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IN THE UNITED STATES DISTRICT COURTFOR THE DISTRICT OF MASSSACHUSETTS

)ZOGENIX, INC., )

)Plaintiff, )

)v. ) Civil Action No. 1:14-cv-11689

)DEVAL PATRICK, in his official capacity as )GOVERNOR OF THE COMMONWEALTH OF )MASSACHUSETTS, )

)and )

)CHERYL BARTLETT, RN, )in her official capacity as )DEPARTMENT OF PUBLIC HEALTH )COMMISSIONER, )

)and )

)CANDACE LAPIDUS SLOANE, M.D., )KATHLEEN SULLIVAN MEYER, ESQ., )MARIANNE E. FELICE, M.D., )ROBIN RICHMAN, M.D., )PAUL R. DeRENSIS, ESQ., )MICHAEL E. HENRY, M.D., in their official )capacities as members of the MASSACHUSETTS )BOARD OF REGISTRATION IN MEDICINE, )

))

Defendants. ))

SECOND SUPPLEMENTAL MEMORANDUM OF PLAINTIFF ZOGENIX, INC.REGARDING REGULATORY LANDSCAPE

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Pursuant to the Courts request at the December 3, 2014 motion hearing, Plaintiff

Zogenix, Inc. respectfully notifies the Court of the following developments relevant to the status

of this proceeding:

On January 30, 2015, the U.S. Food and Drug Administration (FDA) approved a new

formulation of Zohydro ER with BeadTek. Ex. 1 (FDA Supplement Approval). BeadTek is

a formulation technology designed to provide abuse-deterrent properties without changing the

release properties of hydrocodone when Zohydro ER is used as intended. Ex. 2 (Zogenix Press

Release). BeadTek incorporates pharmaceutical ingredients that immediately form a viscous gel

when crushed and dissolved in liquids or solvents. Id. These are the very same pharmaceutical

ingredients including polyethylene oxide contained in other abuse-deterrent opioid

formulations currently on the market, such as Hysingla, Oxycontin, Opana ER, Nucynta ER, and

Xartermis XL. FDA has approved new labeling for the new Zohydro ER formulation, which

(among other things) reflects the addition of polyethylene oxide and contains new language in

the Abuse section relating to the risks of parenteral abuse. Ex. 3 (Zohydro ER Labeling) at

11, 9.2. In addition, FDA has asked Zogenix to run the same Post-Marketing Requirement

(PMR) studies relating to excipient safety as the agency required of Purdue following approval

of its abuse-deterrent hydrocodone product, Hysingla. Zogenix intends to submit data regarding

the new formulation in the second half of 2015 in order to support an amended product label that

will include more explicit abuse-deterrent claims. Ex. 2.

As explained in briefs currently pending before the Court, the challenged regulations

apply to any hydrocodone-only extended release medication that is not in an abuse deterrent

form. 247 CMR 90.04(8); 243 CMR 2.07(25); 263 5.07(12). Massachusetts already had

crossed the line by unilaterally deeming Purdues drug Hysingla ER to be abuse deterrent even

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though not so labeled by FDA. While FDA has found that Hysingla ER has certain properties

that are expected to deter abuse, FDA has not yet found that the drug actually does deter abuse.

Ex. 4. For that reason, FDA has required Purdue to conduct studies to determine whether the

drug qualifies under FDA standards as abuse-deterrent. Ex. 5 (FDA has determined that you

are also required to conduct the following individual postmarketing studies of Hysingla ER

(hydrocodone bitartrate) extended-release tablets: 2808-2 Conduct epidemiologic

investigations to address whether the properties intended to deter misuse and abuse of Hysingla

ER (hydrocodone bitartrate extended-release tablets) actually result in a significant and

meaningful decrease in misuse and abuse, and their consequences, addiction, overdose, and

death, in the community. The post-marketing study program must allow FDA to assess the

impact, if any, that is attributable to the abuse-deterrent properties of Hysingla ER.).

Nonetheless, the Commonwealth unilaterally has decided to treat Hysingla as though it actually

is abuse-deterrent and therefore exempt from the challenged regulations.

Defendants decision to treat the new formulation of Zohydro ER differently only

underscores the arbitrary line-drawing that Defendants have engaged in when it comes to issues

of drug safety. Following FDA approval of the new formulation, Zogenix asked Defendants

whether they intended to recognize the new formulation of Zohydro ER as exempted from the

challenged regulations, just as they had done for Hysingla. Ex. 6. Defendants responded by

asking for detailed information about the drug and its approval process so that they could either

try to glean FDAs views on the extent of the drugs abuse deterrence or, even more alarmingly,

make their own determination as to whether the drug meets an unspecified Massachusetts

standard to qualify as being in adequate abuse deterrent form:

There does not appear to be any information available to us on the FDAwebsite relative to the new formulation/FDA approval except (as you

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recently indicated would be the case) that the approval does not permit anyclaims of abuse-deterrent properties on the label. Did the FDA form anyconclusion at all at this stage regarding abuse-deterrence? If so, wouldyou be able to supply that documentation to us? If not, was informationsubmitted to the FDA that could potentially demonstrate to our satisfaction(assuming you were willing to provide it to us) that the reformulated drugis, in fact, abuse-deterrent? Ex. 6.

This query and Defendants subsequent refusal to treat the new formulation as exempt

from the challenged regulations when Zogenix refused to supply the Commonwealth with

confidential information regarding its drug approval process before FDA only serves to

highlight that Defendants are engaging in preempted conduct by setting up their own separate

drug approval process in parallel to that undertaken by FDA, even going so far as making their

own unconstitutional determinations about the safety and abuse deterrence of an FDA-approved

drug. The Commonwealth cannot have it both ways: if the statute exempts drugs that contain

ingredients designed to deter abuse, the new formulation of Zohydro ER should be treated as

exempt. And if the Commonwealth intends to try to interpret FDA labeling decisions to

characterize a drug as abuse deterrent, Hysingla should not be treated as exempt.

Defendants effort to classify drugs as either abuse deterrent or not and then restrict

access to drugs accordingly even though FDA does not draw a bright line on this issue - is

preempted by federal law because it conflicts with FDAs careful regulatory scheme. Geier v.

Am. Honda Motor Co., Inc., 529 U.S. 861, 871 (2000) (state restrictionseven those that might

otherwise conceivably stand in harmony with federal lawmust fall where Congress intended

to avoid conflict, uncertainty, cost, and occasional risk to safety itself that too many different

safety-standard cooks might otherwise create.). And by steering physicians and patients away

from Zohydro ER toward a drug that more than twice the amount of hydrocodone -- even

though FDA has not determined that the new drug is abuse deterrent, let alone that it is safer than

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Zohydro ER the challenged regulations seek to supplant FDAs nuanced judgment about the

demonstrated safety and efficacy of approved drug products. The regulations therefore interfere

with FDAs safety determinations and its careful labeling scheme.

Meanwhile, the clock is ticking on Zohydro ERs three-year exclusivity period.

Zogenix respectfully requests that the Court deny the pending motion to dismiss and set a case

schedule, allowing several months for discovery followed by summary judgment briefing

deadlines.

* * *

For the foregoing reasons, as well as those previously presented, Defendants motion to

dismiss should be denied.

Dated: February 12, 2015 Respectfully Submitted,

/s/ Steven P. HollmanKenneth J. Parsigian (BBO # 550770)Steven J. Pacini (BBO # 676132)LATHAM & WATKINS LLPJohn Hancock Tower, 20th Floor200 Clarendon StreetBoston, MA 02116Tel: (617) 948-6000Fax: (617) 948-6001kenneth.parsigian@lw.comsteven.pacini@lw.com

HOGAN LOVELLS US LLPSteven P. Hollman (pro hac vice)Susan M. Cook (pro hac vice)555 Thirteenth Street, N.W.Washington, D.C. 20004(202) 637-5672 (Telephone)(202) 637-5910 (Fax)steven.hollman@hoganlovells.comsusan.cook@hoganlovells.com

Attorneys for Plaintiff Zogenix, Inc.

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CERTIFICATE OF SERVICE

I certify that the foregoing Second Supplemental Memorandum of Plaintiff Zogenix,Inc. Regarding Regulatory Landscape was filed through the ECF system on 12th day ofFebruary and will be sent electronically to the registered participants as identified on theNotice of Electronic Filing (NEF).

/s/ Steven P. Hollman

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