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`ATTACHMENT A
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`ATTACHMENT A
`JON CLARK DECLARATION
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`JON CLARK DECLARATION
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`

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`Case 1:18-cv-00303-RGA Document 15-1 Filed 04/17/18 Page 2 of 42 PageID #: 283
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`BAXTER HEALTHCARE CORPORATION,
`
`Plaintiff.
`
`v.
`
`HOSPIRA, INC. and ORION CORR,
`
`Defendants.
`
`
`
`Civil Action No. 18-303-RGA
`
`DECLARATION OF JON CLARK, M.S.
`
`I, Ion Clark, M.S.. declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`My name is Jon Clark, M.S., and I am an independent consultant with special
`
`expertise in Food and Drug Administration (“FDA") regulatory matters.
`
`2.
`
`Plaintiff Baxter Healthcare Corporation has retained me in connection with the
`
`above-captioned litigation. Specifically, I have been asked to generally explain the processes for
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`submitting and obtaining approval of a New Drug Application (“NBA") and Abbreviated New
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`Drug Application (“ANDA”), and the corresponding labeling requirements. Additionally, I have
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`been asked to detail the proceedings regarding carve-outs in generic labeling for dcxmedetomidine
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`hydrochloride injection.
`
`3.
`
`I am being paid for my work in this litigation at the rate of $500.00 per hour. plus
`
`reimbursement of reasonable direct expenses. My compensation is not dependent on the outcome
`
`of this litigation, and it is not based on the result of any issue in this litigation. I have no personal
`
`interest in this litigation.
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`
`
`

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`ll.
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`BACKGROUND AND QUALIFICATIONS
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`4.
`
`I received a Bachelor of Science degree in chemistry from the University of
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`Michigan in 1980. l subsequently received my Master of Science degree in chemistry fi'om Rutgers
`
`University in 1987. Upon completion of my Bachelor's degree, I worked as a chemist and, later, a
`
`senior chemist at Beecham Laboratories
`
`and Schering-Plough Research Institute, both
`
`simultaneous with my master's degree work. At Beecham and Schering-Plough, I specifically
`
`focused on drug manufacturing processes and synthesis.
`
`5.
`
`I have more than thirty-five years of experience in the pharmaceutical industry,
`
`with a specific focus on drug development. research and development processes, and chemistry
`manufacturing and controls (“CMC”) review. For more than twenty years, I worked at FDA;
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`including as Associate Director of Program Policy with the Office of Pharmaceutical Science,
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`where I
`
`led the development and implementation of CMC policy for the Center for Drug
`
`Evaluation and Research. I also served as a Review Chemist and Electronic Submission Expert.
`
`6.
`
`As part of my more than twenty years of experience at FDA, I reviewed more than
`
`200 market applications (including NDAS and AN DAs'), over 500 supplements. and over 700 drug
`
`master files (“DMFS”). During my tenure at FDA. 1 also held several leadership roles with respect
`
`to stability guidelines for both ANDAS and NDAs.
`
`7.
`
`My expertise in labeling requirements and carve-outs was developed as part of my
`
`role as Associate Director of Program Policy and GMP at FDA- A complete understanding of the
`
`policies and practices of each program area subordinate to the Office of Pharmaceutical Science
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`was required to perform my role, and the Office of Generic Drugs (“OGD") is one of those
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`subordinate program areas. These requirements were practiced on a routine basis at OGD with
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`

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`periodic consultation at the Office of Pharmaceutical Science level. These consultations were
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`generally done with my participation.
`
`8.
`
`Since leaving FDA in 2013, l have served as Vice President of Chemical Medicines
`
`and Industry Standards Collaboration at US Pharmacopeia. U.S. Phannacopeia (“USP”) is a
`
`scientific nouprofit organization that sets standards for the identity, strength, quality, and purity of
`
`medicines, food ingredients, and dietary supplements manufactured, distributed, and cousumed
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`worldwide. I also currently serve as a consultant for NBA Partners, LLC, a global strategy firm
`
`specializing in product development and regulatory advice.
`
`III.
`
`NEW DRUG APPLICATION
`
`9.
`
`A person who wants to market a new drug must first submit, and obtain
`
`approval of, an application under the Federal Food, Drug, and Cosmetic Act (the "‘Act"). An
`
`application for a novel product is a New Drug Application (“NBA”). An NDA is submitted
`
`under section 50503) of the Act.
`
`10.
`
`An NDA contains, among other components, extensive scientific data and
`
`information regarding the safety and effectiveness of the drug for the conditions of use set
`
`forth in the label for which approval is sought.
`
`1 1.
`
`One of the required components of an NBA is a list of patents covering the drug
`
`product and the active drug substance ofthe product. in addition, any patent claiming a method
`
`of use for the drug product described in the NDA is also required to be listed.
`
`12.
`
`FDA is required to publish patent information submitted for approved NDAs. FDA
`
`does this in a publication titled Approved Drug Products with Therapeutic Equivalence
`
`Evaluations (the “Orange Book"). For the last several years, the Orange Book is a searchable
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`database accessible on the internet.
`
`U)
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`
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`

`

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`13.
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`After approval of an NDA, when listing a patent claiming a method of use, the
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`NDA holder must include a description of that method of use, as required for publication. See
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`21 CPR. § 314.53(c)(2)(0). This description appears in the Orange Book electronic database
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`as a link from the listing for the relevant patent. This description is commonly referred to as
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`a “use code.”
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`IV.
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`ABBREVLATED NEW DRUG APPLICATION
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`14.
`
`A drug product approved under section 505 ofthe Act is known as a listed drug.
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`See 21 CPR. § 314.3(1)). The Act permits submission ofan abbreviated new drug application
`
`(“ANDA”) for approval of a generic versions of a listed drug. Unlike an NDA, which is
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`submitted under section 505(b) of the Act, an ANDA is submitted under section 5050) of the
`
`Act.
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`15.
`
`In its ANDA, an applicant must clearly identify the listed drug on which it relies
`
`for approval. This is referred to as the reference listed drug (“RLD”) for that ANDA. See 21
`
`C.F.R. § 314.3(b).
`
`16. When compared to the NDA process, the ANDA process reduces the time and
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`resources needed for approval. The principal means by which the ANDA process does this is
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`that the ANDA applicant relies on the FDA’s previous finding of safety and effectiveness for
`
`the RLD rather than requiring that the ANDA applicant independently demonstrate the safety
`
`and effectiveness of its proposed drug.
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`17.
`
`To successfully rely on the FDA’s earlier finding of safety and effectiveness of
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`the RID, an ANDA must show that the proposed generic product is the same as the RID in
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`many fundamental respects. These include active ingredient, dosage form, strength, and route
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`of administration. The ANDA applicant must also provide information showing that its
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`

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`proposed generic product is bioequivalent to the RLD. A generic drug and the RLD are
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`regarded as bioequivalent if the rate and extent of absorption of the drugs are not significantly
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`different. See 21 U.S.C. § 3550)(8)(B).
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`18.
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`Labeling of a generic is also expected to be the same as the labeling for the
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`RLD. with certain differences permitted, as discussed further below.
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`19- With respect to each patent listed in the Orange Book for the RLD, the ANDA
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`applicant generally must submit
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`to the FDA one of four certifications under section
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`5050)(2)(A)(vii) of the Act. The certification must state one of the following:
`
`a.
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`That the required patent information relating to such patent has not been
`
`b.
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`c.
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`filed (paragraph I certification);
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`That such patent has expired (paragraph II certification);
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`That the patent will expire on a particular date (paragraph III certificatiOn);
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`or
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`(1.
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`That such patent is invalid or will not be infringed by the drug for which
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`approval is being sought (paragraph IV certification).
`
`20.
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`If an applicant files a paragraph I or II certification to a particular patent. that
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`patent will not delay ANDA approval. If an applicant files a paragraph 111 certification to a
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`patent. the applicant agrees to wait until that patent has expired before seeking full approval
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`of its ANDA.
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`21.
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`If an ANDA applicant wants full approval of its ANDA before a listed patent
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`has expired by asserting the invaiidity or unenforceability of the patent andfor asserting that
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`its proposed product does not infringe the patent. the applicant must submit a paragraph IV
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`certification.
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`

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`22.
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`An applicant filing a paragraph IV certificatiou must also provide a notice to
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`the holder of the NDA for RLD, and the patent owner if different fiom the NDA holder. The
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`notice must state that the ANDA has been submitted and explain the factual and legal bases
`
`for the applicant's opinion that the patent is invalid or not infringed. See 21 U.S.C. §
`
`3550)(2)(B).
`
`23.
`
`For those patents listed for the RLD in the Orange Book at the time of the
`
`original submission of the ANDA, if the NDA holder or patent owner brings a patent
`
`infringement suit against the ANDA applicant within 45 days of the date the notice of the
`
`paragraph IV certification is received. the approval of the ANDA will he stayed for 30 months
`
`from the date the notice of the paragraph IV certification was received, unless prior to 30
`
`months a court issues a decision or dismisses the patent case, or the court otherwise orders a
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`longer or shorter period- See 21 U.S.C. § 3550)(5)(B)( iii).
`
`24. When the 30 months have expired, the paragraph IV patent(s) subject to the suit
`
`islare no longer a barrier to final ANDA approval, even if the patent litigation is ongoing.
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`Similarly, if the NDA holder or patent owner do not sue within 45 days of receipt of the
`
`paragraph IV notice, the paragraph IV patent(s) will not be a barrier to ANDA approval.
`
`V.
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`ANDA LABELING
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`25.
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`As mentioned above. certain iabeling differences between the RLD and a
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`generic drug are permitted. One permitted difference pertains to method-of—use patents listed
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`in the Orange Book for the RLD.
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`26.
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`The Act requires that an ANDA contain “information to show that the labeling
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`proposed for the new [generic] drug is the same as the labeling approved for the listed drug .
`
`.
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`. except for changes required because of differences approved under a petition filed under
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`

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`[section SOSU)(2)(C) of the Act] or because the new drug and the listed drug are produced or
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`distributed by different manufacturers." 21 U.S.C. § 3550)(2)(A)(v).
`
`2?.
`
`FDA regulations provide examples of permissible differences in labeling that
`
`may result because the generic drug product and listed drug are produced or distributed by
`
`different manufacturers. These
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`differences
`
`include
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`expiration
`
`date,
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`formulation,
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`bioavailability, or pharmacokinetics labeling revisions made to comply with current FDA
`
`labeling guidelines or other guidance, or omission of an indication or other aspect of labeling
`
`protected by patent or accorded exclusivity. See 21 CPR. § 314.94(a_)(8)(_iv).
`
`28.
`
`To approve an ANDA containing proposed labeling that omits information
`
`protected by patent or exclusivity. the FDA must determine that the "differences do not render
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`the proposed drug product less safe or effective than the listed drug for all remaining,
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`nonprotected conditions of use.” See 21 C.F.R. § 314.127(a)(7).
`
`29.
`
`If an ANDA applicant wishes to omit labeling pertaining to the use protected
`
`by a patent, the applicant generally may do so.
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`In such a case, the ANDA applicant, in lieu
`
`of one of the four certifications listed above, may submit a statement under section
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`505(j)(2)(A)(viii} of the Act (commonly refer to as a section viii statement) acknowledging
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`that a given method-of-use patent has been listed. but stating that the applicant is not seeking
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`approval for the method of use claimed in the patent.
`
`30.
`
`Omitting a protected method of use from generic labeling is commonly referred
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`to as “carving out” the method of use, and is typically accomplished by the redaction of
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`pertinent language in the labeling that discloses the protected use-
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`31.
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`If an ANDA applicant files a section viii statement, and the FDA approves the
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`“carved out" labeling, the patent claiming the protected method of use is not a barrier to
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`approval of the ANDA.
`
`32.
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`To be approved. a label must have at least one indication for use. This means
`
`that if a RLD has only one approved use, and that use is protected by a method of use patent.
`
`a generic applicant cannot successfully “carve out” the use from its label. Similarly, if a RLD
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`has two approved uses, and both are protected by patent, one approved use, but not both, could
`
`be carved out.
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`VI.
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`2014 PROCEEDINGS REGARDING USE OF A CARVE-OUT IN GENERIC
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`LABELING FOR DEXMEDETOMIDINE HYDROCHLORIDE INJECTION
`
`33.
`
`Precedex® is
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`the
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`brand
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`name
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`of
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`dexmcdetomidine
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`hydrochloride-
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`Dexmedetomidine is a sedative delivered by injection.
`
`34.
`
`FDA approved NDA 021038 for Precedex on December 17, 1999. Hospira, Inc. is
`
`the current holder of NBA 021038. When approved in 1999, only one form of Precedex was
`
`available: a concentrate that required dilution before administration.
`
`35.
`
`Two “ready to use" forms of Precedex were approved in supplements to NBA
`
`021038 in March 2013, and a third was approved in November 2014. The 2014 proceedings
`
`pertained to ANDAs citing the concentrate form of Precedex as the RLD.
`
`36.
`
`All four forms of Precedex share a common label. Precedex is approved for:
`
`a.
`
`Sedation of initially intubated and mechanically ventilated patients during
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`treatment in an intensive care setting. Administer Precedex by continuous
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`infusion not to exceed 24 hours.
`
`b.
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`Sedation of non-intubated patients prior to andi’or during surgical and other
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`procedures.
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`

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`37.
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`For ease of reference, the first indication is referred to as “ICU sedation,” and the
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`second as “Procedural sedation.”
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`38.
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`When Precedex was first approved in 1999, the only approved indication was ICU
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`sedation. That was the only indication for Precedex until the Procedural sedation indication was
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`approved on October 1?, 2008.
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`39.
`
`Based upon information from the proceedings, Sandoz Inc. submitted the first
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`ANDA for generic dexmedetomidine injection (ANDA 091465) on April 7, 2009. When FDA
`
`tentatively approved ANDA 091465 on March 15, 201 1, there were three unexpired patents listed
`
`for Precedex: U.S. Patent Nos. 5,344,840 (“the '840 patent"), 4,910,214 (“the ’214 patent”), and
`
`6,?16,867 (“the ’867 patent”). The ’840 patent expired on September 6, 201 1. and the ”214 patent
`
`expired on July 15, 2013. See, e.g., Exhibit 1, FDA Tentative Approval Letter of ANDA 091465
`
`(Mar. 15, 2011).
`
`40-
`
`A pediatric exclusivity period, during which the FDA could not approve an ANDA
`
`referencing Precedex, began upon expiratiou of the ’214 patent on July 15, 2013, and expired on
`
`January 15, 2014.
`
`41.
`
`After July 15. 2013, only one unexpired patent (the ”'86? patent) remained listed for
`
`the concentrate form of Precedex. The ”867 patent is a method-of-use patent and expires on March
`
`31, 2019. The ’86? patent is among the patents listed for the “ready to use” forms of Precedex. A
`
`pediatric exclusivity period, during which the FDA may not approve ANDAS referencing
`
`Precedex, will begin upon expiration of the ”863"f patent, and will expire on October 1, 2019.
`
`42.
`
`Hospira originally listed the ’86? patent in the Orange Book in May 2004 with a
`
`use code of Intensive care unit sedation.
`
`In November 2008, shortly after the FDA approved
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`Prcedex for Procedural sedation, Hospira listed U.S. Patent No. 5,344,840 (“the ”840 patent”), a
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`
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`

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`method-of-use patent with a use code of Sedation ofnon-intimatedpatients prior to and/or during
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`surgicai and other procedures. The '840 patent expired on September 6, 2011. See, e. g, Exhibit
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`2, FDA Decision Letter, at 2 (Aug. 14, 2014).
`
`43.
`
`Based upon information from the proceedings, at least two ANDAs were submitted
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`that did not contain a paragraph IV certification to the ’86? patent (as occurred in the Sandoz
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`ANDA). Instead, these ANDAS contained a section viii statement regarding the ’867 patent and
`
`contained proposed labeling that carved out the “ICU sedation” indication.
`
`44-
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`No change to the use code of the ’86? patent was made at the time of approval of
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`the Procedural sedation indication in connection with the ”840 patent in October 2008, nor at any
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`time after that until January 8, 20} 4. when, upon Hospira’s request, the use code for the ’ 867 patent
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`was amended from “Intensive care unit sedation” to “Intensive care unit sedation.
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`including
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`sedation ofnon-imubotedpotiems prior to and/or during surgical and other procedures,” Id.
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`45.
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`On January 15, 2014, a week after the change in the use code for the ’86? patent,
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`the FDA established a public docket in which it placed a letter it sent the same day to Hospira and
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`to all applicants who submitted ANDAs using Precedex as the RLD. The purpose of the letter was
`
`to obtain public comments from interested parties on some of the issues presented by the revised
`
`use code for the ”867' patent. In particular, the agency asked whether the “breadth" of the new use
`
`code might “foreclose” a permissible carve out, thereby preventing approval of an ANDA until
`
`after the “867 patent expires.
`
`46.
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`Initial continents were due on January 24, 2014, and reply comments were due on
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`January 3, 2014. Twenty-two comments were submitted from fourteen parties.
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`47.
`
`One of the commenters was Hospira. Hospira argued that “[b]ecause the use code
`
`overlaps with both indications, generic filers cannot carve out the first [ICU sedation] indication
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`10
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`and seek approval for only the second [Procedural sedation] indication." Docket No. FDA-2014-
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`N-0087. Hospira Submission, at 8 (Jan. 24, 2014). FDA rejected this argument.
`
`48.
`
`On August 18, 2014, FDA issued its decisiori in a letter addressed to NDA holder
`
`H05pira and ANDA applicants, and posted in the public docket. The FDA concluded that “ANDA
`
`sponsors for dexmedetomidine hydrochloride injection can submit a section viii statement and
`
`carve out references to ICU sedation under either Hospira’s original use code or its amended use
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`code without adding additional language.” This is true “regardless of whether the original use code
`
`or the revised use code applies,” so long as the ANDA “omits labeling that discloses the protected
`
`use.” Ex. 2, FDA Decision Letter, at 1, 14.
`
`49.
`
`FDA also explained how, in a 2008 citizen petition response involving the drug
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`repaglinide, it would allow a generic applicant to include a single broad indication “even though
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`the scope of the broad indication partially overlapped in substance with the method of use
`
`described by the use code .
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`.
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`. because the patented use described in the use code was not expressly
`
`disclosed in the labeling as carved out.“ Id. at 11.
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`50.
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`Additionally, on August 18. 2014, FDA approved two AN DAs that each contained
`
`a section viii statement with regard to the ’86? patent and provided labeling that carved out
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`language that disclosed the protected use.
`
`51.
`
`On August 19, 2014, Hospira filed a complaint and a motion for temporary
`
`restraining order andi’or preliminary injunction in the US. District Court for the District of
`
`Maryland to stay the FDA’s August 18 Decision Letter and rescind approval of the two ANDAs.
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`Hospira, Inc. et al. v. Sylvia Mathews Burwefl. e: at, Case No. GJH-14-02662 (D. Md).
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`11
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`52.
`
`Although a temporary restraining order was initially granted, it was reversed shortly
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`thereafter on September 5, 2014, when the court granted the FDA’s motion for summaryjudgment
`
`in an order accompanied by a memorandum opinion. 1d.
`
`53.
`
`Hospira appealed the summary judgment order, but on October 28, 2014, the parties
`
`entered into a settlement agreement and concluded the matter. Under the settlement, according to
`
`Hospira's filing with the SEC, the two parties agreed that generic products could continue their
`
`sales under the carved-out label until near the end of the first quarter of 2015, after which sales
`
`may continue under either the carved-out label or a “full
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`label.” SEC filing, available at
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`https:ffwww.sec .gow’Archivesfedgari/dataf 12 7405 7f0001 2 7405 715 0000 I 2R3 3 . htm.
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`I declare under penalty of peijury of the laws of the United States of America, that the
`
`foregoing is true and correct, to the best of my knowledge and belief.
`
` 9th
`Executed on this 2m day of April, 2018.
`
`CécFW
`
`Jon Clark, MS.
`
`12
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`
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`EXHIBIT 1
`FDA TENTATIVE APPROVAL LETTER OF ANDA 091465
`(MAR. 15, 2011)
`(MAR. 15, 2011)
`
`FDA TENTATIVE APPROVAL LETTER OF ANDA 091465
`
`EXHIBIT 1
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`Case 1:18-cv—00303-RGA Document 15-1 Filed 04/17/18 Page 20 of 42 PageID #: 301
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`EXHIBIT 2
`FDA DECISION LETTER (AUG. 14, 2014)
`FDA DECISION LETTER (AUG. 14, 2014)
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`EXHIBIT 2
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`Case 1:18-cv-00303-RGA Document 15-1 Filed 04/17/18 Page 21 of 42 PageID #: 302
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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` Food and Drug Administration
` Rockville, MD 20857
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`Docket No. FDA-2014-N-0087
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`SENT VIA EMAIL
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`Dear Dexmedetomidine Hydrochloride Injection NDA Holder/ANDA Applicant:
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`On January 15, 2014, the U.S. Food and Drug Administration (FDA or the agency) established a
`public docket to solicit comment on certain legal and regulatory issues that pertain to Precedex
`(dexmedetomidine hydrochloride injection, 100 mcg (base)/mL packaged in 200 mcg (base)/2
`mL single-dose vials). As described in detail below, FDA also sent a letter describing the issue
`to Hospira, Inc. (Hospira), the holder of New Drug Application (NDA) No. 21-038 for Precedex
`and to all applicants that submitted Abbreviated New Drug Applications (ANDAs) to FDA
`referencing Precedex. The letter also was posted on the website for FDA’s public dockets at
`http://www.regulations.gov.
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`Today’s letter reflects FDA’s determinations with respect to permissibility of labeling carve outs
`for ANDAs referencing Precedex. For the reasons set forth below, FDA concludes that
`regardless of whether the original use code or the revised use code applies, the agency can
`approve an ANDA that submits a “section viii” statement and omits labeling that discloses the
`protected use (as identified by Hospira). FDA further concludes that such omissions do not
`render the drug less safe or effective for the remaining non-protected conditions of use.
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`I.
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`In the letters sent to NDA holder Hospira and ANDA applicants and posted to the docket, FDA
`noted the following:
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`Precedex is approved for the following indications:
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`1. Sedation of initially intubated and mechanically ventilated patients during treatment in an
`intensive care setting. Administer Precedex by continuous infusion not to exceed 24
`hours.
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`2. Sedation of non-intubated patients prior to and/or during surgical and other procedures.
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`FACTUAL BACKGROUND
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`Hospira has, over time, listed several patents covering the Precedex product referenced above.
`Only a method-of-use patent remains: U.S. Patent No. 6,716,867 (the ‘867 patent), which
`expires (including a pediatric exclusivity period) on October 1, 2019.1
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`1 U.S. Patent No. 4,910,214 expired on July 15, 2013, and an associated pediatric exclusivity period expired on
`January 15, 2014.
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`Reference ID: 3611876
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`Case 1:18-cv-00303-RGA Document 15-1 Filed 04/17/18 Page 22 of 42 PageID #: 303
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`Hospira originally listed the ‘867 patent in May 2004 with the following use code (U-572):
`“Intensive care unit sedation.” In November 2008, Hospira listed U.S. Patent No. 5,344,840 (the
`‘840 patent) with the following use code (U-912) in the Orange Book: “Sedation of non-
`intubated patients prior to and/or during surgical and other procedures.” That patent expired on
`September 6, 2011. On January 6, 2014, Hospira sought to amend the ‘867 patent use code to
`“intensive care unit sedation, including sedation of non-intubated patients prior to and/or during
`surgical and other procedures.” FDA, in accordance with the ministerial manner in which it
`implements patent use code information, changed the use code on January 8, 2014.
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`FDA sought comments on the following issues:
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`1. Does the breadth of the new use code description for the ‘867 patent foreclose ANDA
`applicants from gaining approval for any of the approved indications (or for any subset of
`those indications) before the ‘867 patent expires? For example, would it be permissible
`as a scientific, regulatory, and legal matter for an ANDA applicant to submit a statement
`under 21 U.S.C. §355(j)(2)(A)(viii) and a corresponding carve out that results in an
`approval for a subset of the second approved indication, i.e., an approval explicitly
`limited to procedures outside of an intensive care setting? In this context, is it acceptable
`to add new words to the approved indication to limit the indication to exclude only that
`portion of the indication that is covered by the use code (i.e., to exclude sedation of non-
`intubated patients in the ICU setting only)? If you believe a carve out of this type is
`permissible, if you wish, you may submit a side by side of the indication section of the
`labeling for dexmedetomidine hydrochloride injection showing the carve out that you
`believe would be acceptable.
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`2. Whether the fact that Hospira changed the use code information outside of the 30-day
`window after the patent issued means that the use code change is late listed as to any
`ANDAs pending with a section viii statement at the time the use code was changed. See
`21 C.F.R. § 314.53(c), (d). If so, would any ANDA with an existing section viii
`statement be entitled to retain that statement (and corresponding carve out) under 21
`C.F.R. § 314.94(a)(12)(vi), notwithstanding the change in use code?
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`3. What relevance, if any, to a determination of whether the use code change was timely
`submitted is the fact that Hospira previously listed the ‘840 patent with very similar use
`code information to that now listed for the ‘867 patent, and did not change the use code
`for the ‘867 patent until after the ‘840 patent expired?2
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`FDA requested a response by close of business on January 24, 2014. Commenters submitting in
`the initial comment period had an opportunity to respond to comments from other commenters
`by close of business January 31, 2014. The agency received 22 comments, which can be
`accessed at http://www.regulations.gov.
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`2 Dear Applicant Letter from FDA Center for Drug Evaluation and Research to Hospira Inc. re. Dexmedetomidine
`Hydrochloride Injection NDA ANDA , Docket No. FDA-2014-N-0087 (Jan. 15, 2014).
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`2
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`Reference ID: 3611876
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`II.
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`LEGAL AND REGULATORY BACKGROUND
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`A.
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`The Statutory and Regulatory Framework for Patent Protection for NDAs and for
`Labeling Differences for ANDAs
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`The Federal Food, Drug, and Cosmetic Act (the FD&C Act) and FDA regulations require that a
`sponsor seeking to market an innovator drug submit an NDA. NDAs contain, among other
`things, extensive scientific data demonstrating the safety and effectiveness of the drug for the
`indication for which approval is sought.3 Under the statute, an NDA applicant also must submit
`to FDA a list of patents claiming the approved drug substance or drug product, or claiming an
`approved method of using the drug product in the NDA. Specifically, section 505(b)(1) of the
`FD&C Act requires an NDA applicant to file as part of the NDA “the patent number and the
`expiration date of any patent which claims the drug for which the applicant submitted the
`application or which claims a method of using such drug and with respect to which a claim of
`patent infringement could reasonably be asserted if a person not licensed by the owner engaged
`in the manufacture, use, or sale of the drug.”4 FDA is required to publish this patent
`information5 and does so in the publication titled Approved Drug Products with Therapeutic
`Equivalence Evaluations, commonly known as the Orange Book.
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`The statute also provides that if a relevant patent is issued after NDA approval, the NDA sponsor
`must file the required patent information with FDA not later than 30 days after the date the
`patent is issued.6 FDA’s regulations further require that an applicant seeking approval of certain
`supplements, including a supplement for a new indication, submit with its supplement the patent
`information required for NDA approvals for a patent that claims the drug, drug product, or
`method of use.7
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` A
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` drug product with an effective approval under section 505(c) or 505(j) of the FD&C Act is
`known as a “listed drug.”8 Under the Drug Price Competition and Patent Term Restoration Act
`of 1984 (Public Law 98-417) (the Hatch-Waxman Amendments), an applicant may submit an
`ANDA under section 505(j) of the FD&C Act for approval of a generic version of a listed drug
`previously approved under section 505(c).9 The ANDA approval process shortens the time and
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`3 Section 505(b)(1) of the FD&C Act.
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` 4
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` Sections 505(b)(1) of the FD&C Act (emphasis added). See also 21 CFR 314.53(c)(2)(ii).
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` Section 505(b)(1), (c)(2) and (j)(7) of the FD&C Act.
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` Section 505(c)(2) of the FD&C Act; 21 CFR 314.53.
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` 21 CFR 314.53(d)(2).
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` Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.
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`3
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` Under 21 CFR 314.3(b), “[l]isted drug means a new drug product that has an effective approval under section
`505(c) of the act for safety and effectiveness or under section 505(j) of the act, which has not been withdrawn or
`suspended un