The Generic Challenge:
`
`Understanding Patents, FDA &
`
`Pharmaceutical Life—Cycle Management
`
`Second Edition
`
`Martin A. Voet, B.S., M.B.A., ].D.
`
`BrownWalker Press
`
`Boca Raton
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`page1
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`BDSI EXHIBIT 1024
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`Page 1
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`The Ce/mi: C/ya//enge:
`U/1a’erJ‘ta/zdzflg Palentx, FDA @" Pbzzrmaz‘eutz2'a/L1fl—C}c/e Management
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`Copyright © 2008 Martin A. Voet
`A ll 1'i_L{h tr 1'-‘.’.‘i(’1‘U:’3{l .
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`Brow/1 ll’/4/ker Pm‘;
`Bom Rafa/1, Florida ' U.5'A
`2008 /7
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`111111111. brozwzu/a//éer. £077!
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`Yjpexet by Tremirette Publication, India.
`
`Library of Congress Catalog1'ng—inrPublicaLion Data
`
`Understanding Patents, FDA 6’ Pharmaceutical
`rtin A. Voer. — 2nd ed.
`
`Voet, Martin A., l942—
`The Generic Challenge :
`Life~cycle Management/ Ma
`D.
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`ISBN-I3: 978-I-59942-444-I’: (pink.
`lSBN-IO: l-59942-444-4 (plain : alk. paper)
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`Page 2
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`82
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`_
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`_
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`The Generic Challenge
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`HIERARCHY 0F PATENTS
`
`Compound Parents
`The best pharmaceutical patent is a compound patent. This type
`of patent claims the active drug compound as well as its salts, es—
`ters and hydrates. It also typically covers a broad range of similar
`compounds to prevent a competitor from making a chemically
`similar drug. One common strategy is to file a broad patent on
`the compound, and then file a continuing application narrowly
`covering the active drug agent that is expected to become the
`approved product. This will result in the granting of two patents
`with the same expiration date both covering the approved prod—
`uct. The first one will‘be “good” as it is broad and the second will
`be “strong” as it is narrow.
`
`The reason the compound patent is the best pharmaceutical
`patent is that it covers a drug product no matter how it is formu'—
`lated, no matter how it is made, no matter what it is sold for and
`no matter what use it is put to, as long as it contains the patent—
`ed compound. According to a recent Court of Appeals decision
`which overturned a lower court ruling on this issue (SmithKline
`42 Apotex, CAFC 2004), even the amount of that compound is
`not important, so that a -drug product will infringe a compound
`patent even if it contains only a trace of the patented cornpound
`and even if an infringer did his best to try to keep that trace out
`of his product.
`
`Medical Use Patents
`
`The ‘next most valuable type of pharmaceutical patent is a medi«
`cal use patent. This type 0i'paI:cnt covers the approved medical
`use or inclication of an appmyccl drug product. It can also cover
`tI1‘i:1ppri3\rerl medical
`1_l5E‘.S. Typically, a meclical use claim for
`treatrrienr of a spec-ific rlisense or condition is directly izifringed
`only by 21. pat'ient with that riisezise or contlition or by the doc—
`tnr for p1'escri|1ing it, but not by the drug product mt-mufacturer.
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`Pharmaceutical, Bioiogicai and Medical Device Patents
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`83
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`However, the law makes one that actively induces another to
`infringe liable as a direct infringer. When a drug product is put
`on the market, it must contain instructions for use and these in-
`structions provide the necessary “active inducement” to charge
`the manufacturer with infringement. As a result, a medical use
`patent will effectively prevent infringement of a drug product
`labeled for the patented use.
`
`What about infringement of off-label patents, that is\,\ pat-
`ents which cover a medical use not on the label of a drug prod—
`uct, since many drugs today are used extensively by doctors
`for off—label medical uses? That is a more difficult question
`to answer and that is one reason why a compound patent is
`better than a use patent, since there is infringement with a
`compound patent regardless of the use or whether the use is
`approved or not.
`
`There are two general situations in which off—label infringe—
`ment occurs. The first is off-label use where an infringing prod-
`uct is labeled and sold for a given use, but prescribed by physi-
`cians for a patented use not on the FDA approved label. In
`order to show inducement of infringement, the patent owner
`would have to provide evidence that the drug manufacturer
`knew of the off—label use and actively induced others to in—
`fringe. This tends to be an issue that revolves around obtaining
`evidence of knowledge and intent of the drug manufacturer
`including evidence of any overt acts to induce infringement.
`Examples of activities that could suggest active inducement are
`any promotional or informational activities for the off—label use
`by the manufacturer or by third parties connected to the manu-
`facturer in one way or another, such as statements by company
`sales people, company website references to the indication or
`educational programs for physicians to teach the off—label use
`that are directly or indirectly sponsored by the manufacturer.
`
`The second off—label use is in the context of an abbreviated
`new drug application (ANDA) (see page 50 under Types of
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`84
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`The Generic Challenge
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`Drug Filings) filing for a generic drug. Until 2003, it was com»
`mon practice for innovators to list off—label patents in the FDA
`Orange Book which would then require generic companies to
`file Paragraph lV certifications which would allow the patent
`holder/innovator to file suit against the generic company for pat-
`ent infringement and would prevent the FDA from approving
`the generic drug for 30 months. The current case law (W/amer—
`Lambert 4/ Apotex, CAFC 2003) and related FDA regulations and
`federal legislation make it clear that innovators can no longer
`list off—label patents in the Orange Book. This is discussed in
`more detail in future chapters.
`
`However, where a generic company tries to obtain labeling
`for less than all the approved uses for an innovative drug, and
`one of those uses is patented by the innovator, the innovator
`may still sue for infringement. In a recent case, (Takeda U W/at»
`son Pharmaceuticals, ZOO3), a lower court ruled a patent holder
`may sue a generic company for inducing infringement of its use
`patent based on the filing of an ANDA even though the appli—
`cation was pending and no sales had been made.
`
`Formulation Patents
`
`The third basic type of patent for drug products is a formulation
`patent that typically cm»'i':i':a the active drug agent in the specific
`formulation for use in the hcidy. Sometimes. the formulation pat—
`ent covers a unique exc.ipii:nt such as a stabilizer or preservative
`used in the formulation. A formulation patent offers the least
`desirable patent protection because typically it can be avoided
`by using a different formulation. However, in the context of an
`ANDA submission for a generic drug, a formulation patent, no
`matter how narrow, may be ideally suited to prevent copying of
`the drugjby a generic company.
`This is because of the regulatory requirements for pharmaceu—
`tical equivalence and bioequivalence that a generic drug must
`meet. While a generic drug is allowed to have minor changes in
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`Pharmaceutical, Biological and Medical Device Patents
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`35
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`the formulation or even in the active drug agent, typically that
`would require clinical trials to establish bioequivalence since the
`generic drug and the reference drug would not be “the same”. To
`avoid the expense and time of clinical trials, most generic com-
`panies simply copy the innovator’s drug formulation exactly and
`try to invalidate the formulation patent. In this way, even a very
`narrow formulation patent can be extremely valuable in prevent-
`ing generic copying, even though it would be easy to get around
`the patent by reforrnulating. Patent holders should not forget to
`obtain very narrow formulation claims covering an innovator
`product in addition to broad ones, as narrow formulation claims
`are easier to defend against attacks on validity.
`
`BIOLOGICALS PATENTS
`
`Biologicals patents are not different in principle from phanna—
`ceutical patents except that they claim recombinant products,
`genetic material, proteins, monoclonal antibodies, nucleic ac-
`ids and DNA sequences and their methods of manufacture and
`use. According to FDA, biological products, like other drugs, are
`used for the treatment, prevention or cure of disease in humans‘.
`However, in contrast to chemically synthesized small molecules
`which have a well—defined structure and can be thoroughly char-
`acterized, biological products are generally derived from living
`material—human, animal or microorganism—that are large and
`complex in structure and often not fully characterized.
`
`For FDA purposes, even though antibiotics are often produced
`by a biological process such as fermentation, they are handled
`by FDA administratively as drugs rather than biologicals, as are
`hormones such as insulin and human growth hormone. On the
`other hand, all blood products, allergens, vaccines, products
`containing cells or microorganisms, most protein products and
`all recombinant products, are handled administratively as bio—
`logicals regardless how they are made.
`_\\
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`118
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`The Generic Clmiieiige
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`is filed by the same or different manufacturer, there is no second
`five-year exclusivity allowed, even if the first drug product has
`been withdrawn or was never sold or the second drug product
`is in a completely different form for a completely different use
`as long as the first drug product containing the same NCE was
`previously approved.
`
`New Use or New Formulation Exclusivity
`The law provides a new use or new formulation marketing exclu—
`siviry of three years. This exclusivity applies to new indications
`for an old drug or new formulations or other labeling changes of
`an old drug for which the applicant has submitted and obtained’
`approval of a new NDA and which required new clinical trials
`(hut not l.iioav-ailahility stiitliesl funded by the sponsor of the
`NDA that were essential to obtain approval.
`The new indication can involve the same or a different for-
`mulation or dosage as long as it is for a new use of an old drug
`product. During those three years, the FDA will not approve an
`ANDA (or paper NDA) for that new indication. However, the
`FDA will accept the filing of an ANDA (or paper NDA) during
`the three—year period and thus the ANDA could be approved
`by the end of the third year. The FDA will also approve a new
`NDA during the three—year period; however. it
`is unlikely that
`anyone would attempt to prepare and file a full NDA for the
`same indication since they would only have to wait for three
`years to copy it with an ANDA Filing and preparing and filing a
`full NDA would take longer and cost much more.
`
`Pediatric Exclusiviiy
`The pediatric exclusivity adds six months inarketing exclusivity to
`all the other exclusivities for the apprrwetl active drug as well as ef-
`fectively adding six months lto the expiiatioii dates of patents listed
`for the drug product in the FDA Orange Book. \X/hile the patent
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