UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC., SAWAI USA, INC., AND
`
`SAWAI PHARMACEUTICAL CO., LTD.,
`
`v.
`
`BIOGEN MA INC.
`
`November 13, 2019 3'
`
`Blogen Demonstrative Exhibits — Not Evidence
`
`.
`
`

`

`Coalition v. Biogen MA lnc., lPR2015-01993
`
`‘51 l:~|_1ln gar
`__|'I i'-.
`5?! 727277822
`L
`
`U
`
`-
`
`Paper 63
`Enlered: March 2 | . 2017
`'ilkl‘nlifi.U-"\..
`
`We find the degree of efficacy of the 480 mg/day dose of DMF would have
`
`
`
`
`been unexpected.
`HAY'MAN OFFSHORE MANAGE
`HAYMAN INVESTMENTS. LLC;
`NXN PARTNERS. LLC:
`IP NAVIGATION GROUP. LLC:
`
`"
`
`.
`
`We conclude, therefore, that the treatment of MS patients with 480 mg/day of
`
`DMF would not have been obvious.
`
`Before RICHARD E. SCHAFER. SALLY GARDNER-LANE. and
`DEBORAH KATZ, Administrative PatenrJudges.
`SCHAFER, Administrative Parent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. §1l3(a) and 3'! CFR. § 42.73
`
`Bingen Exhibit 2038
`Mylan v. Binge.
`Page 1 at 29 “RIMS-01403
`
`
`
`
`
`Demonstrative Exhibits—Not Evidence
`
`2
`
`

`

`Dr. Duddy’s Contemporaneous Perception
`
`September 2009 (Only Phase II Results Published)
`
`Where will they all fit?
`
`0 mitoxantrone
`
`<> Tysabri
`<> fingolimod
`<> cladribine
`
`
`
`
`<> Campath
`
`
`
`
`<>
`
`teriflunamid
`
`Avone2><><l§ebif
`
`
`
`efficacy
`
`Copaxone
`
`Betaferon/Extavia
`
`
`
`
`disclaimer: to no scientific scale
`
`and based on pure guess-mam
`
`
`
` .~ tget’*i Demonstrative Exhibits — Not Evidence
`
`3
`
`

`

`Dr. Duddy’s Contemporaneous Change of Perception November 2011 (After Phase III Results Known)
`
`laquinimod
`
` O teriflunamide
`
` x‘" “ 7f“ ’1‘ Demonstrative Exhibits— Not Evidence
`
`
`
`4
`
`Where will they all fit?
` <> mitoxantrone
`
`<> Campath <> Tysabri
`
`
`
`
`<>
`
`Avonex ORebif
`
`<><><>
`
`Copaxone
`Betaferon/Extavia
`
`
`
`
` ditclaIMen' to no scienafic scale
`
`O fingolimod
`
`efficacy
`
`

`

`Dr. Duddy’s Contemporaneous Change of Perception
`
`Declaration of Biogen’s Expert Dr. Duddy:
`
`given the modest magnitude of the effect in the Phase II study”
`
`“My perception of BG-12 completely and unexpectedly shifted
`
`when Biogen released the results of its Phase III trials. In November
`
`2011, I reworked that same slide, moving BG-12 into the lower right-
`hand quadrant reflecting the strongest overall performance (higher
`efficacy, lower risk)
`I recall being surprised at that time at the high
`level of reduction in relapse rate and the strength of the MRI results
`
`Ex. 2058 (Dr. Duddy),1I177
`
`POR, 52—53; Sur—reply, 19
`
`

`

`Unexpected Results - Magnitude of Efficacy
`
`Declaration of Biogen’s Expert Dr. Thisted:
`
`mg/day) produces virtually no additional therapeutic benefit.”
`
`“Both the DEFINE and CONFIRM studies show that the therapeutic
`effects on brain lesions at 480 mg/day are essentially the same as those
`seen at 720 mg/day. It is stunning and unexpected to see, in two
`large independent studies, that increasing an ineffective dose (360
`mg/day) by a small amount (120 mg/day) produces a strong
`
`therapeutic effect, and that a further, larger dose increase (to 720
`
`Ex. 2060 (Dr. Thisted), 11100
`
`POR 3, 51; Sur—reply, 17-18
`
`

`

`Unpredictability & Failures in the Art Wiendl (2002):
`
`lHERAP‘l REVIEW
`
`
`
`Therapeutic Approaches in Multiple Sclerosis
`
`
`Lessons from Failed and Interrupted Treatment Trials
`Therapeutic Approaches in Mult'
`
`Lessons from Failed and Interrupted Treatment T .
`
`
`
`
`
`
`
`
`
`
`
`
`
`murmur
`
`
`.
`
`
`
`.....
`
`“However, in contrast to the successfully introduced
`and established immunomodulatory therapies (e.g.
`interferon-B and glatiramer acetate), there have been a
`remarkable number of therapeutic failures as well.
`Despite convincing immunological concepts,
`impressive data from animal models and promising
`
`
`results from phase [/11 studies, the drugs and strategies
`
`
`investigated showed no benefit or even turned out to
`
`
`have unexpectedly severe adverse eflects.”
`
` Pngel one
`
`131“ “mug".
`[PR zone-01403
`
`.
`'
`
`,-—
`
`s,
`
`'5'"
`
`,-
`-.;-
`
`:v-"-'~';
`'-
`
`-
`
`y
`
`
`
`) Biogen. DemmsbafiveExhibits—Novabence
`
`7
`
`

`

`Unpredictability & Failures in the Art
`
`Ulzheimer (2010):
`
`Therapeutic Approaches to Multiple Sclerosis
`An Update on Failed, Interrupted, or Inconclusive Trials of Immunomodulatory
`Therapeutic Approaches t Treatment Strategies
`An Updale cm Failed, Interrupted, or Inco-
`Trealment Strategies
`
`expected or unexpectedly severe adverse effects.
`
`There is a tremendous activity in
`the search for new therapeutics,“~21 which is reflected by the
`
`soaring number of publications. However, one has to realisti-
`
`cally concede that few successful agents in MS stand apart from
`a large number of therapeutic disappointments.[3'5] Despite
`
`rational pathophysiologic concepts, conclusive data from
`
`animal models, promising phase l/II studies, and successful
`
`application in other autoimmune diseases, several trials testing
`
`new compounds in MS patients have shown no benefit. On the
`
`other hand, some effective treatments are associated with un—
`
`’ Biogen. DemmsbafiveErIublb-NotEI/Ib’enae
`
`'
`
`8
`
`

`

`Unexpected Results - Magnitude of Efficacy
`
`Testimony of Biogen’s Expert Dr. Wynn:
`
`Cl:
`
`[Y]ou did not think that 480 milligrams would work, correct?
`
`A:
`
`It certainly wasn’t my invention,
`
`
`
`.
`
`I
`
`wouldn’t have expected the 720 dose in the CONFIRM and DEFINE
`
`trial to show the results it did even at 720 milligrams, it seemed to
`
`
`outperform the Phase II trial. Phase III, and
`
`
`
`Demonstrative Exhibits — Not Evidence
`
`9
`
`

`

`Pent-Up Demand in Anticipation of Tecfidera® Launch
`
`Japan Shiflins
`
`[BMW mm
`
`min “Milli;
`
`New York Times, April 1, 2013:
`
`
`
`efficacy and safety, doctors and Wall Street analysts say. Some patients are
`
`“mumm-
`‘ mwmm '
`
`,
`
`. an
`
`The drug, which will be sold by Biogen Idec under the brand name
`
`Tecfidera, is expected to be a blockbuster. It is only the third oral treatmen i.
`
`to be approved for the disease, and it offers a tantalizing combination of
`
`said to have been delaying treatment until Tecfidera is available.
`
`mi.
`
`'
`
`up.
`
`-u‘Il-l‘va-fllhlnmr‘LMMW-P'”
`
`Modern Slals Bring WAR l madcast Boolh (B.A.B.I.P.. Too]
`
`9L"
`
`
`
`Ex. 2006, 5, 11
`
`POR, 58. 61
`
`

`

`
`
`ORAL MULTIPLE SCLEROSIS THERAPIES
`
`SHARE OF ESTIMATED TOTAL U.S. DAILY RECOMMENDED DOSES
`
`
`Tecfidera® Rapidly Overtook Its Oral MS Competitors
`
`
`Q3 2010 - Q4 2018
`
`nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn o n
`
`
`
`ShiteofEstimatedTotalUS.DailyRecommendedDoses
`
`
`
`
`
`
`03040102030401QEQ3WQIQZQ3Q4Q1020304QIQZQ3Q4QIQZQ3Q4010203Q40102Q3Q4
`
`2010
`Ion
`ZIIIZ
`2013
`2014
`ZOIS
`2016
`2017
`2018
`
`
`—Tocfidaa
`Gilcnya mm Aubagio
`
`
`Notes 8:. Sources:
`
`
`From Appendix 15.
`
`
` .iogen Demonstrative Exhibits—Not Evidence
`
`11
`
`

`

`Tecfidera® Market Share Leads All MS Drugs
`
`MULTIPLE SCLEROSIS THERAPIES
`
`SHARE OF 115. SALES
`
`Q1 2009 - Q4 21118
`
`
`
`ShareofUS.Sala
`
`
` 0% --"'
`
`QIQZQ3Q401020304Q|020304010203in02030401020304010203040| 02030401Q20304010203Q4
`2009
`2010
`2011
`2012
`2013
`2014
`2015
`2016
`2017
`2013
`
`
`—Tocfidcra
`"III- Gilmya
`“can MWO - - Avonex
`II-H-I Copaxone —-Rcbif — «Du-nus
`-
`Tysabri
`
`
`
`Notes & Sources:
`
`
`From Appendix 6.
`
`
`Dues not display drugs with less than $250 million in sales in Q4 2018. Drug; excluded under this criterion are Betasumn‘ Extends, Glatiramcr acetate, 61810138.,
`Plegridy. Lama-ads, Mitoxantmne, and Novantmnc. See Appendix 21
`
`
`’3@an Demonstrative Exhibits—Not Evidence
`
`12
`
`

`

`Dr. Hay’s Independent Economic Analysis
`
`Admissions of Petitioner’s Dr. Hay in Previous Testimony:
`
`
`A: “_ has been a relatively_ oral MS drug with -
`—, less than 2 years after its launch, despite
`directly competing with Gilenya and other MS drugs. Since its launch
`in 2012, Tecfidera has been— from
`Gilenya as doctors and patients understand that—
`
`
`'
`
`Q: And for the first point about the annual sales, you rely on public data
`from IMS; correct?
`
`A: Right. Which doesn’t adjust for the confidential rebates and discounts
`
`Demonstrative Exhibits—Not Evidence
`
`13
`
`

`

`Dr. Hay’s Independent Economic Analysis
`
`Admissions of Petitioner’s Dr. Hay from His Own Publication:
`
`A:
`
`“Dimethyl fumarate dominated all other therapies over the range of
`willingness-to-pays from $0 to $180,000 per QALY [Quality Adjusted
`
`Life Year].”
`
`***
`
`Q: What does “dominated” mean in that sentence?
`
`A:
`
`It means it has better outcomes. So—
`_ based on the
`information we had, which is all public. We didn’t have any private
`information. So it has better outcomes and lower cost, and for a health
`
`economist that’s ideal. You don’t have to struggle with a decision to
`adopt a drug that reduces your cost and produces better outcomes for
`your patients.— You do them-
`
`Demonstrative Exhibits — Not Evidence
`
`14
`
`

`

`’376 Patent Could Not Have Prevented Others From
`
`Developing DMF in Other Forms for MS
`
`
`
`the ormu a
`
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`
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`
`.loshl cl a].
`(as) Date of Patent:
`Jan. 2!. 2003
`
`ornomprising one or more dialkyl
`arates o
`
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` 1:7: i. Demonstrative Exhibits — Not Evidence
`
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`
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`'
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`
`

`

`Unexpected Results - Magnitude of Efficacy
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 204063
`
`W"
`
`Submit Date 2-27-2012
`
`FDA Clinical Review
`
`. of the 240 mg bid dose only.
`
`_' — studied in these efficacy trials, BG-12 240 mg bid and
`- 240 mg tid,— on the primary endpoints
`and all key secondary endpoints. Since the 240 mg tid dose offered
`‘ no additional efficacy to the 240 mg bid dose, I recommend approval
`
`
`
`Intended Population Relapsing [arms of Multiple
`Sderosis
`
`Rm ID‘ 5214415
`
`Biogen Exhibit ZIIIIJ
`Mylnn v. Biogen
`[Plums-mos
`Binge]: Em‘hit 2572
`Bing!!! MA, Inc. 7. Forward. Hanna AIS
`lnkflimmmmmm06,023
`
`
`Page I of 1 l4
`
`L 1:; i. Demonstrative Exhibits — Not Evidence
`
`16
`
`

`

`Unexpected Results - Magnitude of Efficacy
`
`0['UEIUI'EAN |\‘.Ll‘.‘|Q.\'E Q
`
`-- ‘E\-E ma:
`
`-.
`
`‘xCii'NCY
`---
`rI
`
`EMA Assessment Report
`
`Table 24.
`
`Maintenance of the eflect
`
`—— -
`
`The percentage reduction and 95% CI in the annualized relapse rate by
`6-month interval for BG00012 BID compared to placebo are presented in
`
`
`
`MYLAN PHARMS. INC. EXHIBIT I037 PAGE 1
`
`:1
`
`j‘ Demonstrative Exhibits — Not Evidence
`
`17
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`
`
`!' "AL
`
`May 2006 Press Release
`
`'
`
`’ ' The results of the 120 mg and 360 mg BG-12 treated
`groups were not statistically significant versus placebo.
`
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`
`
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Admissions of Petitioner’s Dr. Greenberg:
`
`Q:
`
`In Exhibit 2224, your article in 2008 Where you reference Phase II data
`
`for BG12, there is nothing to indicate that you looked for or found
`
`baseline imbalances in Gd lesions; correct?
`
`A: And so it’s not called out in this paper, no.
`
`Demonstrative Exhibits — Not Evidence
`
`19
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Testimony of Biogen’s Expert Dr. Duddy:
`
`Q: So you disagree with Drs. Fox, Gold, Ruddick, and Cohen; correct?
`
`A:
`
`i
`
`I see it as a potential—— of trying to
`explain away why the Phase II study showed no effect before the 720
`dose and that the Phase III study showed an effect at 480 and 720.
`
`: ;.
`
`f: a
`
`I“. Demonstrative Exhibits — Not Evidence
`
`20
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Declaration of Biogen’s Expert Dr. Wynn:
`
`found.”
`
`“. .. However, post hoc analyses amount to data hunting—hindsight
`attempts to create positive outcomes from negative trials. Post hoc
`analyses would never be accepted to make a negative study
`positive. On the contrary, post hoc analyses are used by skilled artisans
`only to make a positive study negative should unaccounted variables be
`
`Ex. 2061 (Dr. Wynn), 1165
`
`POR, 31, 35; Sur—reply, 10, 13
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Declaration of Biogen’s Expert Dr. Thisted:
`
`“Performing additional analyses post hoc based on a review of
`unblinded data—
`
`_ because such analyses—2111d
`may therefore_. Conducting analyses that are
`motivated by the data (i. e. ,viewing the data and using the same data
`both to decide which after-the-fact analyses might produce favorable
`results and to carry out those analyses), rather than tested by the
`original study design and resulting data, is—
`
`
`
`
`: ;.
`
`f: a
`
`I“. Demonstrative Exhibits — Not Evidence
`
`22
`
`

`

`Petitioner s Post Hoc (Hindsight) Arguments
`
`"I New taunt“) iul'INAI r' ulnlclu:
`
`
`SPECIAL REPORT
`
`Statistics in Medicine— Reporting ofSubgroup
`Analyses in Clinical
`
`-
`
`2199
`
`
`
`
`
`Wang (2007):
`
`
`
`
`Post hoc analy-
`
`Medical research relies on rltnirai trials. H) as
`(primary
`ms therapeutic henet‘nt. Because nt' the «Ten etarntned
`
`
`and met involved in [llt'u‘ studies investigators
`ind s-urv‘
`frequently use analyses (II subgroups- (II stud: gimp:
`
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`
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`
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`
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`
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`
`
`sulcluue “4.“.st;
`
`ANn IELAI’ID [ONCIPYS
`cern because it is often unclear how many were
`
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`MM :"3: undertaken and whether some were motivated by
`lye“: lb; .
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`the levels -
`_
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`A mbgmup analysis is antennae; undertaken nary is sometimes Ember elassified ad liking ei-
`m assess tteatimnt efl'ms int .2 specific patient
`titer WNIIHIIWFOC qualitative. In the first case.
`characteristic, this assessment is often listed as me "film! is always better than the ofltel, hit
`a military at secondary and? memes Fnr Him by Various degrees. whereas in the second case.
`
`pie. Sacks et al.‘ conducted a planetao-mntroiled one Itexrncnt '5 better than the other not one sub—
`ttiai m Whlth the reduction in the incidence of group at patients and Wurst! than the other far
`
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`
` Demonstrative Exhibits — Not Evidence
`
`23
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments Treating Individuals 2
`
`-
`
`I
`I
`
`
`
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`A
`
`
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`Subgroup analysis in randomised controlled trials:
`importance, indications. and interpretation
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`Page 1 «I'll
`Myln v. Bing“
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`I
`
`
`
`
`
`
`
`-
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`
`
`
`
`
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`
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`
` Demonstrative Exhibits — Not Evidence
`
`24
`
`

`

`Benet “Normalized" Lesion Counts
`(Total new Gd+ lesions - Baseline Gd+ lesions)
`
`Benel “Normalized" Lesion Counts
`(Per-scan new Gd+ lesions - Baseline Gd+ lesions)
`
`“Dr. Benet’s Subtraction Analysis Is Also Highly Arbitrary”
`
`
`
`. Declaration of Biogen’s Expert Dr. Thisted:
`
`The particular calculations and adjustments included in Dr. Benet’s
`declaration thus appear to have been selected based on the outcomes
`they produce—exactly the weakness ofpost hoc analyses .
`.
`.
`
` Demonstrative Exhibits—Not Evidence
`
`25
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Admissions of Petitioner’s Dr. McKeague:
`
`A: Yeah, the - - that’s - - that’s correct essentially.
`
`Q: And percent reduction relative to baseline, that’s not one of the primary
`
`endpoints of the original Kappos study. Correct?
`
`Admissions of Petitioner’s Dr. Benet:
`
`Q: And what physically is being measured or what physically does the
`subtraction that you did correspond to?
`
`A: Nothing.
`
`Demonstrative Exhibits—Not Evidence
`
`26
`
`

`

`
`
`Demonstrative Exhibits — Not Evidence
`
`POR, 32 27
`
`

`

`Different Patient Populations
`
`New Gd+ Lesions (Weeks 12 to 24)
`Pre-Specified Primary End Point
`
`l
`
` Baseline Patient Characteristics
`
` Treatment Group
`
`69%
`
`120m-qd
`120 mtid
`
`Placebo
`
`Placebo
`
`120 mg qd
`
`120 mg tid
`
`240 mg tid
`
`Treatment Group
`
`1:
`
`.
`
`Blogen Demonstrative Exhibits — Not Evidence
`
`

`

`Petitioner’s Post Hoc (Hindsight) Arguments
`
`Declaration of Biogen’s Expert Dr. Thisted:
`
`
`
`
`
`—- Even one or two
`outliers having between 20-70 baseline Gd+ lesions in the 360 mg/day
`
`group compared to the other groups could account for the entire difference
`
`in mean values. The likely existence of an outlier is indicated by the size of ‘
`the standard deviation reported for the 360 mg/day group, which is three
`times as great as for the placebo group.”
`
`Demonstrative Exhibits — Not Evidence
`
`29
`
`

`

`Dr. Hay’s Cross-Examination — Expectations in 2007
`
`Admissions of Petitioner’s Dr. Hay:
`
`only modest market sales."
`
`Q: There's a heading "What factors are constraining the mark[et] for
`
`multiple sclerosis therapies." Can you read that first bullet into the
`
`record so I can ask you about it.
`
`"Despite experts' demand for agents that are more efficacious at
`
`delaying disease progression, the majority of MS agents that we expect
`to launch during [our] study period have yet to demonstrate significant
`improvement in efficacy over most current therapies. As a result, most
`
`emerging therapies will capture limited patient shares and garner
`
`4? What do you understand that to mean?
`
`P?
`
`That they don't think that the new drugs -- and keep in mind that they
`are writing this in 2007, so this is before the launch of -- certainly
`before the launch of Tecfidera. I think it's before the launch of
`
`Gilenya and Aubagio.
`
`F Biogen. Demonstrative Exhibits— NotEvidence
`
`30
`
`

`

`Dr. Hay’s Cross-Examination — Expectations in 2007
`
`Admissions of Petitioner’s Dr. Hay:
`
`Q:
`
`In the conclusion they have in 2007 in Exhibit 2210 that "most
`
`several years later after these drugs launched.
`
`emerging therapies will capture limited patient shares and only garner
`modest market sales," that's contrary to what you actually found in
`2014 and 2015; correct?
`
`: Yeah, I think it -- it isn't consistent with what we saw, you know,
`
`Ex. 2230 (Dr. Hay), 119:22-120:7
`
`Reply ISO Mot. Exclude, 2
`
`

`

`
`
`Declaration of Biogen’s Expert Dr. Wynn:
`
`“Disease modification is the key treatment objective for the MS field,
`because—. . .-
`Lengthening the amount of time an individual with MS can work,
`participate in daily activities, maintain social roles, and remain
`independent is important to every MS patient, and to society at
`
`—
`
`'
`
`large. . ..”
`
`***
`
`“[O]nce a patient has MS disease activity, brain damage has already
`occurred.”
`
`Demonstrative Exhibits—Not Evidence
`
`32
`
`

`

`Difficulties of Treating MS
`
`Declaration of Biogen’s Expert Dr. Wynn:
`
`° “For disease-modifying treatments for MS such as DMF, individual
`
`dose titration to determine the optimal effective dose for individual
`patients is not possible because—within
`an individual patient.”
`
`e “[B]ecause the disease course is uncertain and not always observable to
`
`the patient or physician,—
`—, which compare the
`average response of the treated group to the average response of the
`_to determine efficacy.”
`
`‘
`
`e “Given the particular nature of MS and the—
`—, physicians cannot, and do not, dose-titrate disease-
`modifying therapy to treat an individual MS patient.”
`
`’ -
`
`.
`
`' _'
`
`Demonstrative Exhibits — NotEvidence
`
`33
`
`

`

`Published Interview of Petitioner’s Dr. Corboy - Efficacy
`
`toflfocus
`
`Fresh ”preaches
`t© MS Ca re
`
`N W
`
`m l
`
`Q&A with Dr. Corboy (2013)
`
`
`
`Q. What factors (insurance coverage/costs, convenience,
`trial data. experience) would you say are mos: relevant to
`
`you in your therapeutic decision-making?
`—. Risk. Compliance (convenience
`and side effeccs). Insurance/c055 never play a role in philo‘
`" sophical choice, but often play a praCtical role in what we can
`attually get for the patient.
`
` I'P'R 2m 84" 403
`
`
`
` Demonstrative Exhibits — Not Evidence
`
`34
`
`

`

`Dr. Brundage’s Testimony - Side Effects
`
`Testimony of Biogen’s Expert Dr. Brundage:
`
`Q: Okay. And so you wouldn't want to give a high dose that would cause
`
`too many adverse events; correct?
`
`walking and stay out of wheelchairs.
`
`A: That is a relative statement that I cannot agree with. When you're
`
`facing the consequences of MS, you may be quite willing to tolerate
`
`a higher frequency of some side effects for the ability to keep
`
`Ex. 1131 (Dr. Brundage), 95:8-17
`
`Sur—reply, 9-10
`
`

`

`Temporary Side Effects
`
`Sclerosis
`
`CLINICAL:E
`
`Schimrigk 2004:
`
`Mild to moderate gastrointestinal discomfort was initially
`
` Multiple
`
`
`
`
`experienced by 6 of 7 patients, but decreased gradually during
`
`the first 6 weeks of treatment in all patients. All other side
`
`effects were generally mild and transient.
`
`cDDDDD
`Journals
`RC
`13"?
`.M35
`
`Ex. 1006 5
`’
`
`POR, 24; Sur-reply, 6
`
`

`

`Temporary Side Effects
`
`Declaration of Biogen’s Expert Dr. Wynn:
`
`“[T]he results of Biogen’s Phase II study disclosed in the Kappos 2006
`
`Slides demonstrated that 720 mg/day of DMF was well-tolerated and,
`in fact would have motivated a skilled artisan to seek potentially
`higher-efficacy doses. Ex. 1046 at 25-27. Accordingly, in my opinion,
`one of ordinary skill would not have been motivated to optimize the
`dose of DMF to 480 mg/day given the relative tolerability associated
`
`with fumarate administration.”
`
`Ex. 2061 (Dr. Wynn) 1189
`
`FOR, 24
`
`

`

`Similar Side Effects Across All Doses
`
`Declaration of Biogen’s Expert Dr. Duddy:
`
`below 720 mg/day at all. (Ex. 1046 at 24.)”
`
`“. . .There were also the same number of serious adverse events for the 720
`
`mg/day and 360 mg/day dose groups, both of which had fewer serious
`adverse events than the non-treatment (placebo) group, indicating that one
`would not have expected to improve on side effects by lowering the dose
`
`Ex. 2058 (Dr. Duddy), 1197
`
`Serious Adverse Events
`
`Treatment Group
`
`Placebo
`n=65
`
`120 mg qd
`n=64
`
`120 mg tid
`n=64
`
`240 mg tid
`n=63
`
`otaISAE
`
`8(12)
`
`4 (6)
`
`Infections
`
`Neoplasm
`
`CNS (MS)
`
`Ear
`
`Vascular
`
`GI
`
`Renal
`Injury
`
`0
`
`1 (2)
`
`5(8)
`
`1 (2)
`
`0
`
`O
`
`O
`1 (2)
`
`O
`
`O
`
`4(6)
`
`0
`
`0
`
`0
`
`0
`0
`
`7(11)
`
`1 (2)
`
`0
`
`6 (9)
`
`0
`
`1(2)
`
`O
`
`0
`0
`
`7 11
`
`D
`
`0
`
`5 (8)
`
`0
`
`0
`
`1 (2)
`
`1 (2)
`0
`
`Ex- 1046! 24
`
`POR. 39
`
`

`

`Similar Side Effects Across All Doses
`
`Dalmatian]: {iii Humans km” I}: Dudm
`
`
`
`Ex.1046,18
`
`POR. 39
`
`

`

`Dr. Duddy’s Testimony - W0 ’342
`
`Testimony of Biogen’s Expert Dr. Duddy:
`
`range, none of which is linked to any fumarate or multiple sclerosis.
`
`A: With [the knowledge that DMF monotherapy effectively treated
`MS from Biogen’s Phase II studies] that in my head, I come to '342,
`and I find a long list of diseases with nothing pointing me towards
`multiple sclerosis. I find a long list of fumarates, none of which is
`specifically linked to multiple sclerosis, and I find a massive dose
`
`Ex. 1125 (Dr. Duddy), 174:14-175:1o
`
`Sur—reply, 16
`
`

`

`W0 ’342 - Biogen MA Inc. v. Forward Pharma A/S (PTAB 2017)
`
`
`
`.' llFi-Z
`3:!Nilll.‘lic.1ilt’
`Entered: March 31, 20]?
`Tel: 571-2724n83
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENTTRIAL AND APPEAL BOARD
`
`
`BIOGEN MA INC.
`Junior Party Patent 8399.5” 32,
`V.
`
`
`
`
`
`FORWARD PHARMA NS
`Senior Party Application 1 11'57637I.
`
`
`
`
`
`There is no discussion that would guide one
`
`: skilled in the art to treat MS with a therapeutically effective dose of 480 rug/day, or
`
`
`
`\deIlLb-INH
`
`any other therapeutically effective doses Within the ranges disclosed.
`
`orwar ‘ arma s
`‘ pp icatlon
`u..
`e :
`app tea ion .
`
`
`
`Biogen's patenl was also the subject oflPRlOlS-Ol993.
`Biugen’s involved patent issued on March I9. 2013, Ex. 200111.]; I.
`Subsequently, on December 3. 20 | 3. F? filed an amndment in its application
`cancelling all its previously filed claims. adding claim substantially copied from
`Biogen’s patent and requesting an interference wilh the patent. Application
`
`Page I ol'30
`
`Binge- Exhibil 2030
`Mylln v. Biogen
`lPRZfllS—lllm
`
`.
`
`'
`
`'
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`
`I.
`'
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`
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`
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`
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`
`I
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`
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`
`II
`I
`
` Demonstrative Exhibits—Not Evidence
`
`41
`
`

`

`Psoriasis vs. Multiple Sclerosis
`
`Declaration of Biogen’s Expert Dr. Wynn:
`
`“Second, MS and psoriasis are very different diseases. Psoriasis
`
`manifests itself in the skin and can be treated intermittently. As a result,
`
`the dose for psoriasis can easily be titrated based on an observed
`improvement in skin lesions. In contrast, MS is largely a clinically
`silent disease, and once there are clinical manifestations, damage
`has already been done. Given the course of MS and the grave
`consequence of undertreatment, the dose for disease modifying
`therapies cannot be titrated to effect such as in blood pressure or
`psoriasis, and such therapies are not given intermittently. Moreover, a
`person of ordinary skill in the art would not have thought that a
`
`dose of one active ingredient to treat psoriasis would necessarily be
`
`effective given the different pathophysiologies.”
`
`)
`
`.
`Blogen. Demonstrative Exhibits— Not Evidence
`
`42
`
`

`

`Psoriasis vs. Multiple Sclerosis
`
`Admissions of Petitioner’s Dr. Benet:
`
`Q: The concentration at different sites within the body, the brain, the heart,
`
`the skin, they could be different for the same plasma concentration; is
`that correct?
`
`A: They are usually different.
`
`Q: And how variable can they be between different sites within the body
`even given a common plasma concentration?
`
`A: _-
`
`*u’n':
`
`Q: And could it also be a function of the disease state?
`
`A: Could be a function of disease state, also, yes.
`
`Demonstrative Exhibits—Not Evidence
`
`43
`
`

`

`Psoriasis Drug Lenercept Made MS Worse
`
`TNF neutralization in MS
`
`Results of a randomized, placebo-controlled
`multicenter study
`
`The Lanna-cum. Muiliplu ‘
`
`An increase in the exacerbation rate was noted
`
`in lenercept-treated patients. This finding resulted in the
`
`sponsor’s decision to terminate the study and to release
`
`Ex. 2087, 459
` This finding suggests a final caution. An
`
`agent that demonstrates a beneficial effect in one
`autoimmune disease should not be presumed to have
`beneficial effects in another.
`
`I Mvhnv. Illegal
`m...
`
`'
`
`Ex. 2037, 464
`
`Ex. 2053.1135; POR, 32;, 4142,, 56-57
`
`

`

`Psoriasis vs. Multiple Sclerosis - Lenercept
`
`Declaration of Biogen’s Expert Dr. Duddy:
`
`“In fact, it was known in the art that drugs meant to shift the Th1/Th2 balance away from
`Th1 or Th1-type cytokines in favor of Th2 cytokines—
`_. In contrast, some of these drugs had a—
`
`
`
`v "-- a
`5'
`s."
`-
`‘
`lo 1.;
`.
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`m"
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`.
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`
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`
`“The results of reported clinical studies in human patients, however, demonstrated that
`3 '.I
`.
`
`.
`
`l
`
`‘
`
`‘
`
`“Based on this collection of data, a person of ordinary skill in the art would have
`recognized that statements such as those in Schimrigk 2004 and ClinicalTrials regarding
`the— to be just that—_ and
`
`potentially interesting for future investigation.—
`
`Demonstrative Exhibits—Not Evidence
`
`45
`
`

`

`Fumaderm® Is a Combination of Four Active Fumarates
`
`Summary of Product Characteristics
`
`
`Fumaderm® Initial
`
`
`
`
`Fumaderm® Initial
`Fumaderm®
`
`
`‘ll
`
`Nlm oflflo Inldldllll product
`Puma-on Inlfiu
`
`
`Fumaderm®
`Farr-dorm
`
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`than
`
`
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`
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`
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`
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`
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`
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`
`
`1.
`
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