The PIV Notice Letter
Essential Considerations and Necessary Requirements
Chad A. Landmon
cal@avhlaw.com
90 State House Square
Hartford, CT 06103
(860) 275-8170
October 26, 2012
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Background
•
21 USC§355(j)
Drug Price Competition and Patent Term Restoration Act of 1984
(i.e., the Hatch-Waxman Act)
Permitted a generic drug manufacturer to seek regulatory approval of the generic product via
submission of an Abbreviated New Drug Application (ANDA)
•
The generic manufacturer must certify with respect to each patent
related to the listed drug:
I:
II:
III:
No related patents have been filed
The related patent has already expired
The generic company will not market the generic product until after the
related patent expires
IV: The related patent is invalid, unenforceable or will not be infringed by
the manufacture, use or sale of the drug product for which the ANDA is
submitted
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Paragraph IV Certification Timeline
ANDA with Paragraph IV certification filed and notice letter
provided to brand; brand company has 45 days to bring suit
1.5 months
~18 months
If no lawsuit, FDA
reviews the ANDA
If lawsuit filed, 30-month stay period is
triggered; FDA reviews ANDA but only
tentative approval possible
FDA approves the ANDA; generic may
enter the market as first filer
24 months
30 months
Other generics may enter the market
180 days later
Generic and brand-name companies do not reach agreement or
litigation is not complete; FDA approves ANDA; generic may enter
the market at-risk or wait for outcome of lawsuit
36 months
If generic launched the product at-risk after FDA
approval, other generics may enter the market
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Orange Book
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Approved Drug Products with Therapeutic Equivalence Evaluations
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•
Identifies drug products approved on the basis of safety and effectiveness by FDA
Patents listed in the Orange Book:
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www.accessdata.fda.gov/scripts/cder/ob/default.cfm
Drug Substances (compound/active ingredient)
Drug Products (formulation/composition)
Method of use covering approved uses of a drug
Polymorphs if they claim equivalent active ingredient as the approved product
Product-by-process where the patent claimed is novel
Not listed:
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–
–
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Metabolites & Intermediates
Packaging features
Methods of manufacture (process)
Unapproved methods of use
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Orange Book
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www.accessdata.fda.gov/scripts/cder/ob/default.cfm
Drug Delivery System Patents
– Can be listed
– Considered to be patents claiming drug products (drug product = formulation
+ device), e.g., metered dose inhalers, dry powder inhalers, pre-filled syringes
– Drug delivery device integral to administration of an active, but what about
where patent does not recite active? Companies will probably list.
•
Improperly Listed Patents
– FDA does not review the propriety of patents submitted for listing. Apotex,
Inc. v. Thompson, 347 F.3d 1335, 1352 (Fed. Cir. 2003).
– Pre-Litigation
• 21 C.F.R. 314.53(f)
– Otherwise, ANDA applicant will need to certify to improperly-listed patent
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Orange Book
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www.accessdata.fda.gov/scripts/cder/ob/default.cfm
Search online by
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Proprietary Name
Active Ingredient
Applicant Holder
Application Number
Patent Number
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Lipitor® (Atorvastatin)
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$7.2 billion in sales in 2010
7
Patent Use Codes
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•
Brand-name drug manufacturers are required to provide a
description, known as a use code, of any method-of-use patent it
holds that covers the marketed drug.
Examples include:
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U-1 PREVENTION OF PREGNANCY
U-3 TREATMENT OF HYPERTENSION
U-4 PROVIDING TREATMENT AND NAUSEA IN MAMMALS
U-12 METHOD OF TREATING A HUMAN SUFFERING FROM
DEPRESSION
– U-56 AID TO SMOKING CESSATION
– U-90 TREATMENT OF PSYCHOTIC DISORDERS
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Patent Use Codes
•
•
21 USC§355(j)(2)(A)(viii)
FDA does not verify accuracy of use codes
Use codes govern appropriateness of label “carve-outs” and section
viii statement
– Where patent is listed for a method of use which does not claim a use for
which the applicant is seeking approval, the applicant may make a statement
that the listed patent does not claim such a use.
•
•
Notice letter does not need to address patents for which the ANDA
applicant has submitted a section viii statement (or PI, PII, PIII
certifications)
Split certifications permitted
– PIV certification to the drug product claim or applicable method of use claim
and section viii statement to the method of use and accompanying label carveout
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Timing of the Notice
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21 USC§355(j)(2)(B)(ii)
21 CFR § 314.95
If the certification is in the application,
– Not later than 20 days after the date of the postmark on the notice with which
the Secretary informs the applicant that the application has been filed (“filing
acceptance”).
•
If the certification is in an amendment or supplement
– At the time at which the applicant submits the amendment or supplement
•
Tip:
– In most all cases, OGD will fax a copy of the Acknowledgement letter to the
sponsor for a PIV ANDA the same day OGD postmarks the filing acceptance
letter. The 20-day clock begins to run on the day following the date of the
postmark.
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Recipients of the Notice
•
21 USC§355(j)(2)(B)(iii)
21 CFR § 314.95
Each patent owner listed in the Orange Book
– The name and address of the patent owner or its representative may be
obtained from the United States Patent and Trademark Office
•
The NDA holder, if domestic, or the application holder's attorney,
agent, or other authorized official if the holder has no place of
business in the United States
– The name and address of the application holder or its attorney, agent, or
authorized official may be obtained from the Orange Book Staff, Office of
Generic Drugs, 7500 Standish Pl., Rockville, MD 20855
•
•
FDA does not need a copy of the notice letter
FDA will not advise on who correct recipients are
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Method of Delivery
•
21 CFR §314.95(e)
Registered or certified mail, with return receipt requested.
– Date of receipt is critical – this starts the 45-day clock
– 30-month stay calculated from date of receipt
• For multiple recipients, date of latest-receiving party of notice letter will
be used by FDA to calculate 30-month stay.
•
Alternate delivery methods, like UPS or FedEx, require prior written
permission in advance from OGD.
•
Once delivery is complete, amend the ANDA to document delivery of
the notice letter.
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Contents of the Notice
21 USC§355(j)(2)(B)(iv)
21 CFR § 314.95
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A statement that FDA has received an ANDA submitted by the
applicant containing any required bioavailability or bioequivalence
data or information
•
The ANDA number
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The established name, if any, of the proposed drug product
•
The active ingredient, strength and dosage form of the ANDA
product
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Contents of the Notice
21 USC§355(j)(2)(B)(iv)
21 CFR § 314.95
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If the applicant does not reside or have a place of business in the
United States, the name and address of an agent in the United States
authorized to accept service of process for the applicant
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The patent number and expiration date of each patent alleged to be
invalid, unenforceable or not infringed
•
A detailed statement of the factual and legal basis of the applicant's
opinion that the patent is not valid, unenforceable or will not be
infringed.
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Offer of Confidential Access
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21 USC§355(j)(5)(C)(i)(III)
Preserves right to file declaratory judgment action if ANDA
applicant is not sued within the 45-day window (MMA)
– Required for non-infringement notice letters
– Not required for only invalidity notice letters (DJ action can still be brought
after 45-day window runs)
•
•
•
ANDA pursuant to OCA can be redacted to remove any information
of no relevance to any issue of patent infringement
Unreasonable restrictions in OCA and failure to negotiate acceptable
terms may still give rise to jurisdiction for suit by brand company
Terms of OCA apply to ANDA not Notice Letter
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Disclosure of Notice Letters
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Can be disclosed in litigation or the citizen petition process
– Nycomed v. Tolmar, 10-cv-2635 (D.N.J. Apr. 28, 2011) (unpublished)
•
FDA believes the notice letter is a public document once it has been
provided to the NDA holder and patent owner.
– FDA Response to Nycomed’s Request re Graceway Pharmaceuticals’ Cit. Pet.
Docket 2009-P-0423 (Jan. 7, 2010)
– FDA made Nycomed’s notice letter public as part of the CP process where the
brand company attached a copy of the notice letter it received as one of its CP
attachments
– The OCA allows for exchange of confidential ANDA information
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Consequences of Deficient Notice Letters
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FDA declines to review notice letters for sufficiency; some courts
have done the same
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Baseless non-infringement or invalidity positions could lead to
liability for attorneys’ fees
– Takeda Chem. Indus., Ltd. v. Mylan Laboratories, Inc., 459 F. Supp. 2d 227
(S.D.N.Y. 2006) aff'd, 549 F.3d 1381 (Fed. Cir. 2008)
– Yamanouchi Pharm. v. Danbury Pharmacal, 231 F.3d 1339 (Fed. Cir. 2000)
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Consequences of Deficient Notice Letters
•
Takeda Chem. Indus., Ltd. v. Mylan Laboratories, Inc., 459 F. Supp. 2d
227 (S.D.N.Y. 2006)
– Litigation conduct, warranting attorneys’ fees, may be predicated on baseless
ANDA certifications and “proceeding to challenge a patent’s invalidity
despite glaring weaknesses in the theory of invalidity”
– Opinion of counsel not relied upon by the applicants as a defense
– Notice letter contained “clear errors” and arguments that were abandoned by
the time of trial
– Awarded Takeda $11,400,000 from Mylan and $5,400,000 from Alphapharm
– Two-thirds of award allocated to Mylan as lead counsel
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Consequences of Deficient Notice Letters
•
Examples of notice letter deficiencies identified by Takeda district court
– Total failure to identify the lead compound later relied on heavily at trial;
failure to identify motivation for selection of that compound or its
modification in a way that would lead to discovery of pioglitazone
– Lack of due care and good faith exemplified by misidentification of
substituents on prior art compound
– No reason to substitute out certain substituents because prior art was silent as
to any benefit, increased efficacy or reduced toxicity from such a substitution,
i.e., no reasonable basis to expect success
– Misdescribed prior art compound’s structural relationship with pioglitazone
and its efficacy
– Failure to address secondary considerations
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Consequences of Deficient Notice Letters
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Notice letter deficiencies coupled with litigation misconduct following
notice letter filing
– Roadmaps for obviousness during depositions changed entirely from notice
letter
– Expert reports changing the obviousness arguments from deposition
testimony and identifying new prior art
– Baseless inequitable conduct allegations
– Identifying new motivations for selecting lead compound for the first time at
trial
•
•
“Ever-evolving theory of obviousness”
“The assertion of obviousness in a Section 355 Statement must be rooted
in an analysis of prior art and made with due care.”
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Consequences of Deficient Notice Letters
•
Takeda Chem. Indus., Ltd. v. Mylan Laboratories, Inc., 549 F.3d 1381
(Fed. Cir. 2008)
– Lower court did not commit clear error
– Did not disagree with any of the bases set forth by the district court
• Failure to provide any reason in notice letter for identification of
purported lead compound; cataloguing scientific errors underscoring lack
of due care and good faith
• Abandonment of arguments at trial because “they were unsupportable,
not because Alphapharm made a tactical decision regarding which
argument should be emphasized at trial”
• Mylan’s own witness refuted their selection of the purported lead
compound described in the notice letter during his deposition
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Consequences of Deficient Notice Letters
•
The Federal Circuit did not find that the outcome would deter ANDA
filings or litigation
– “Well-supported filings challenging the validity and infringement of patents
owned by an NDA holder should not raise the specter of an unjustified
holding of an exceptional case.”
– Affirmed amount of award due Takeda despite its unusual size
•
Yamanouchi – baseless notice letter and litigation misconduct justified
fees for an exceptional case
– failed to address unexpected potency, safety and lack of adverse effects of the
claimed compound
– mainly structural obviousness argument that was predicated on an erroneous
interpretation of a compound disclosed in the prior art
– failed to mention the prior art patent relied upon heavily at trial
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How to Avoid Negative Outcomes
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Involve litigation counsel early and often
Consider timing of notice letter preparation - after an ANDA is
submitted to FDA, FDA has 60 days to determine whether it will be
accepted for filing. Once accepted, the 20 day clock to send out the
notice letter begins.
Engage experts, even for notice letter preparation
Engage testing laboratories if needed to assess possible infringement
Review/evaluate draft ANDA documents
Include invalidity arguments
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Questions?
Chad A. Landmon
cal@avhlaw.com
90 State House Square
Hartford, CT 06103
(860) 275-8170
October 26, 2012
AXINN, VELTROP & HARKRIDER LLP © 2007
|
www.avhlaw.com
1330 Connecticut Ave, N.W.
Washington, D.C. 20036
(202) 721-5415