AXINN, VELTROP & HARKRIDER LLP © 2007 | The PIV Notice Letter Essential Considerations and Necessary Requirements Chad A. Landmon 90 State House Square 1330 Connecticut Ave, N.W. Hartford, CT 06103Washington, D.C (860) (202) October 26, 2012

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 2 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: No related patents have been filed II: The related patent has already expired III: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

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 3 Paragraph IV Certification Timeline ANDA with Paragraph IV certification filed and notice letter provided to brand; brand company has 45 days to bring suit If no lawsuit, FDA reviews the ANDA Other generics may enter the market 180 days later 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 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 If generic launched the product at-risk after FDA approval, other generics may enter the market 1.5 months 30 months ~18 months 24 months 36 months

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 4 Orange Book Approved Drug Products with Therapeutic Equivalence Evaluations –Identifies drug products approved on the basis of safety and effectiveness by FDA Patents listed in the Orange Book: –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: –Metabolites & Intermediates –Packaging features –Methods of manufacture (process) –Unapproved methods of use

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 5 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 (f) –Otherwise, ANDA applicant will need to certify to improperly-listed patent Orange Book

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 6 Orange Book Search online by –Proprietary Name –Active Ingredient –Applicant Holder –Application Number –Patent Number

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 7 Lipitor ® (Atorvastatin) $7.2 billion in sales in 2010

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 8 Patent Use Codes 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: –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

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 9 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 carve- out Patent Use Codes 21 USC§355(j)(2)(A)(viii)

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 10 Timing of the Notice 21 USC§355(j)(2)(B)(ii) 21 CFR § 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.

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | USC§355(j)(2)(B)(iii) 21 CFR § 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 FDA does not need a copy of the notice letter FDA will not advise on who correct recipients are Recipients of the Notice

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 12 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. Method of Delivery 21 CFR §314.95(e)

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 13 Contents of the Notice 21 USC§355(j)(2)(B)(iv) 21 CFR § A statement that FDA has received an ANDA submitted by the applicant containing any required bioavailability or bioequivalence data or information The ANDA number The established name, if any, of the proposed drug product The active ingredient, strength and dosage form of the ANDA product

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | USC§355(j)(2)(B)(iv) 21 CFR § Contents of the Notice 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 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.

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 15 Offer of Confidential Access 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

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 16 Disclosure of Notice Letters 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

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 17 Consequences of Deficient Notice Letters FDA declines to review notice letters for sufficiency; some courts have done the same 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)

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 18 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

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 19 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 Consequences of Deficient Notice Letters

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 20 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.” Consequences of Deficient Notice Letters

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 21 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 Consequences of Deficient Notice Letters

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 22 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 Consequences of Deficient Notice Letters

AXINN │ VELTROP │ HARKRIDER │ LLP © 2012 | 23 How to Avoid Negative Outcomes 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

AXINN, VELTROP & HARKRIDER LLP © 2007 | Questions? Chad A. Landmon 90 State House Square 1330 Connecticut Ave, N.W. Hartford, CT 06103Washington, D.C (860) (202) October 26, 2012