Case 1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 1 of 44 PagelD #: 3512
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`IN RE COPAXONE 40 MG CONSOLIDATED
`CASES
`
`)
`)
`)
`)
`
`)
`)
`
`Civil Action No. 14- 1171 -GMS
`
`(CONSOLIDATED)
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`FOURTH DECLARATION OF EDWARD J. FOX, M.D., PH.D.
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`I am the same Edward J. Fox who submitted declarations in this case dated September
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`11, 2015, October 2, 2015, and December 18, 2015. I submit this declaration to address certain
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`opinions expressed in the Declaration of Samuel J. Pleasure, M.D., dated December 18, 2015
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`( "Pleasure Dec. "), concerning the meaning of two claim terms in U.S. Patent 9,155,776 ( "the
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`'776 patent "). I reserve the right to supplement this declaration as appropriate and to respond to
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`any declaration or report submitted on behalf of the Defendants in this action.
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`COMPENSATION ANI) PRIOR TESTIMONY
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`1.
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`I am being compensated for my time spent working on this case at the rate of
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`$500 per hour.
`
`2.
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`1 have not testified as an expert at trial or by deposition in the previous four years.
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`MATERIALS CONSIDERED
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`3.
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`I have reviewed the Declaration of Samuel J. Pleasure, M.D. in support of
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`Defendants' Opening Claim Construction Brief Regarding U.S. Patent No. 9,155,776, dated
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`December 18, 2015, including the exhibits attached thereto and defendants' opening claim
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`construction brief. My opinions in this declaration arc based on my education and over twenty -
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`three years of experience as a practicing clinician and scientist /researcher. I have also reviewed
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`and considered other documents attached to this declaration as Exhibits A -C.
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`r
`EXHIBIT 101
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`WIT:
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`DATE:
`Marsha Yarberry, CSR
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 1
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`SUMMARY OF OPINIONS
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`4.
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`1 disagree with Dr. Pleasure's opinion that a person of ordinary skill in the art
`
`( "POSA ") would have interpreted the claims of the '776 patent in various ways as of the priority
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`date and therefore the severity terms are indefinite.' (Pleasure Dec. ¶¶ 26 -27 and 30.) In my
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`opinion, a POSA would have readily understood the meaning of the severity terms in view of
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`their plain and ordinary meanings, their use in the patent specification, and the knowledge and
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`practice of a POSA. Thus, as explained in my third declaration, a POSA would have understood
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`the scope of the inventions claimed in the '776 patent with reasonable certainty. A POSA also
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`would have known how to determine whether a reduction in the frequency and severity of
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`injection reactions had occurred through clinical observation and study.
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`5.
`
`I also disagree with Dr. Pleasure's opinion that the constructions of the severity
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`terms should specify that the reduction in severity and/or frequency is limited to an individual
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`patient, as opposed to a patient population. (Pleasure Dec. ¶¶ 25 and 29.) In my opinion, the
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`severity terms do not require construction because, as used in the claims of the '776 patent, they
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`have plain and ordinary meanings that would have been readily understood by a POSA. If it is
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`determined that the terms need to be construed, in my opinion, a POSA would have understood
`
`them to encompass a reduction in the frequency and severity of IPIRs and ISRs in a group of
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`patients as well as an individual patient. Dr. Pleasure's proposal to limit the constructions to an
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`individual patient would introduce redundancy because several claims contain the phrase "in the
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`human patient" immediately after the severity terms. In addition, Dr. Pleasure's proposal is
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`inconsistent with how the severity terms are used in the patent specification.
`
`I The disputed claim terms - "reduced severity of injection site reactions" the "reduced
`frequency and severity of immediate post injection reactions and injection site reactions" - are
`collectively referred to herein as "the severity terms."
`
`2
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`THE SEVERITY TERMS ARE NOT INDEFINITE
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`6.
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`Dr. Pleasure contends that in 2009 "there was no agreed upon meaning in the art
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`regarding severity." (Pleasure Dec. IT 38.) This is simply not true. As explained in my third
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`declaration, in 2009, severity was generally understood to mean the same thing as intensity. Dr.
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`Pleasure acknowledged this in his declaration. (Pleasure Dec. ¶ 28.) This definition is adopted
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`by various literature from the relevant timeframe. For example, several books defined "severity"
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`as "intensity of a specific event, as in mild, moderate or severe. "2 In addition, based on my
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`personal experience treating thousands of patients and participating in more than 60 clinical
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`trials, several of which evaluated the severity of injection reactions associated with Copaxone, in
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`my opinion, POSAs and patients being treated for multiple sclerosis would have understood the
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`meaning of severity as it is used in the claims of the '776 patent. There was no confusion in the
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`art among clinicians or patients about what constituted a more or less severe IPIR or ISR.
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`7.
`
`1 also disagree with Dr. Pleasure's opinion that "there is no established or agreed -
`
`upon way to measure severity (or a reduction thereof)." (Pleasure Dec. ¶¶ 26, 30, 38.) In 2009,
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`there was a well -established and widely -used scale for grading the severity of injection reactions
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`called Common Terminology Criteria for Adverse Events ( "CI'CAE ") published by the National
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`Institutes of Health of the U.S. Department of Health and Human Services (attached hereto as
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`Exhibit C). These criteria were commonly used by clinicians to grade and evaluate the severity
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`of various adverse events, including injection reactions. The C'l'CAE provides Grades 1 through
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`2 See, e.g., Cobert et al., "Practical Drug Safety from A to Z," page 328 (2009) ( "The term
``severe' is often used to describe the intensity (severity) of a specific event (as in mild, moderate,
`or severe myocardial infarction) ..." (attached hereto as Exhibit A); "A Practical 1 landbook on
`the Pharmacovigilance of Antiretroviral Medicines," published by World Health Organization,
`page 132 (2009) (In the English language, "severe" is used to describe the intensity (severity) of
`a specific event (as in mild, moderate or severe) ..." (attached hereto as Exhibit B).
`
`3
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 3
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`5 with unique clinical descriptions of severity for each adverse event based on the following
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`general guidelines:
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Mild; asymptomatic or mild symptoms, clinical or diagnostic observations
`only; intervention not indicated.
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`Moderate; minimal, local or noninvasive intervention indicated; limiting
`age -appropriate instrumental ADL.
`
`Severe or medically significant but not immediately life- threatening;
`hospitalization or prolongation of hospitalization indicated; disabling;
`limiting self care ADL.
`
`Grade 4
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`Life- threatening consequences; urgent intervention indicated.
`
`Grade 5
`
`Death related to AE.
`
`With regard to injection reactions, Grades 4 and 5 are typically not used because such adverse
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`events almost never lead to life- threatening consequences or death.
`
`8.
`
`In my opinion, a POSA interpreting the claims of the '776 patent would have used
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`the criteria set forth in the CTCAE, or a similar set of criteria, to determine whether the claimed
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`dosing regimen reduced the severity of injection reactions relative to the 20 mg daily regimen.
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`In particular, a clinician or patient evaluating the severity of one or more injection reactions
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`observed in a patient would grade each reaction as mild, moderate, or severe. A POSA would
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`have known how to aggregate the severity grades observed in a group of patients and /or multiple
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`injection reactions in the same patient to compare them to determine how they compared to the
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`20 mg daily regimen. Regardless of whether a POSA used the exact criteria set forth in the
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`CTCAE or a slight variation, in my opinion, there would not have been an appreciable difference
`
`in the results and Dr. Pleasure does not contend otherwise. Indeed, Dr. Pleasure's declaration
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`provides no evidence that using slightly different methods of evaluating severity of injection
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`reactions would lead to appreciably different results.
`
`4
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`9.
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`As an example, starting in July 2009, just one month before the priority date of
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`the '776 patent, I participated as a primary investigator in a study comparing, among other
`
`things, the severity of injection reactions in two different dosing regimens: once -daily
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`administration of injections of GA 20 mg /1 mL (Copaxone® marketed formulation) and once -
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`daily administration of injections of GA 20 mg /0.5 mL (reduced volume formulation).
`
`In this
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`study known as SONG (Study of New Glatiramer Acetate Formulation), using a Visual Analog
`
`Scale (VAS), patients recorded in daily diaries the severity of injection pain immediately and 5
`
`minutes post- injection, and the presence and severity of injection reactions (swelling, redness,
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`itching, lump) within 5 minutes and 24 hours post -injection. The degree of injection reaction
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`severity was rated 0 -3, with 0 = none, 1 = mild, 2 = moderate, and 3 = severe. In my opinion, a
`
`POSA evaluating severity of the methods claimed in the '776 patent would have used a scale like
`
`this or something similar. Regardless of which grading scale was used, the overall results would
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`have been roughly the same. Accordingly, a POSA would have understood the scope of the
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`10.
`
`invention described in the claims of the '776 patent with reasonable certainty.
`Dr. Pleasure also contends that "severity ... can be subjective (and some
`reactions are more amendable to objective measurement than others); ... even a single person
`can have a variety of reactions (at the same time); and ... a certain category of reaction may be
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`inherently more or less severe than another category of reaction." (Pleasure Dec.
`
`26, 30, 34-
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`37.) I do not disagree with the premise of these generalizations. However, there is no evidence
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`that, even if these statements are true, using one grading scale to evaluate severity of injection
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`reactions would lead to a different answer to the overall question compared to a slightly different
`
`scale. As explained above, in my opinion, a POSA would have readily understood the meaning
`
`of the severity terms in view of their plain and ordinary meanings, there was a well- established
`
`scale for grading the severity of injection reactions, there is no evidence that using any method
`
`5
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`Case 1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 6 of 44 PagelD #: 3517
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`for evaluating severity other than that scale would lead to a different result, and thus a POSA
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`would have understood the scope of the claims of the '776 patent with reasonable certainty.
`
`11.
`
`T also disagree with Dr. Pleasure's opinion that "the specification and the
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`prosecution history do nothing to inform those skilled in the art what is meant by reduction in
`
`severity." (Pleasure Dec. 111126, 30, 34.) The specification explains that tolerability is associated
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`with frequency and severity of IPIRs and ISRs, and describes a clinical study where tolerability
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`of GA treatment will be determined in a population of patients.3 Neither the claims nor the
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`specification limit the severity terms to a particular method of evaluating "severity." They just
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`describe "reduced severity" of IPIRs and ISRs relative to the 20 mg daily regimen. Thus, a
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`POSA reading the severity terms in view of the intrinsic record would understand that either the
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`accepted criteria set forth in the CTCAE or a slight variation could be used to evaluate severity
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`as long it is applied consistently.
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`THE SEVERITY TERMS SHOULD NOT BE LIMITED TO A SING LE PATIENT
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`12.
`
`I disagree with Dr. Pleasure's opinion that "Plaintiffs' constructions [of the
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`severity terms] are incorrect and /or incomplete because they do not include the phrase `a
`
`patient. "' (Pleasure Dec. ¶ 41.) As explained in my third declaration, the severity terms do not
`
`require construction because, as used in the claims of the '776 patent, they have a plain and
`
`ordinary meaning that would have been readily understood by a POSA. In my opinion, a POSA
`
`would have understood them to encompass a reduction in the frequency and severity of IPIRs
`
`and ISRs over a group of patients as well as an individual patient. Dr. Pleasure's proposal to
`
`limit the terms to a single patient would introduce redundancy because some of the claims in
`
`which the terms are recited already contain the phrase "in the human patient" immediately after
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`3 See '776 patent at col. 7, lines 39 -40; col. 8, lines 62 -67; col. 9, lines 21 -24; col. 12, lines 56-
`67.
`
`6
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 6
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`Case 1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 7 of 44 PagelD #: 3518
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`the severity terms. Dr. Pleasure's declaration does not take into account the redundancy that
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`Defendants' construction would introduce. Dr. Pleasure's proposal to limit the severity terms to
`
`a single patient also ignores portions of the patent specification that a POSA would consider
`
`relevant when interpreting the meaning of the terms. In particular, the specification explains that
`
`tolerability is associated with frequency and severity of IPIRs and ISRs and describes a clinical
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`study where tolerability of GA treatment will be evaluated in a group of patients by measuring
`
`the "proportion of subjects ( %)" who prematurely discontinue from the study due to adverse
`
`events.4 Dr. Pleasure's declaration does not account for this part of the specification.
`
`13.
`
`Dr. Pleasure's opinion that the severity terms should be limited to a single patient
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`also does not consider the point made in my third declaration that if a POSA wanted to
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`scientifically show a reduction in the frequency and severity of injection reactions for the 40 mg
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`three -times- per -week dosing regimen relative to the 20 mg daily dosing regimen, while they may
`
`consider how the regimen effects individual patients, they would be more interested in the
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`frequency and severity of these reactions reported by a population of patients.
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`4 See '776 patent at col. 12, lines 62 -67.
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`7
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 7
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`Case 1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 8 of 44 PagelD #: 3519
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`I declare that the foregoing statements are truc and correct to the best of my knowledge.
`
`Dated: January 8, 2016
`
`C
`
`Edward J. Fox, M P ., Ph.D.
`
`8
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 8
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`Case 1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 9 of 44 PagelD #: 3520
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`EXHIBIT A
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 9
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`

`
`MI 302
`,5
`.C634
`2009
`Copy 1
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 10
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`

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`from
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`nari o;ßá. L. Çobert, MD, FACP, FACG, FFPM
`Vice President, Global Regulatory Initiatives
`and Pharmacovigilance
`Medidata Solutions Worldwide
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`Pierre Biron, MD
`Honorary Professor of Pharmacology
`Department of Pharmacology
`Université de Montréal
`
`JONES AND BARTLETT I'UBLISIHERS
`Sudbury, ilgnssnch
`ette
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`BOSTON
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`SING.POItI.
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 11
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`

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`-GMS Document 155 Filed 01/08/16 Page 12 of 44 PagelD #: 35,23
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`Practical drug safety from A to Z ! Barton Cobert, Pierre Biron.
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`2. Drugs -Side effects -- Handbooks,
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`IL Cobert, Barton L. Pharmacovigilance from A to Z.
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`Treatments and side effects described in this book may not be applicable to all people; likewise.
`some people may require a dose or experience a side effect that is not described herein. Drugs and
`medical devices are discussed that may have limited availability controlled by the Food and Drug
`Administration (FDA) for use only in a research study or clinical trial. Research, clinical practice, and
`government regulations often change the accepted standard in this field. When consideration is
`being given to use of any drug in the clinical setting, the health care provider or reader Is responsible
`for determining FDA status of the drug. reading the package insert, and reviewing prescribing infor-
`mation for the most up -to -date recommendations on dose, precautions, and contraindications, and
`determining the appropriate usage for the product. This is especially important in the case of drugs
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 12
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`

`
`Serious Adverse Event (SAE) 327
`
`SENTINEL SITE OF SURVEILLANCE
`The use of a designated institution, hospital, physician, etc., to
`search for and report particular diseases or AEs. For example, in
`the early influenza season a few hospitals in each region of the US
`may be asked to report to the CDC all cases of influenza in order to
`get an early warning of an impending flu pandemic.
`In the case of pharmacovigilance, after the release of a new drug,
`certain hospitals or physicians may be asked to report all cases of
`a particular AE that is under increased surveillance or is suspected
`of occurring. For example, a new statin might have some sentinel
`sites on the look -out for rhabdomyolysis. Also, certain hospitals
`may be chosen as sentinel sites for collecting all serious ADRs from
`all new drugs. This approach is used in Japan.
`
`SERIOUS ADVERSE DRUG REACTION (SADR)
`A noxious and unintended response to any dose of a drug or bio-
`logic product for which there is a reasonable possibility that the
`product caused the response, fulfilling the criteria for seriousness.
`In this definition, the phrase "a reasonable possibility" means that
`the relationship cannot be ruled out.
`
`SERIOUS ADVERSE EVENT (SAE)
`"A serious adverse event (experience) or serious adverse reaction is
`àny untoward medical occurrence that at any dose:
`results in death,
`is life -threatening,
`requires inpatient hospitalization or prolongation of existing
`hospitalization,
`results in persistent or significant disability/incapacity, or
`is a congenital anomaly /birth defect.
`"Medical and scientific judgment should be exercised in decid-
`ing whether expedited reporting is appropriate in other situations,
`such as important medical events that may not be immediately
`life -threatening or result in death or hospitalization but may jeop-
`ardize the patient or may require intervention to prevent one of
`the other outcomes listed in the definition above.
`These should also usually be considered serious. "Examples of
`such events are intensive treatment in an emergency room or at
`home for allergic bronchospasm; blood dyscrasias or convulsions
`that do not result in hospitalization; or development of drug depen-
`dency or drug abuse ".
`Authors' note: Thus fur reporting purposes, suspected adverse re-
`actions thatarr judged to be medically important events will be con-
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 13
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`

`
`328 Serious Adverse Reaction (SAR)
`
`sidered serious, even if they do not meet the preceding, more rigid
`criteria.
`
`SERIOUS ADVERSE REACTION (SAR)
`Any adverse reaction which results in death, is life- threatening, re-
`quires inpatient hospitalization or prolongation of existing hospi-
`talization, results in persistent or significant disability or incapacity,
`or is a congenital anomaly /birth defect. For reporting purposes,
`suspected adverse reactions that are judged to be medically im-
`portant events will be considered serious, even if they do not meet
`the preceding criteria.
`
`SERIOUS, DEFINED
`See Serious Adverse Event.
`The word "serious" is used in a specific regulatory manner in
`drug safety and must not be confused with "severe." The term "se-
`vere" is often used to describe the intensity (severity) of a specific
`event (as in mild, moderate, or severe myocardial infarction); the
`event itself, however, may he of relatively minor long -term medical
`significance (such as short -lived severe headache, severe urticaria).
`This is not the same as "serious," which is based on patient /event
`outcome usually associated with medical problems that pose a
`threat to a patient's life or functioning. Seriousness (not severity) is
`used for defining regulatory reporting obligations: postmarketing
`AEs must be serious and unexpected to be considered expedited
`reports.
`
`SERVICE ORGANIZATIONS IN PHARMACEUTICAL INDUSTRY
`Vendors that serve the pharmaceutical industry by doing certain
`functions that the company does not want or is unable to do itself.
`These organizations are commonly used by small or start -up com-
`panies to run clinical trials or collect safety data because the com-
`pany is too small to do it by itself. Clinical /Contract Research
`Organizations (CROs) are a very common group of service organ-
`izations. They may be very specific, handling only, say, monitoring
`of clinical trials or they may be large international "full- service" or-
`ganizations that are willing and able to do everything needed to
`submit an NDA or dossier to the health authority for approval, in-
`cluding preclinical studies and phase I, II, and III trials.
`In drug safety, there are several service organizations that
`specialize in handling AE collection, databasing, analysis, and
`reporting.
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 14
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`

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`Side- Effect 329
`
`SEVERE, DEFINED
`Sec Serious, Defined.
`
`SEX (GENDER)
`
`In drug safety, sex refers to one of the criteria (identifiable patient)
`for a valid individual case safety report. Sec Minimum Information
`for Reportability
`Gender is also a risk factor for some ADRs and for ADRs in gen-
`eral. Women are slightly more likely than men to develop ADRs
`when exposed to pharmacotherapy for multiple reasons:
`Higher consumption rates.
`frequent polypharmacy,
`v1ore
`interactions.
`Lower body weights.
`More very elderly twonlen alive, vvith the ensuing diminishing
`renal function that comes \with advanced age.
`
`to drug -drug
`
`leading
`
`Serum glutamic oxaloacetic transaminase, also called aspartate
`aminotransferase (AST). This is one of several enzymes present in
`various organs of the body, in particular the liver and heart, that is
`elevated when there is damage to one of those organs (e.g., hepa-
`titis and myocardial infarction, respectively).
`In drug safety, because liver problems are a very common ADIl,
`an elevation in SGOT (and other "liver enzymes ") should raise the
`suspicion of a drug related cause.
`See Liver Function Tests and SGPT.
`
`SGOT
`
`SGPT
`
`Serum glutamic pyruvic transaminase, also called alanine amino -
`transferase (ALT). Very similar to SGOT in clinical use. See SGOT
`and Liver Function Tests.
`
`SIDE EFFECT
`
`A somewhat out -of -date popular term that generally should be
`avoided in medical and scientific usage. The better terns is adverse
`event (AE) or adverse drug reaction (ADH) (see these terms).
`However, in discussions with patients the term "side effect" is still
`more widely used and recognized than 'AE /ADR" and should be
`used if there is any doubt about the patient's understanding when
`questioned about AEs.
`
`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 15
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`EXHIBIT B
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`MYLAN PHARMS. INC. EXHIBIT 1072 PAGE 16
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`1:14 -cv- 01171 -GMS Document 155 Filed 01/08/16 Page 17 of 44 PagelD #
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`A practical
`handbook on the
`pharmacovigilance
`of antiretroviral
`medicines
`
`e World Health
`
``y Organization
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`WHO Library Cataloguing -in- Publication Data:
`A practical handbook on the pharmacovigilance of antiretroviral medicines.
`1.Drug monitoring. 2.Drug utilization review - methods.
`3.Anti- retroviral agents - adverse effects. 4.Adverse drug reaction
`reporting systems. 5.Handbooks. I.World Health Organization.
`(NLM classification: QV 771)
`ISBN 978 92 4 154794 9
`
`World Health Organization 2009
`All rights reserved. Publications of the World Health Organization can be obtained from WIIO
`Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41
`22 791 3264; fax: +41 22 791 4857; e-mail: bookorders @who.int). Requests for permission to
`reproduce or translate WHO publications - whether for sale or for noncommercial distribu-
`tion - should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail:
`permissions @vho.int).
`The designations employed and the presentation of the material in this publication do not imply
`the expression of any opinion whatsoever on the part of the World I-Iealth Organization con-
`cerning the legal status of any country, territory, city or area or of its authorities, or concerning
`the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
`border lines for which there may not yet be full agreement.
`
`The mention of specific companies or of certain manufacturers' products does not imply that
`they are endorsed or recommended by the World Health Organization in preference to others
`of a similar nature that are not mentioned. Errors and omissions excepted, the names of propri-
`etary products are distinguished by initial capital letters.
`
`All reasonable precautions have been taken by the World Health Organization to verify the
`information contained in this publication. However, the published material is being distributed
`without warranty of any kind, either expressed or implied. The responsibility for the interpreta-
`tion and use of the material lies with the reader. In no event shall the World Health Organization
`be liable for damages arising from its use.
`
`Desgned by minimum graphics
`
`Printed in ) )) a ?)
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`Contents
`
`Abbreviations
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`1. Pharmacovigilance
`1.1 Definition
`1.2 Explanation
`1.3 General aims
`1.4 Specific aims
`1.5 Pharmacovigilance of antiretrovirals
`2. Pharmacovigilance centre
`
`1. Passive pharmacovigilance
`2. Active pharmacovigilance
`
`1.
`
`Introduction
`1.1 Background
`1.2 Adverse reactions
`2. Objectives
`2.1 The purpose of spontaneous reporting
`2.2 Background to the methodology
`2.3 Serious reactions
`3. Minimum reporting requirements
`3.1 WHO criteria
`3.2 Other practical conditions
`4. How to report
`4.1 Reporting form
`4.2 Other options for reporting
`5. Where to report
`6. What to report
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`6.1 Essential data elements
`6.2 Advice to reporters
`6.3 Follow -up when necessary
`7. When to report
`8. Who should report
`9. Sharing the results
`Individual, immediate
`9.1
`9.2 Relevant summaries or reviews
`9.3 Regular transmission to the WHO database
`10. Data entry
`10.1 Options
`10.2 VigiFlow
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`1.
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`Introduction
`1.1 Event monitoring
`1.2 Description
`1.3 Objectives
`1.4 Selection of drugs to monitor
`1.5 Basic processes
`1.6 Programme duration
`2. Epidemiology
`2.1 Observational
`2.2 Prospective
`Inceptional
`2.3
`2.4 Dynamic
`2.5 Longitudinal
`2.6 Descriptive
`3. First step - Implementation
`3.1 First action
`3.2 Pilot exercise
`3.3 Sites and training
`3.4 Advocacy
`3.5 Reasons for monitoring
`3.6 Approaches to advocacy
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`A PRACTICAL HANDBOOK ON THE PHARMACOVIGILANCE OF ANTIRETROVIRAL MEDICINES
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`4. Second step - establishing the cohort(s)
`4.1 Numbers of patients
`4.2 Selection of patients
`4.3 Patient identification
`4.4 Other patient data
`4.5 Background data
`4.6 Controls or comparators
`5. Third step - acquiring the data
`The medicines
`5.1 Details of administration of ARVs
`5.2 Concomitant medicines
`The events
`5.3 Principles of event reporting
`5.4 What kind of events?
`5.5 Recording event details
`5.6 Reporting forms (questionnaires)
`5.7 Logistics of data recording
`5.8 Frequency and duration of monitoring
`5.9 Reasons for lack of adherence
`5.10 How and where to send the completed questionnaires
`5.11 Record linkage
`6. Database fnr CEM
`6.1 Choice of database
`6.2 Data elements /fields
`7. Maximizing the reporting rate
`7.1 Prepare the ground
`7.2 Removing barriers to reporting.
`7.3 Other health facilities
`7.4 Feedback
`8. General advice and information
`8.1 Don't ask for too much
`8.2 Non -serious events
`8.3 Be open- minded
`8.4 Privacy
`9. Fourth step - Clinical review
`9.1 The event should be specific to be acceptable for recording
`
`CONTENTS
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`9.2 Determining the event term
`9.3 The events dictionary
`9.4 Dictionary maintenance
`9.5 Seriousness
`9.6 Severity
`9.7 Outcome of the event
`9.8 Relationship to the medicine /regimen
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`1. Data entry
`1.1 Requirements
`1.2 Standard formats
`2. Quality control
`2.1 Control at entry
`2.2 Systematic checks
`3. Coding of medicines and diseases
`3.1 WHO Drug Dictionary
`3.2
`ICD -10
`3.3 Standardized recording of event details