehrich Declaration report is not reliable at
`
`18
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`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Supplemental Declaration of Kinam Park, Ph.D.
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`all, because no pharmacokinetic information was provided when the naltrexone
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`concentrations were measured. Yet, Alkermes had no problem suggesting that its