se, is usually filed very early in the develop- Chemical Compounds and Biologics ment process. Since the ultimate patent term (species IP exclusivity) is 20 years from the original filing date of the application, entity Developing Issues Relevant species-IP exclusivity is often substantially limited at the time (if and when) the entity to Market Exclusivity receives regulatory approval.

BY PATRICK H. HIGGINS OF Biologics REGULATORY APPROVAL ECKERT SEAMANS Biopharmaceuticals, on the other hand, Human testing does not begin with any CHERIN & MELLOTT, LLC tend to be relatively large and complex gly- therapeutic entity before the filing and FDA cosylated proteins of secondary and tertiary approval of an Investigational New Drug conformation which are, in many ways, dif- application (IND).6 The IND application ficult to define structurally at the molecular contains preclinical data in pharmacology 2, 3 level. Nevertheless, biologics are gener- and toxicology, manufacturing information, ally defined in terms of function and exact as well as clinical protocols and investiga- starting materials (identity, features, and tor information. At that point, the entity sequences of nucleic acid constructs), the falls under the Federal Food, Drug, and This article originally appeared as a two- cell-line employed for synthesis, and exact Cosmetic Act (FDCA (21 USC §§301, 4 part series in Intellectual Property Today production conditions. In other words, in 321)) and becomes a new drug subject to (July & August 2011 issues) contrast to small molecule compounds, not requirements of the drug regulatory system. only are exact forms of a biologic difficult to define structurally, exact means of pro- Clinical Trials duction in fact frequently define what the Phase I clinical trials are conducted PHARMA / BIOPHARMA INDUSTRY biopharmaceutical is, per se. in a small group (20-100) of healthy individuals to determine dosage range, he drug-discovery industry is funda- duration of activity, and safety profile (nor- mentally based upon the development, R&D mally take from six months to one year). An R&D investment of about $1 bil- T regulatory approval, and prospect in Pharmacokinetic studies also examine how lion and 14 years is generally required to fact for a period of market exclusivity for a drug is absorbed, distributed, metabo- bring a new therapeutic entity to market.5 therapeutic entities, i.e., chemical com- lized, and excreted. Small molecule compounds are tradition- pounds and biologics. Since a total of Phase II clinical trials are placebo- ally developed by means of screening large controlled to establish efficacy and optimal about 14 years is generally required to compound collections or rational design at dosage. Phase II also takes between six bring a new therapeutic entity to market, the molecular level to identify or otherwise months and one year and usually involve the period of exclusivity afforded in terms generate a “lead” which exhibits pharmaco- 100 to 500 volunteer patients diagnosed IP and/or Regulatory is paramount in the logical/biological activity. Medicinal chem- with the prospective indication. business equation. Each of these classes ists then adjust and substitute atoms and Phase III randomized placebo-con- moieties on the lead structure to optimize of therapeutics, however, presents distinct trolled trials are then conducted to gener- activity and bioavailability while minimizing advantages as well as challenges to the ate statistically significant efficacy and toxicity. Similar to the rational design route industry. This article briefly reviews the side-effect data. These studies normally of small molecule compounds, biologics process and developing issues relevant to take one to four years involving 1,000 to tend to be directed to modulating specific market exclusivity characteristic of each 5,000 closely-monitored volunteer patients. biological mechanisms of human disease class of therapeutics. by having affinity to a specific biological NDA Small Molecule Compounds target. Biologics are generally constructed The NDA (New Drug Application (FDCA The Pharmaceutical Industry has histor- from portions of native entities including 505 (21 USC §355)) or BLA (Biological signal transduction molecules, receptors and ically been based upon highly characterized License Application (Public Health Service ligands, or are monoclonal antibodies which Act (PHS) §351 (42 USC §262)) is filed small synthetic organic molecules that are bind a specific site. Nevertheless, similar — seeking approval from the FDA upon easily reproduced. Indeed the Holy Grail to small molecule compounds, biologics in completion of clinical trials — if the small of the industry, until relatively recently, development frequently require many types molecule compound or biologic, respec- has been an efficacious small molecule of adjustments in production at the molecu- tively, is demonstrated to be both safe compound that exhibits high bioavailabil- lar level to maximize efficacy while minimiz- and effective.7 Typically 100,000 pages ity, low toxicity, a long biological half-life, ing side-effects. or longer, the NDA or BLA sets forth all is inexpensive to manufacture, and is free Patent Applications relevant to the of the studies, data and conclusions, i.e., of third party IP rights. Chemical species prospective therapeutic entity, production, preclinical testing, all clinical trials, dos- tend to be easily described in exact terms of formulations and methods of use, including ing information, manufacturing details and dosage and administration, are normally proposed labeling. definite structure and physical properties.1 filed throughout the development and regu- PHS emphasizes the importance of man- Importantly, once a compound structure is latory process. However, the original and ufacturing control for all biological entities known, regardless of the process, the spe- most important composition of matter disclo- and provides for a system of controls over cies can be reproduced. sure of the prospective therapeutic entity, per all aspects of the manufacturing process.

24 INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 PHS §351 defines “biological product” and ket the generic version (e.g., during appeal Section 351(k) of the PHS Act (42 USC how to obtain FDA approval to market a to the Federal Circuit).13 During the period §262(k)), added by the BPCI Act, describes biologic by issuance of a Biologics License. of exclusivity no other ANDAs can be filed. the general requirements for an Abbreviated Importantly, PHS was amended March Accordingly, significant incentive is pres- Biological Product Application (ABPA) 23, 2010 (BPCI Act), discussed infra, to ent for prospective generic manufacturers (§351(k) application) for a “biosimilar” and change the statutory authority under which to challenge pharmaceutical IP exclusivity. for a proposed “interchangeable” biosimilar. biologics are regulated by amending the a. New Chemical Entity exclusivity A biosimilar may be approved under new sec- definition of “biological product”. Section (NCE), provided by the Hatch Waxman tion 351(k) of the PHS Act if clinically dem- 351(i) of PHS is now amended to include a Act, grants a five (5) year period of regula- onstrated to be “highly similar” to a reference protein except any chemically synthesized tory exclusivity which comes into existence biopharmaceutical in terms of safety, purity polypeptide.8 upon approval of a new small molecule and potency. To meet the higher standard FDA NDA/BLA review requires about 14 compound.14 NCE exclusivity effects a 5 of “interchangeability,” a candidate biologic months. Fast Track, Accelerated Approval, year bar to ANDA submission and runs con- must be demonstrated to be expected to pro- and Priority Review FDA programs are current with any patent protection.15 duce the same clinical result as the reference available to reduce review time approxi- b. Supplemental NDA (sNDA) product in any given patient. mately in half. Nevertheless, a total of about exclusivity, also resulting from the Hatch BPCIA provides a maximum one-year twelve (12) years is generally required to Waxman Act, is a three (3) year bar to period of market-exclusivity incentive for obtain FDA approval, if at all, of a new ANDA approval awarded upon approval of a the first ABPA “interchangeable” biosimi- therapeutic entity. supplemental application for a new indica- lar (similar to the 180-day market-exclusiv- tion or formulation.16 New clinical investi- ity incentive provided to the generic drug 20 MARKET EXCLUSIVITY gation must be human studies conducted by industry under the Hatch Waxman Act). The discovery industry is fundamentally the applicant toward safety or effectiveness. i) 12 Years New Biologic Exclusivity based upon prospects in fact for a period of Supplemental NDA Exclusivity runs con- (NBE) market exclusivity, i.e., IP (patent) and/or current with any patent protection. Similar in concept to NCE under the regulatory exclusivity. 2. Orphan Drug Exclusivity Hatch Waxman Act, under BPCIA the (ODE).17 Orphan Drug Act (PL 97-414) biopharmaceutical industry is now afforded Regulatory Exclusivity 12-years NBE (data exclusivity) upon amended FDCA January 4, 1983 to create Regulatory exclusivity is effected by approval of a new biologic therapeutic an incentive for the drug discovery industry statutory barrier to FDA acceptance of a entity.21 Specifically, PHS Act §351(k) to address treatment of rare diseases and competing application or approval of a com- (7) now provides a 12-year period bar conditions. ODE creates a 7 year bar to any peting therapeutic entity. to §351(k) ABPA (biosimilar application) approval of the same entity, including bio- 1. Hatch Waxman Act - Small approval from the approval date of the inno- logics, from the initial approval date to treat Molecule Compounds vative biologic. the same rare condition (fewer that 200,000 The Hatch Waxman Act was passed Similar to small molecule compounds, US patients). 21 USC §360cc. by Congress in 1984 to create a com- NBE exclusivity can be extended 180 days 3. Pediatric Exclusivity.18 Food and petitive balance between the discovery for performing pediatric studies. However, and generic sectors of the industry. 9 The Drug Administration Moderization Act of in contrast to 3-year supplemental NDA Act relieves the generic sector from con- 1997 (PL 105-115) amended FDCA to (sNDA) Exclusivity available for small mol- ducting clinical trials of proposed generic create incentive for “pediatric studies”, ecule compounds (resulting from the Hatch versions of currently approved pharmaceu- i.e., at least one clinical investigation in Waxman Act) BLA supplements which ticals. Particularly, Abbreviated New Drug a pediatric age group in which a thera- yield approval for new formulations or new Applications (ANDAs) require generic man- peutic entity is anticipated to be used. indications for the original biologic species ufacturers to demonstrate bioequivalence to Although not contingent upon approval of fall within the original 12-year period of currently marketed FDA-approved refer- the therapeutic entity for pediatric use, exclusivity. Independent 12-year periods of ence listed drugs.10 A paragraph IV ANDA Pediatric Exclusivity adds 6 months to any exclusivity are available for next generation may be filed, for example, if certification is existing regulatory and/or patent exclusiv- (new species) biologics which result from provided that an otherwise relevant patent ity. All applicant-owned pharmaceutical modification to the structure of the biologi- listed in the FDA Orange Book is invalid, products containing the drug, or biologic cal entity to yield a change in safety, purity, unenforceable, or not infringed. 11 However, are affected. or potency. 35 USC §271(e)(2) provides that it is an 4. We are at a similar crossroads ii) ABPA Procedure: Similar to a act of patent infringement to submit an today with respect to biopharmaceuti- paragraph IV ANDA, a §351(k) applica- ANDA for an FDA-approved drug otherwise cals as we were in 1984 with respect tion however, can submitted to FDA 4 years claimed in a patent.12 The patent owner to traditional pharmaceuticals. after the approval date of the reference therefore usually brings a patent infringe- a. The Biologics Price Competition biologic). In the event of an Abbreviated ment lawsuit which, if filed within 45 days and Innovation Act (BPCIA) Biological Product Application the appli- of the ANDA, starts an automatic 30 month (Biosimilars Act), similar in nature to the cant is required to provide the innovator stay of FDA approval of the ANDA. FDA Hatch Waxman Act, recently established “confidential access” to a copy of the cannot approve the generic drug during an abbreviated approval pathway for bio- ABPA and a description of the manufactur- the stay unless a court rules that the patent logics demonstrated to be “highly similar” ing process within 20 days of FDA notice of is invalid or not infringed. If the ANDA is (biosimilar) to, or “interchangeable” with, acceptance of the ABPA. Then, within 60 approved the generic company receives a a currently approved biopharmaceutical days of receiving the ABPA, the innovator 180-day period of FDA-exclusivity to mar- (FDA-licensed biological product). 19 must provide the ABPA applicant a list of

INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 25 patents for which a claim of patent infringe- of the ABPA as required by the BPCIA, patentability under the Patent Act (title 35 ment could “reasonably be asserted,” and for example, the innovator can proceed of the United States Code). an identification of those patents the inno- with action(s) for Declaratory Judgment a. Chemistry - The statutory require- vator would be willing to license to the concerning any patent drawn to product or ment for non-obviousness under 35 ABPA filer. Within 60 days of receipt of use. Should the ABPA applicant not comply USC §103 is the most common issue the patent list, similar to paragraph IV cer- with later BPCIA requirements, the innova- raised by the generic industry in para- tification under the Hatch Waxman Act, the tor can proceed with DJ action(s) concern- graph IV ANDA litigation. Since small ABPA filer must provide a detailed well- ing patents identified in the patent listings. molecule compound therapeutics tend to reasoned “factual and legal” statement Suit can be brought on any patent after be definite structures simply described on a “claim by claim basis” as to why the biosimilar launch. in exact molecular terms including salts, identified claims are invalid, unenforce- hydrates, enantiomers, metabolites, ana- able or will not be infringed by the ABPA. PATENT (IP) EXCLUSIVITY - SMALL logs, and derivatives AND the exact struc- Similarly, within 60 days of receipt of the MOLECULE COMPOUNDS AND BIOLOGICS tures are publicly available, combined with ABPA filer’s response, the innovator must the fact that historical chemical records are provide a detailed well-reasoned “factual Since a total of about fourteen years, comprehensive; validity issues of statutory and legal” opinion on a “claim by claim more or less, is generally required to bring subject matter, novelty, written description, basis” as to why the patents are valid, a new therapeutic entity through develop- enablement, and definiteness, although enforceable, and infringed. ment and regulatory approval, and patent present in the chemical space, are atypical. iii) BPCIA Patent Resolution term is 20 years from the earliest applica- 35 USC §§101, 102, and 112. However, Parties are required to negotiate toward tion for patent, remaining patent term upon since medicinal chemistry offers a limited “patent resolution” in good faith. Should FDA approval of a species therapeutic, per number of elements, i.e., atoms and moi- an agreement as to patents relevant to se, is generally on the order of about six (6) eties with known properties to work with the ABPA be reached within 15 days, the years.23 in these small structures and the fact that innovator must file a lawsuit asserting the The Hatch Waxman Act, discussed many developmental structures are related, patents within 30 days of the agreement. supra, amended the Patent Act (35 USC) the statutory requirement for non-obvious- Should the parties, however, not reach to create a means to extend a single patent ness under 35 USC §103 is the most com- an agreement within 15 days the ABPA term a maximum of 5 years to compensate mon issue raised by the generic industry in applicant must provide notice identifying for time lost during regulatory approval. paragraph IV ANDA litigation. the patents to the innovator that should 35 USC §156. Term extension, available Obviousness is a question of law. The be, from its legal position, the subject of a for both small molecule compounds and starting point from which to begin analysis patent infringement action. Then, within 5 biologics, is equivalent to one half IND in a chemical case is paramount. Similar days, under the BPCIA, the parties simul- regulatory time plus all NDA/BLA regula- in fact to many small molecule compound taneously exchange the identity of patent tory time.24, 25 cases Eli Lilly & Co. v. Zenith Goldline claims each believes should be the subject The Hatch Waxman Act also, however, Pharmaceuticals, Inc. involved a paragraph of litigation. The innovator must then file IV ANDA lawsuit wherein Zyprexa® (olan- created the avenue for paragraph IV ANDA suit within 30 days asserting each patent zapine) was alleged to be obvious in view to be filed, for example, if “certification” identified in the exchange.22 of a very close structurally-related prior art is provided to the patent holder that an iv) Motions for Preliminary “lead compound” as a starting point (ethyl otherwise relevant claim is invalid, unen- Injunction substitution for a methyl group).26 forceable, or not infringed. BPCIA simi- The ABPA applicant is required, under A hypothetical ability, however, to larly requires the ABPA filer to provide a BPCIA, to provide 180-days notice to the simply substitute one known element for innovator prior to commercial launch of the detailed well-reasoned “factual and legal” another in the closest compound that exists biosimilar entity. The innovator may seek statement on a “claim by claim basis” as to in the prior art does not control the legal preliminary injunction at that time to pre- why an otherwise relevant claim is invalid, conclusion. Particularly, a person of skill vent commercial launch of the biosimilar if unenforceable, or not infringed. Claim in the art may not be motivated to choose any asserted patent(s) are identified in the validity is by far the most challenged a particular compound as a candidate spe- innovators original list but are not agreed attribute. cies, i.e., as a “lead compound”, per se, to upon by the parties under the BPCIA The statutory requirements for patent- modify.27 Indeed, as in the case of Lilly, exchanges as relevant. ability, e.g., 35 USC §§101, 102, 103, often thousands of compounds exist in the v) Declaratory Judgment Actions and 112 apply to all subject matter, in prior art as examples from which Structure Actions for Declaratory Judgment (DJ) the same manner, as a matter of law. Activity Relationships (SARs) are identi- concerning patent claims may not be filed, if However, because of the general nature of fied and characterized during the quest for the ABPA applicant has met BPCIA require- the respective fields and physical differ- a therapeutic entity or an improved version. ments before the ABPA applicant provides ences between small molecule compounds Although, as accurately pointed out by the 180-days notice to the innovator prior to com- and biologics, distinct approaches are nec- ANDA filer in the Lilly case, a compound mercial launch of the biosimilar entity. Once essarily required to particularly point out very close to olanzapine existed at the time the 180-days prior to commercial launch and describe therapeutic entities. of the invention amongst a myriad of other notice is received, however, DJ action can be 1. Claim validity is dependent upon compounds; the state of established SAR filed concerning any patent identified on the whether the properly construed language known and accepted at the time would original innovator list of patents. of the claim in view of the disclosure meets not direct a medicinal chemist to proceed Nevertheless, should the ABPA appli- the current authoritative judicial inter- with that compound. The prior art at the cant fail to provide the innovator a copy pretation of the statutory requirements for time of olanzapine particularly taught away

26 INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 from using the type of compound that, in USC §112.1 is the most common a newly identified, isolated, and charac- hindsight, was closest structurally, i.e., a validity issue decided by the Federal terized native biological target can yield non-halogenated compound. Circuit. generic claims to antibodies that meet the The US Supreme Court basically clari- Biologics, in contrast to small molecule statutory requirements for written descrip- fied in the decision of KSR International compounds, due to their biosynthetic origin tion. Nevertheless, these type claims have Co. v. Teleflex Inc. that if something is and structural complexity, tend to be dif- not posed significant problems in the drug- obvious to try it is fundamentally obvious. ficult to define precisely at the molecular discovery industry for several reasons. 550 U.S. 398 (2007): level. Accordingly, biologics are normally First, truly novel targets no longer abound When there is a design need or mar- exemplified by processes of production and in the industry; i.e., due to evolution of ket pressure to solve a problem and claimed in terms of structure, function, and technical methods, most biological targets there are a finite number of identi- effect. have had antibodies generated against them fied, predictable solutions, a person i. Biologics tend to be products as a common tool for characterization in the of ordinary skill has good reason to of elegant science and elucidation art. Second, even if an initial broad claim to pursue the known options within his of mechanisms of human disease. a genus of antibodies against a newly dis- or her technical grasp. If this leads However, a) identifying a mechanism of covered biological target issues, this type to the anticipated success, it is likely human disease and an integral biological of claim is normally expired by the time the the product not of innovation but of target for intervention; and, b) providing a target becomes of true development interest ordinary skill and common sense. In specific entity to do the job, are indeed dis- to the drug-discovery industry. that instance the fact that a combina- tinct accomplishments. Therefore, defining iii. The Federal Circuit ultimately tion was obvious to try might show an entity merely by what it does, i.e., purely clarified the statutory requirement that it was obvious under § 103. functional definition, rather than what it is, for written description and how it 550 US at 421 (emphasis added). While i.e., structure, does not meet the statutory applies to purely functionally defined 28 the KSR Court rejected a rigid application requirement for written description. therapeutics - no matter how elegant of the teaching, suggestion, or motivation The statutory requirement is interpreted the science - in the much anticipated (“TSM”) test in an obviousness inquiry, to require the patent disclosure to illustrate March 2010 en banc decision Ariad the Court acknowledged the importance ‘possession’ of the full scope of the subject Pharms., Inc. v. Eli Lilly & Co. 598 of identifying “a reason that would have matter, as claimed, to one of ordinary skill F.3d 1336 (Fed. Cir. 2010). Preeminent 29 prompted a person of ordinary skill in the in the art at the time of the invention. A inventors, including a Nobel Laureate, were relevant field to combine the elements in seminal case which addressed this issue the first to identify NF-κB and to elucidate the way the claimed new invention does” in was Univ. of Rochester v. GD Searle & Co., the precise mechanism by which NF-κB an obviousness determination. KSR, 127 S. wherein scientists were the first to identify activates gene expression which, in turn, Ct. at 1731. Thus, in cases involving new and characterize the biological enzymes mediates certain disease conditions. The chemical compounds, it remains necessary COX1 and COX2 and to recognize the method claims at issue each require the to identify some reason that would have led pharmacological value of the prospective single step of reducing NF-κB activity. The a chemist to modify a known compound in ability to antagonize COX2 without affect- claims encompass the use of all substances a particular manner to establish prima facie ing the activity of COX1. 375 F.3d 1303 that achieve the desired result, e.g., reduc- obviousness of a new claimed compound. (Fed. Cir. 2004). Importantly, however, ing the binding of NF-κB to its biological Otherwise it is not obvious to try. Takeda no means, per se, of antagonizing COX2 recognition sites. Similar to the facts of Chem. Indus., Ltd. v. Alphapharm Pty., without affecting the activity of COX1, was Rochester, however, no substances are dis- Ltd., 492 F.3d 1350 (Fed. Cir. 2007). disclosed.30 Nevertheless, a claim issued closed in the specification for employment Obviousness based on structural similar- to a method of controlling inflammation by as agents in the claimed methods. Also, ity can be shown by identification of some administering a compound that selectively similar to the facts of Rochester, the pat- motivation that would have led one of inhibits COX-2. The patent holder sued ent holder brought suit the day the patent ordinary skill in the art to select and then alleging infringement by Pfizer’s sale of its issued alleging infringement by the sale modify a known compound in a particular selective-COX-2 inhibitors CELEBREX® of EVISTA® and XIGRIS®. The Federal way to achieve the claimed compound. The and BEXTRA®. The Federal Circuit con- Circuit followed the rationale and holding requisite motivation can come from any cluded, inter alia, that the asserted claims of Rochester. The current authoritative number of sources and need not necessarily recite a description of the problem to be interpretation of the statutory requirement be explicit in the art. Eisai Co. Ltd. v. Dr. solved while claiming all solutions to it - is that a physical description of what an Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. “leaving it to the pharmaceutical industry invention is, per se, rather than purely Cir. 2008). However, “[t]o the extent an art to complete an unfinished invention”. The functional and/or conclusory terms of a is unpredictable, as the chemical arts often description must convey what the entity is, problem to be solved, is required as part are, KSR’s focus on ‘identified, predictable not just what it does. of the quid pro quo for the right to exclude solutions’ may present a difficult hurdle ii. However, Noelle v. Lederman, others. The disclosure of the specification because potential solutions are less likely still stands wherein the Federal Circuit fun- itself must demonstrate possession of the to be genuinely predictable.” Id at 1359. damentally held that if a novel biological claimed subject matter to one of ordinary See, also, P&G v. Teva, 566 F.3d 989 (Fed. target (antigen) is deposited or otherwise skill in the art at the time of filing. 31 A Cir. 2009); Daiichi Sankyo Co. v. Matrix characterized in a manner that meets the description that merely renders the inven- Laboratories, Ltd., 619 F.3d 1346 (Fed. statutory requirement for written descrip- tion obvious does not satisfy the require- Cir. 2010). tion, a genus of antibodies that bind that ment A sufficient description of a genus of b. Biologics - The statutory require- target is necessarily disclosed as well. 355 therapeutic entities fundamentally requires ment for written description under 35 F.3d 1343 (Fed. Cir. 2004). Accordingly, the disclosure of either a representative

INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 27 number of species falling within the scope reduction to practice. What it does demand indeed; and, in and of itself, is a substantial of the genus or structural features common is that one of skill in the art can ‘visualize impediment to any prospective competitor. to the members of the genus so that one of or recognize’ the claimed antibodies based Biologics currently have double the skill in the art can “visualize or recognize” on the specification’s disclosure … [o]ne of approval rate of small molecule com- 34 the members of the genus. The Federal skill in the art cannot look at a mouse vari- pounds. IPT Circuit succinctly stated, “[p]atents are able region and know how to turn it into a not awarded for academic theories, no mat- human variable region with the same affin- [email protected] ter how groundbreaking or necessary to ity and activity as the mouse antibody.” the later patentable inventions of others.” Id. The Federal Circuit concluded that the ENDNOTES Requiring a written description limits pat- scope of the right to exclude cannot over- (Parts I (IPT July 2011) and II) ent exclusivity to those who provide a mate- reach the scope of the contribution. 1. Small molecule compounds, corresponding rial solution, per se, to a problem - while hydrates, enantiomers, salts, prodrugs, metab- disallowing any preemption of the future CONCLUSION olites, analogs, and polymorphs are precisely before it has arrived. Ariad Pharms., Inc. v. defined. In other words chemists and pharma- The industry is clearly in the process cologists are aware of and can describe in certain Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. of shifting toward biologics for several terms what exact form of a drug exists. 2010) (en banc). reasons. 2. The average weight of a pharmaceutical compound iv. Antibodies (Centocor) Patent protection relevant to a cur- is around 500 daltons; whereas, a biopharmaceu- Although, under Noelle, a newly discov- rent or prospective biopharmaceutical has tical entity such as ENBREL® (etanercept), for ered biological target may support a broad been, in effect, incidental to maintain- example, weighs (300x) about 150,000 daltons. generic claim to antibodies against that ing market exclusivity due to the lack of 3. Biologics are typically derived and/or created target, antibodies against an old target must threat of generic biologics (no Abbreviated from native biological entities including receptors, be described particularly.32 The Federal Biological Product Applications (ABPAs)). ligands, and antibodies against natural targets. Circuit recently decided an important case Small molecule compound patents figure 4. Nucleic acid construct, expression host species, involving claims to antibodies which bind much more prominently in the scheme of and production conditions (including temperature a specific pharmacologically-effective site and media composition) define the identity of the market exclusivity, compared to biologics biologic species, per se (transcriptional splicing, on a previously known biological target. for several reasons. ANDAs are a litigious post-translational modification, glycosylation, as The decision emphasized the fact that the process which most frequently stand or fall well as association of entity subunits). statutory requirement for written descrip- on the validity of patent claims. Ownership 5. $1.2 billion and fifteen (15) years, according tion applies to the complete subject mat- of a valid and enforceable patent claim to Pharmaceutical Research Manufacturer’s ter of the claim, i.e., the disclosure must which encompasses relevant NDA subject Association (PhRMA). illustrate possession of the claimed subject matter for the purpose of excluding compe- 6. Preclinical development involves biological model matter, including all of its limitations.33 tition for the remaining term of the patent determination whether a new entity is reasonably Centocor Ortho Biotech, Inc. v. Abbott will continue to be paramount concerning safe for initial use in humans and if the compound Laboratories (Fed. Cir. 10-1144, Decided exhibits pharmacological activity to justify com- small molecule compounds. Biologics are mercial development. February 23, 2011). afforded 12y NBE, compared to 5y NCE for Centocor and Abbott both commercial- 7. Biological products subject to PHS also meet small molecule compounds. Since a total of the definition of drugs under FDCA. Since bio- ized antibodies against the same TNFα about fourteen years, more or less, is gen- logical products are a subset of drugs, both are epitope for the treatment or arthritis. Mouse erally required to bring a new therapeutic regulated under FDCA. However, only biological antibodies against human TNFα previ- entity through development and regulatory products are licensed under section 351 of PHS. ously existed; however, the antibodies did approval, and patent term is 20 years from Regulations regarding BLAs include 21 CFR not necessarily bind a pharmacologically- the earliest species application for patent, §§600, 601, and 610. effective site. Centocor developed a human- remaining patent term upon FDA approval 8. Section 351(k) of PHS Act (42 USC §262(k)) ized mouse antibody (REMICADE®). of a species therapeutic, per se, is generally added by the BPCI Act, describes requirements Abbott developed a fully human antibody for an application for a proposed biosimilar and on the order of about six (6) years. That an application (or a supplement) for a proposed ® (HUMIRA ). The asserted Centocor pat- leaves, in this general example, about six interchangeable biological product. ent described mouse-derived antibodies (6) years (plus any 35 USC §156 exten- 9. Drug Price Competition and Patent Term against a specific TNFα epitope. Centocor sion) exclusivity for the small molecule Restoration Act. 21 USC §§355, 360cc; 35 asserted claims to an isolated recombi- compound, the last of which depends upon USC §§156, 271), amended by the Medicare nant antibody against the TNFα epitope, patent protection; and, twelve (12) years Prescription Drug Improvement and Modernization “wherein the antibody comprises a human exclusivity for the biologic, none of which Act (MMA), Pub. L. No. 108-173, 117 Stat. variable region”. The binding site (variable depends upon patent protection. Moreover, 2066 (June 18, 2003) (collectively, the “Hatch- Waxman Act”). region) of all Centocor exemplified antibod- although NDAs and BLAs, including mate- ies was of mouse origin. Importantly, no rials and process of production, are con- 10. FDCA §505(j). 21 USC §355(j). As part of the ANDA process, a generic manufacturer must human variable regions (binding portion) fidential, small molecule compounds are make a certification addressing each patent iden- were disclosed. Centocor argued that the simply produced, regardless of the exact tified in the Orange Book. 21 USC §355(j)(2)(A) written description requirement demands NDA process. Not so for FDA approved (vii). A prospective generic manufacturer must neither actual reduction to practice nor biologics. Exact production conditions and select one of four alternatives permitting use of working examples to claim an invention. processes frequently define critical phar- the patented product or process: (I) no such pat- The Federal Circuit panel responded, “[i] macological characteristics of approved ent information has been submitted to the FDA; (II) the patent has expired; (III) the patent is set ndeed, we have repeatedly indicated that biopharmaceuticals. Accordingly, produc- to expire on a certain date; or (IV) the patent is the written description requirement does tion of a BPCIA biosimilar (much less an invalid or will not be infringed by the manufac- not demand either examples or an actual “interchangeable” one) is a daunting task ture, use, or sale of the generic drug.

28 INTELLECTUAL PROPERTY TODAY JULY-AUGUST, 2011 11. FDA publication of Approved Drug Products with menting the law (BPCIA) in the form of regula- to antibodies against a fully characterized novel Therapeutic Equivalence Evaluations (Orange tions. target antigen can meet the statutory requirement Book (list of drugs, applicable patents and their 20. The one year period of exclusivity, however, may for written description. Noelle v. Lederman, 355 associated use codes)). 21 USC 355(j)(2)(A)(vii) expire if an approved “interchangeable” fails to F.3d 1343 (Fed. Cir. 2004). (IV) (paragraph IV certification). launch within 18 months of either a final court 29. The written description requirement does not 12. Alternately, for example, toward FDA approval for decision on all the asserted patents under BPCIA require the applicant to describe every embodi- an approved use not covered by a method-of-use against the first approved interchangeable or the ment within the scope of the subject matter patent for a listed drug, a generic manufacturer matter is dismissed (with or without prejudice); claimed; however, the description must clearly may make a “section viii statement.” 21 USC -or- 42 months pass since approval of the first allow persons of ordinary skill in the art to recog- §355(j)(2)(A)(viii). interchangeable and a patent infringement lawsuit nize that what is claimed was in fact conceived. under BPCIA is still ongoing; -or- no lawsuit and 30. The specification did not describe any compound 13. This provision was amended June 18, 2003 failure to launch first interchangeable within 18 (MMA), to allow multiple ANDA applicants to capable of performing the claimed method (a months of approval. COX-2-selective compound). obtain the 180-day exclusivity period. A limita- 21. 351(k) applications are barred from submission to tion was placed on the approval of any ANDA or 31. Ensures that the public receives a meaningful the FDA for the first four years. 505(b)(2) application to a single 30-month stay. disclosure in exchange for being excluded from 68 Fed. Reg. 36676. The stay is the lesser of 22. Innovator must add relevant patents which come practicing an invention for a period of time. 30 months or the amount of time required for a into existence during the process to the list to 32. This concept is not new. Novel chemical species, Federal Court judgment, settlement order, or con- provide notice within 30 days the patent. for example, although within the scope of a previ- sent. 21 USC §355(j)(5)(B)(iii). The court enter- 23. Claims to specific forms, methods of use, specific ously disclosed structural genus, are patentable if taining this suit has discretion to order a shorter dosage/administration regimen, and formulations, demonstrated to possess unexpected properties. or longer stay if either party to the action fails to for example, frequently contribute to term of IP “Claiming antibodies with specific properties, reasonably cooperate in expediting the action. exclusivity. e.g., an antibody that binds to human TNF-α with certain specificity, can result in a claim 14. 21 USC §355(j)(5)(F)(ii). See, 21 CFR 314.108 24. Total patent life with the patent extension cannot that does not meet written description even if New Drug Product Exclusivity. Prior approval of exceed 14 years beyond approval. the human TNF-α protein is disclosed because an acid form of a drug, for example, does not bar 25. Patent term restoration under 35 USC §156 also antibodies with those properties have not been NCE exclusivity for a salt or ester of the same applies to biologics generated by recombinant adequately described.” Centocor Ortho Biotech, drug. DNA. Inc. v. Abbott Laboratories (Fed. Cir. 10-1144, 15. Paragraph IV ANDAs are barred from submission 26. A prima facie case of obviousness requires struc- Decided February 23, 2011). to the FDA for four years only. tural similarity between claimed and prior art 33. As stated supra, as part of the quid pro quo for 16. 21 USC §355(j)(5)(F)(iii). subject matter where the prior art gives reason or the right to exclude others, a physical description motivation to make the changes. Further, a reason- of what an invention is, per se, is required rather 17. 21 USC §360. 21 CFR §316. able expectation of success, not absolute predict- than purely functional and/or conclusory terms of 18. 21 USC §355(a). 21 CFR §§201, 312, 314, 601. ability, supports a conclusion of obviousness. 471 a problem to be solved. Possession must be illus- F.3d 1369 (Fed. Cir. 2006). 19. Title VII of the Patient Protection and Affordable trated to one of ordinary skill in the art at the time Care Act amends PHS (PL 111-148 (Biologics 27. However, a single compound must not necessarily of filing. A description that renders the subject Price Competition and Innovation Act (BPCIA) be selected as a “lead compound” to support an matter of the claim obvious does not satisfy the (Biosimilars Act) of 2009)), signed into law by obviousness rejection. requirement. President Obama on March 23, 2010. FDA is 28. The Federal Circuit has made a standing excep- 34. Berkrot B., Success Rates for Experiemental currently in the process of interpreting and imple- tion to this general rule in that generic claims Drugs Falls: Study, Reuters, February 14, 2011.

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