Case IPR2018-00943
`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
`
`
`
`
`
`
`AMN1061
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`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
`
`
`
`
`
`
`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.
`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ........................................................................................... 1
`
`I.
`
`II.
`
`SUMMARY OF OPINIONS ........................................................................... 1
`
`III. A PERSON OF ORDINARY SKILL IN THE ART ...................................... 2
`
`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
`
`V.
`
`TECHNICAL BACKGROUND AND STATE OF THE ART ....................12
`
`A. The Area Under The Curve (AUC) ........................................................12
`
`B. AUC Calculations And Time Zero .........................................................13
`
`C. AUC And Plasma Level .........................................................................19
`
`D. AUC And Sample Frequency .................................................................22
`
`E. AUC And Prior Administration ..............................................................24
`
`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
`
`i
`
`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.
`
`
`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
`
`2. Vivitrex Specimen ............................................................................58
`
`3. Wright ..............................................................................................59
`
`ii
`
`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.
`
`
`
`
`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
`
`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.
`
`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
`
`
`
`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.
`
`Patent Owner’s Response
`
`(“Response”)
`
`(Paper No. 14), and
`
`I provide
`
`supplemental evidence in support of my opinions that the claims of the ’499 Patent
`
`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
`
`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.
`
`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.
`
`2
`
`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.
`
`IV. CLAIM CONSTRUCTION
`I understand that it is often desirable to construe the meaning of claim
`8.
`
`terms to eliminate ambiguity when possible. I also understand from counsel that
`
`the claims in this IPR are to be given their broadest reasonable interpretation
`
`(“BRI”) unless they are specifically defined otherwise. My understanding of
`
`broadest reasonable interpretation is that the definition must be consistent with the
`
`understanding of a POSA in the field and with the patent specification and the
`
`patentee’s statements made during prosecution. Terms are not necessarily limited
`
`to only those examples recited in the specification. Under the BRI standard, terms
`
`can be given a more inclusive meaning.
`
`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
`
`AUC resulting from administering 50 mg/day orally.
`
`3
`
`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.
`
`
`11. As stated in my Prior Declaration, the claim reflects a broad dosing
`
`range of 310 to 480 mg. The AUC for each of these doses will necessarily be
`
`different. As the ’499 Patent did not provide a consistent set of data points to use
`
`for the comparative oral dosing, it is almost impossible to know if the resulting
`
`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
`
`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
`
`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
`
`Decision, the Board also accepted the Cohort B value of 35.2 µg∙h/L (or
`
`4
`
`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.
`
`1.468 ng∙day/mL) in Table 8, although this value is less appropriate considering
`
`that it is based on repeat doses. Based on this, Alkermes and Dr. Berkland suggest
`
`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
`
`necessarily encompass at least 27.8 µg∙h/L (to cover Tice) to 30.5 µg∙h/L (to cover
`
`Cohort A).
`
`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
`
`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.
`
`16.
`
`I understand Alkermes has taken the position that “administering a
`
`long acting formulation” means administering “a single injection of a long acting
`
`formulation” to a POSA. I struggle with this opinion as I do not understand how
`
`the broadest reasonable construction of the general term “administering” could be
`
`so narrow as to be limited to only a single injection.
`
`5
`
`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.
`
`
`17. None of the claims of the ’499 Patent indicates “a single injection.”
`
`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
`
`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.
`
`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
`
`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.
`
`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
`
`the terms of the claim should be interpreted. It does not matter if the oral dose
`
`referenced in the claims was one 50 mg tablet, or two 25 mg tablets, or five 10 mg
`
`6
`
`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.
`
`tablets, the swallowing of each tablet separated by a brief moment. Indeed using
`
`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
`
`administered two 50 mg capsules).) In the same way, it does not matter whether
`
`the claimed depot injection comprises one 380 mg injection in the right buttock or
`
`two 190 mg injections, given within moments of each other, one in each buttock or
`
`even both in the same buttock. In any event, the individual is administered 380 mg
`
`of depot naltrexone.
`
`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
`
`daily for carotid endarterectomy, and up to 3 grams/day for certain arthritis. (See
`
`Ex. 1065, at 3053.) Ecotrin enteric-coated aspirin is supplied in tablets of three
`
`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
`
`six 500 mg tablets. The same is true for other well-known drugs. (See id. at 2663
`
`(Pepto Bismol label indicating that 2 tablets or caplets are one adult dose, 1 tablet
`
`7
`
`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.
`
`or caplet is a dose for children 9-12 years, and 2/3 of a tablet/caplet is a dose for
`
`children 6-9 years).)
`
`21. Further, the word “single” is used in the ’499 Patent four times.
`
`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
`
`could be achieved by a single IM administration of Vivitrex®.”
`
`b. Column 4, lines 56-58. “The therapy can end after a single dose
`
`or can be maintained for longer periods of time.”
`
`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
`
`consumption of four or five alcoholic beverages, such as the
`
`number of drinks characterizing an episode of "heavy
`
`drinking,"
`
`d. Column 6, lines 54-56. “The ambient polymer and drug
`
`solutions were mixed together until a single homogeneous
`
`solution (organic phase) was produced.
`
`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
`
`8
`
`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.
`
`(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
`
`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
`
`conclusion. The fact that the specification may describe using one injection in one
`
`instance would not suggest to a POSA that the claimed method could only be
`
`practiced using a single injection.
`
`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
`
`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.”
`
`(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
`
`naltrexone given as two 190 mg injections, which is the only data that would be
`
`relevant to PO’s proposed construction. And, as noted above, if anything, the
`
`Ehrich Declaration supports my position that the claim is actually referencing a
`
`9
`
`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.
`
`temporal component. Indeed, in the study reflected in the declaration—which is the
`
`same study reference in the ’499 Patent—a single 380 mg dose, given on day one
`
`of a month, is compared to smaller doses given once a day for the entire month;
`
`one “single” administration as opposed to 28 or 32 separate administrations.
`
`C. “initial oral dose of naltrexone”
`24. Claim 11 requires the individual not receive an “initial oral dose” of
`
`naltrexone. The ’499 Patent does not define this term, and the only instance of the
`
`phase “initial oral dose” is in the claims. Alkermes and Dr. Berkland have taken
`
`the position that “initial” should mean “first” and point to a dictionary definition
`
`(Ex. 2055), which defines “initial” as “1: of or relating to the beginning…2: placed
`
`at the beginning: FIRST.”
`
`25. But by only construing the word “initial,” rather than the phrase
`
`“initial oral dose of naltrexone,” Alkermes fails to provide proper context. The
`
`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
`
`to achieve a specific therapeutic effect. The only reference to “dosing” in the
`
`’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
`
`of the recited “dose” is long term addiction treatment. Accordingly, the “dose” of
`
`this claim would lead a POSA to the conclusion that the claim intended to exclude
`
`10
`
`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.
`
`a method in which an initial amount of oral naltrexone is provided orally as part of
`
`a long-term treatment.
`
`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
`
`naltrexone as part of a detoxification process. (Ex. 1010, at 353.) Comer provided a
`
`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
`
`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
`
`expose the patient to naltrexone continuously over 30 days. Testing a patient by
`
`giving a single smaller amount orally would be a responsible way of confirming
`
`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
`
`distinguishes initial “treatment doses” from prior doses given for other purposes,
`
`11
`
`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.
`
`and I don’t think a POSA would read claim 1 as excluding such earlier doses for
`
`other purposes.
`
`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
`
`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
`
`injection according to the invention, would fall outside of the claims. This is an
`
`irrational result, and I cannot believe that a POSA would accept such an
`
`interpretation.
`
`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
`
`12
`
`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.
`
`to calculate AUC. It can be determined in any of the conventional ways that area is
`
`determined, and AUC has been calculated for decades.
`
`31. Regardless of the oral naltrexone data used for comparison, the
`
`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
`
`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
`
`formulation and then it must diffuse through the musculature or connective tissue
`
`before it even reaches the blood stream. In fact, intramuscular and subcutaneous
`
`13
`
`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.
`
`routes are used when an immediate drug effect is not required, unlike an
`
`intravenous injection which results in blood levels rising virtually as rapidly as the
`
`time necessary to empty the syringe. (Ex. 1066, at 1110.) The same is true for oral
`
`administration of naltrexone. The drug concentration in the blood after oral
`
`administration at time zero is clearly zero because no drug is absorbed. (Ex. 1067,
`
`at 353.) Thus, for all AUC calculations, the drug concentration at time zero is zero,
`
`and the only exception is when a drug is administered directly to the bloodstream,
`
`i.e., by an intravenous injection. A time zero measurement may be taken to ensure
`
`that any prior dose of naltrexone will not meaningfully impact the data. This is
`
`discussed more below, but was not necessary in a study like in Comer, where the
`
`workup for each patient before they were given the depot injection was well
`
`controlled and well monitored. It included a small dose (50 mg) of naltrexone but
`
`provided a two day wash out period, which was more than enough given the short
`
`half-life (approximately four hours) of naltrexone to ensure that any remaining
`
`naltrexone would not impact the study. Indeed, even the reference cited by
`
`Dr. Berkland (Ex. 2028) concludes that the mean half-life of naltrexone is
`
`3.57±2.62, as described in Table 3. He, however, relied on an outlier as discussed
`
`herein.
`
`34. Dr. Berkland’s cites a draft guidance published by FDA in 2013
`
`(Ex. 2026) entitled Bioequivalence Studies with Pharmacokinetic Endpoints for
`
`14
`
`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.
`
`Drugs Submitted Under an ANDA. This draft guidance was intended mainly for
`
`oral formulations and some non-orally administered drug products, such as
`
`transdermal delivery systems and certain rectal and nasal drug products. To
`
`compare the bioequivalence of two different formulations, area under the
`
`plasma/serum/blood concentration-time curve (i.e., AUC) from time zero to time t
`
`is used as an indicator for extent of absorption. As described above in
`
`paragraph 33, at time zero, the blood concentration from a depot injection is zero.
`
`35. Furthermore, a POSA would appreciate that any missing data between
`
`time zero and the initial sample taken by Comer would have a negligible effect on
`
`the total AUC, which in this case is measured over 28 days or more. AUC is a
`
`measurement of area, including a “height” component provided by the plasma
`
`concentration on the y-axis of a pharmacokinetic profile graph and a “length”
`
`component provided by a time interval on the x-axis of the same graph. The first
`
`blood draw of Comer is taken at two hours, followed by 1, 2, 3, 4, 5, 6, 8, 11, 15,
`
`18, 22, 25, 29, 32, 36, and 39 days after administration. The drug concentration in
`
`the blood at time zero is clearly zero, as the depot formulation was administered
`
`subcutaneously at time zero. Even where that two-hour data point represented Cmax,
`
`the maximum “length” component for any missing plasma concentration data
`
`between time zero and Comer’s first sample is two hours, or .08 days, in relation to
`
`the 28 days over which the total AUC is measured. Because that component is so
`
`15
`
`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.
`
`small, any area provided by missing “height” data prior to Comer’s first sampling
`
`will be negligible in relation to the total AUC over 28 days.
`
`36. Comer measured the first naltrexone concentration at two hours,
`
`which is 8.80 ng/mL. Using the pharmacokinetic profile of Comer showing the
`
`naltrexone concentration ranging from time 0 to day 39, I calculated the AUC0-28d
`
`using the manual trapezoidal method, as shown below. The calculated AUC is
`
`103.12 ng∙day/mL, which is basically the same value as 103.7 ng∙day/mL, which I
`
`calculated through the use of Photoshop in my Prior Declaration. (Ex. 1030.)
`
`For the 28-day depot formulation, measuring the first data point at two hours
`
`provides a complete pharmacokinetic profile to calculate accurate AUC values. If
`
`one considers a hypothetical measurement at 10 min after administration, then the
`
`
`
`16
`
`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.
`
`following calculation can be made. Assuming that the naltrexone plasma
`
`concentration at 10 min is 12 ng/mL, the area from time zero to two hours as
`
`indicated in red in the figure below can be calculated to be 12 ng∙h/mL, or
`
`0.5 ng∙day/mL. This accounts for only 0.5% of
`
`the
`
`total AUC0-28d of
`
`103.12 ng∙day/mL, and clearly, it does not affect the calculated AUC values from
`
`Comer’s pharmacokinetic profile.
`
`
`
`
`
`And even if the hypothetical concentration at 10 min were assumed to be
`
`30 ng/mL, the area from time zero to two hours is 1.25 ng∙day/mL, which accounts
`
`for only 1.2% of the total AUC0-28d and still has no significant effect on the
`
`calculated AUC.
`
`37.
`
`I acknowledge that during my deposition I testified that “if you do not
`
`include
`
`time zero…you’re not going
`
`to have a whole picture of
`
`the
`
`17
`
`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.
`
`pharmacokinetic profile.” (Ex. 2025, at 66-67.) And I stand by that statement. But
`
`the Patent Owner misconstrues my testimony in its papers. My answer was given
`
`to a question that was specific to oral formulations, as Exhibit 1044, described
`
`calculating AUC of oral formulations which maintain the drug concentration in the
`
`blood for only 24 hours. In that situation, measuring the first time point much later
`
`than time zero, e.g., start measuring AUC from at 12 hours later will not provide a
`
`whole picture of the pharmacokinetic profile for oral formulations. Dr. Berkland
`
`confuses this with not including the drug concentration at time zero. For oral and
`
`depot administration, the drug concentration at time zero is zero, and thus, in the
`
`AUC calculation, time zero with the zero drug concentration is automatically
`
`added.
`
`38.
`
`I note that neither the study reported in the ’499 Patent nor the study
`
`described in the Ehrich Declaration report pharmacokinetic profiles for accurate
`
`AUC calculation, as presented in Comer. It is not clear whether the first time point
`
`in the Ehrich Declaration report was 12 hours or 24 hours, as there is no
`
`information on the pharmacokinetic profile. Thus, if Dr. Berkland and Alkermes
`
`have issues with the first time point at two hours (since the drug concentration at
`
`time zero is zero) measured in Comer, then their concern should apply similarly to
`
`the Ehrich Declaration report itself. In fact, Dr. Berkland and Alkermes are
`
`implying that the AUC claimed in the Ehrich Declaration report is not reliable at
`
`18
`
`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.
`
`all, because no pharmacokinetic information was provided when the naltrexone
`
`concentrations were measured. Yet, Alkermes had no problem suggesting that its
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
