[Methods and Principles in Medicinal Chemistry] Prodrugs and Targeted Delivery (Towards Better ADME Properties) || Intellectual Property Primer on Pharmaceutical Patents with a Special

3Intellectual Property Primer on Pharmaceutical Patents with aSpecial Emphasis on Prodrugs and MetabolitesEyal H. Barash

3.1Introduction

An example of a prodrug on the market today is enalapril, the active ingredient inMerck�s Vasotec�. When orally administered, an esterase enzyme metabolizesenalapril hydrolyzing it into the active moiety. FDA approved enalapril, an ACEinhibitor used for the treatment of hypertension, on December 24, 1985. It wentgeneric on August 22, 2000 whenMerck�s pediatric exclusivity expired. On that date,FDA approved generic versions of Vasotec belonging to nine different generic drugcompanies.1)Nevertheless,Merck enjoyed a nearly 15-yearmonopoly on sales of thisblockbuster drug due to its vigorous patent portfolio. Merck�s protection includedpatents directed to compounds, compositions, methods of treatment, processed ofmanufacture, and metabolites.

This chapter is divided into two principal sections. Section 3.2 discusses theinterface of FDA and patent law, or the Hatch-Waxman Act. Its effect on thepharmaceutical industry cannot be underestimated, and it is a major driver ofpharmaceutical patent strategy for both innovators and generic companies. InSection 3.3, several basic concepts of patentability are presented. These conceptsfocus on pharmaceuticals and discuss the nuances associated with prodrugs andmetabolites.

3.2Patents and FDA Approval Process

FDA has two simple, but arduous, requirements for drug manufacturers to meet inorder to legally sell their products in the United States: safety and efficacy. These

1) Data collected from Orange Book located at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm and by searching for enalapril maleate and tabulating the number of approvals on August 22,2000.

Prodrugs and Targeted Delivery: Towards Better ADME Properties. Edited by Jarkko RautioCopyright � 2011 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32603-7

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deceptively simple standards consume tremendous amounts of resources and moreoften than not, lead to failure. When a pharmaceutical company embarks upon adevelopment program, it must generate data that the company will use to file a NewDrug Application (NDA). The NDA is usually directed to a particular chemical entityand formulation. However, an NDA filer who wishes to protect its product againstother innovatorsmust think beyond the commercial product. In other words, it musthave �genus� protection so as to include products for which it may have little if anydata. Consider, for example, the drug Humira�.

Abbott�s Humira drug had sales of about $4.5 billion in 2008.2) A competingproduct, Johnson & Johnson�s Remicade� had sales of 3.748 billion that same year.3)

Both drugs employ monoclonal antibodies that are specific to TNF-a. Humira isderived solely from human cells using recombinant DNA technology. Remicade, onthe other hand, is composed of �human constant and murine variable regions�4)

Humira was approved on December 31, 2002 and Remicade on August 24, 1998.Johnson & Johnson filed suit against Abbott for patent infringement. The act ofinfringementwasnot based onAbbott using the sameproduct as Johnson& Johnson,but on a different one that, according to Johnson & Johnson fell within the claims ofU.S.Patent7,070,775.The juryagreedwith Johnson&Johnsonandawardeddamagesto the tune of nearly $1.7 billion. Claims 1 and 2 of the patent read as follows:

1) An isolated recombinant anti-TNF-a antibody or antigen-binding fragmentthereof, said antibody comprising a human constant region, wherein saidantibody or antigen binding fragment (i) competitively inhibits binding of A2(ATCCAccessionNo. PTA-7045) to human TNF-a, and (ii) binds to a neutralizingepitope of human TNF-a in vivo with an affinity of at least 1� 108 liter/mole,measured as an association constant (Ka), as determined by Scatchard analysis.

2) The antibody or antigen-binding fragment of claim 1, wherein the antibody orantigen-binding fragment comprises a human constant region and a humanvariable region.

Thus, although Johnson & Johnson never made a fully humanized monoclonalantibody product, Claim 2 of its �775 patent was not limited to such an antibody.Rather, the claim language states that the fragment �comprises a human constantregion and a human variable region.� The jury agreed with Johnson & Johnson thatsuch claim language included within its scope an antibody or fragment thereof,which was fully humanized. In the abstract, the fact that Johnson & Johnson hadnever made such an antibody is not necessarily fatal to the patent. There is norequirement in patent law that an applicant makes working examples of all speciesthat fall within a genus. However, if a claim is too broad, it may fail if it is determinedthat the claim encompasses matter that is neither described in the patent norreproducible. Thus, the question that will certainly be raised on appeal is whetherthere was sufficient data that include human antibodies in the Johnson & Johnson

2) See Abbott Laboratories 2008 10-K Annual Report, March 3, 2009, p. 61.

3) See Johnson & Johnson 2008 10-K Annual Report, February 20, 2009, p. 36.

4) See Remicade label.

62j 3 Intellectual Property Primer on Pharmaceutical Patents

patent application to support such a claim.5) Nevertheless, if Johnson & Johnsonprevails on appeal, it may eliminate a competing innovator product from themarketplace.

The more common foe to the patentee of pharmaceutical drugs is the ANDA filer.The Abbreviated New Drug Application (ANDA) and differs substantially in scopefromanNDA.Rather than having to prove safety and efficacy, anANDAholder needsmerely to show that its drug product is �bioequivalent� to the NDA holder�s drugproduct and cite to theNDA for proof of efficacy and safety.6)Because they donot haveto pay for costly research, development, and clinical programs, ANDA holders(typically generic drug companies) spend only a tiny fraction of money of bringingtheir drug to market compared with the innovator�s expenses for their brand-nameproduct.

In order to avoid performing safety and efficacy tests, ANDA filers must have thesame active ingredient as the innovator used in its NDA filing. Thus, from a patentperspective, it would appear relatively straightforward to protect against genericcompetition. One should have what patent practitioners refer to as a �picture� claim,namely, a patent claim covering the chemical entity used in the drug product andnothing more. For example, the drug Abilify� was first marketed in 2002 for thetreatment of schizophrenia and has since grown into a blockbuster drug. It isprotected by U.S. Patent 5,006,528 that claims the following in Claim 12:

12: 7-f4-½4-ð2; 3-DichlorophenylÞ-1-piperazinyl�butoxyg-3; 4-dihydrocarbostyril:This claim simply recites the chemical structure of the active ingredient inAbilify�

known as apripazole and nothing more. The claim derives value from the require-ment that the generic drug copy the active ingredient of the innovator. The situation isnot always so straightforward, however. Often pharmaceutical companies sue overinfringement of formulation patents with limitations based on characteristics of theformulation or ingredients. The claim may require, for example, a particularexcipient, a particle size distribution, or a release profile. Thus, because the innovatorbears burden of proof, it may have to perform tests on the generic formulation toprove infringement.

Effective protection against generic competition also requires a thorough under-standing of howpatent law and FDA law overlap.While such a comprehensive reviewis beyond the scope of this chapter, it is worth discussing the basics so that the readerappreciates how prodrugs andmetabolites can be used to protect, or to defeat, patentcoverage on pharmaceutical products.

5) In order to obtain a patent, there must besufficient �support� in the patent application tosupport the patent claim. 35 U.S.C. x 112 {1states that �[t]he specification shall contain awritten description of the invention, and of themanner and process ofmaking and using it, insuch full, clear, concise, and exact terms as toenable any person skilled in the art to which itpertains, or with which it is most nearly con-

nected, tomake and use the same, and shall setforth the best mode contemplated by theinventor of carrying out his invention.� Thereis considerable controversy currently onwhether the written description and enable-ment provisions are separate. This topic isbeyond the scope of this chapter.

6) See 21 U.S.C. x355 et seq.

3.2 Patents and FDA Approval Process j63

A practical place to begin the discussion of brand name and generic drugs is todiscuss the case of Roche v. Bolar.7) Roche had developed the drug Dalmane� andbrought it onto themarket. Bolar wished to develop a generic version ofDalmane andbegan its research and development program prior to the expiration of the patentcovering Dalmane. Roche learned of this program and filed a patent infringementsuit against Bolar arguing that this work infringed Roche�s patent. The court agreed.Although Bolar attempted to argue that such use was merely research-based andexperimental, the court ruled that no such exception to patent infringement wasavailable to Bolar and Roche was able to prevent Bolar from developing a genericversion of Dalmane during the term of its patent.

Shortly after deciding this case, Congress enacted theHatch-WaxmanAct that wasmeant to regulate the tug-of-war between innovator and generic companies. Amongthe things it attempted to do was to create a balance between the need for patentexclusivity for innovator companies and the access to generic drugs for the public. Itstruck a compromise that legislatively overturned Roche v. Bolar, and among otherprovisions, established a �safe harbor� from patent infringement whereby the abilityto perform research and development on patented pharmaceutical products for thefiling of an ANDA was exempt from patent infringement.8) The Hatch-Waxman Actalso created a procedure by which innovators and generics could fight their patentdisputes in court prior to the market entry of a generic product.

The disputes begin with the FDAOrange Book that lists all approved drug productsin theUnited States. It also lists the patent status associatedwith each product.9)Oncea generic company decides to launch a product, it must consult the Orange Book todetermine the patent status of the product whose NDA it wishes to refer. There arefour possible outcomes according to the statute:

(I) There is no patent covering the pharmaceutical product (Paragraph I)(II) The patents covering the product have expired (Paragraph II)(III) There are active patents covering the product, but the generic company

seeking approval will not launch any drug until the patent covering theproduct has expired (Paragraph III); or

(IV) Apatent covering the product has not expired and a generic believes that it willeither not infringe the patent or the patent is invalid and wants the FDA togrant approval the patents notwithstanding (Paragraph IV).

7) 733 F.2d 858 (Fed. Cir. 1984).

8) The actual language of the statute, 35 U.S.C. x271(e)(1), reads �It shall not be an act ofinfringement to make, use, offer to sell, or sellwithin the United States or import into theUnited States a patented invention . . . solelyfor uses reasonably related to the developmentand submission of information under a Fed-eral law which regulates themanufacture, use,

or sale of drugs or veterinary biologicalproducts.� It has been interpreted to bebroader than the mere filing of an ANDA (seeMerck KGaAv. Integra Lifesciences I, Ltd.545US193 (2005)) and it is still amatter of debate as tohow far the safe harbor extends.

9) The Orange Book is publicly available on theFDA Web site www.fda.gov, and is regularlyupdated.


The first three outcomes involve only the ANDA applicant and the FDA. Incertifications involving these first three paragraphs, FDAwill approve the applicationwithout regard to any patent exclusivity associated with the innovator�s product. In aso-called Paragraph IV certification, however, the ANDA applicant is required by lawto notify the innovator of its intent to enter themarket prior to patent expiry.10)Uponreceipt of the notice, which is supposed to contain the bases for theANDA applicant�sbelief that the patent neither will be infringed nor is valid, the innovator has less than45 days tomake a critically important decision –whether to file a patent infringementlawsuit against the ANDA applicant under the assumption that if it were to get FDAapproval, its commercial product would infringe the Innovator�s patent.11) If such asuit is filed, a 30-month stay or hold is placed on FDA�s approval process and duringthe time of the stay, although the agencymay review the ANDA, it may not approve itabsent court intervention. Thus, the filing of a lawsuit in effect puts an automaticdelay of 30 months on the market entry of a generic product.12) It is not hard toappreciate how this stay is of tremendous value to innovators as they plan a strategy toprotect their valuable products from generic competition.

A critical caveat to this strategy is that only those patents that the innovator electsto list in the Orange Book are eligible to receive the 30-month stay protection. Thus,failure to list an appropriate patent can have devastating consequences. Unsurpris-ingly, the law regulates the kinds of patents that may be listed in the Orange Book.Under the Code of Federal Regulations, only the patents such as the following areeligible for listing: drug substance (ingredient) patents, drug product (formulationand composition) patents, and method of use patents. Metabolite patents, forexample, are not eligible for listing in the Orange Book.13) In other words, theOrange Book requires that patents covering the active ingredient prior to patientingestion may be listed, but transformations upon human consumption, whileeligible subject matter for patent protection, generally are not eligible for the addedprotection afforded by listing in the Orange Book. Accordingly, prodrug patents areeligible for listing in the Orange Book. There is no requirement to identify to FDAthat the listed drug is a prodrug.

3.3Obtaining a Patent

Before one can devise an effective patent enforcement strategy, onemust go throughthe patent procurement process. In the United States, the Patent and TrademarkOffice (PTO) is responsible for issuing patents based on properly preparedpatent applications claiming appropriate subject matter. This section explores therequirements of how to obtain such protection with a special emphasis on

10) See 21 U.S.C. x 355(b)(2)(A)(iv).11) See 21 U.S.C. x 355(c)(3)(C).12) See id.Acourtmay choose to shorten or lengthen the stay although neither is a common occurrence.

13) 21 CFR x 314.53(b)(1).

3.3 Obtaining a Patent j65

pharmaceutical products with alerts for special issues that relate to prodrugs andmetabolites.

3.3.1Utility

An invention must be useful in order to be patentable. In the pharmaceutical arts,such as for prodrugs and metabolites, this does not mean an invention must be safeor effective as those terms are used by the FDA. This issue arose In re Brana14)wherethe inventors had filed for a patent application on a class of compounds that theyclaimed to have antitumor capabilities. The compounds were described as moreeffective than structurally similar compounds found in the published literature anddata were presented in the application showing �good action� against human tumorcells in vitro.15) The examiner rejected the claims arguing that there was insufficientevidence to establish the claimed chemical compounds had a practical utility. UnderPTO procedure, when an examiner has rejected a case,16) the applicantmay appeal toa board of administrative law judges who sit at the PTO. In this case, the board agreedwith the examiner. Applicants have the right to appeal a board decision to the UnitedStates Court of Appeals for the Federal Circuit,17) which sits in Washington, DC.Upon appeal, the court reversed the board and found that the applicants hadmet theutility requirement. The court ruled that the standard tumor models, using in vivotests, were sufficient to meet the utility requirement. It may be worth noting,however, that an even stronger case for utility can be made by using art-recognizedanimal models. Indeed, in prior cases, the courts had ruled that �proof of an allegedpharmaceutical property for a compound by statistically significant tests withstandard experimental animals is sufficient to establish utility.�18) However, theManual of Patent Examination Procedure, the MPEP, which is the guide used byexaminers in examining patent applications, summarizes case law stating that�[c]ourts have repeatedly found that the mere identification of a pharmacologicalactivity of a compound that is relevant to an asserted pharmacological use provides an

14) 51 F.3d 1560 (Fed. Cir. 1995).

15) Id. at 1563.

16) In prosecution, after an examiner makes arejection, the applicants have an opportunityto respond to the examiner. The examinerthen reviews the case and arguments a sec-ond time and if there is still disagreement, theexaminermay issue a �final� rejection. Such afinal rejection may be appealed to the PTOBoard.

17) The Court of Appeals for the Federal Circuitis a subject–matter based court unlike theother courts of appeal. For example, in mostcases in the federal system, the disputingparties will choose a trial court based upon

geography. The losing side then has the rightto appeal the trial court ruling to an appealscourt. In most cases, the appeals court whichhears the case is based on the location of thelower court. Thus, a lower court�s decision inChicago will be appealed to the Court ofAppeals for the Seventh Circuit. A lowercourt�s decision in Los Angeles will be heardby the Court of Appeals for the Ninth Circuitand so on. For patents, however, all appeals,regardless of the location of the lower courtare heard by Court of Appeals for the FederalCircuit that also hears appeals from the Pat-ent Office.

18) 51 F.3d at 1567.


�immediate benefit to the public� and thus satisfies the utility requirement.�19) TheCourt in In re Brana also noted that structural similarity to known compounds isrelevant in the utility inquiry.20)

3.3.2Novelty

One cannot obtain a patent on an invention that is not new. Trying to determinewhether something is new, however, can be daunting, especially with patents tometabolites. A traditional view of novelty rests with an analysis of what is termed�prior art.� Prior art may be such as journal references, patents, sales, and importsthat all occur before a particular date. Sometimes, that date is the date before whichthe applicant filed for a patent application. In other circumstances, the date is thatwhich is before the inventor conceived of the invention. Section 102 of title 35 of theUnited States Code sets forth the specific requirements of novelty. The two mostrelevant sections for this chapter are subparts (a) and (b).

Section 102(a) in its entirety reads as follows:

A person shall be entitled to a patent unless (a) the invention was known orused by others in this country, or patented or described in a printedpublication in this or a foreign country, before the invention thereof by theapplicant for patent.21)

Deconstructing section 102(a) reveals that only activities occurring prior to theinvention are relevant. Such actions include patents or publications anywhereworldwide whereas knowledge or use is limited to the Untied States. Also note thatonly actions by third parties may be used as novelty-defeating art under section 102(a). Actions by the inventors are immune to attach under section 102(a). Thus, it is tothe advantage of the inventor to have evidence showing a date of invention that is asearly as possible. For this reason, among others, pharmaceutical companies developlaboratory notebook and corroboration evidence policies. Once a third-party publi-cation publishes, even though a patentmay not yet be on file, properly kept laboratorynotebooks showing a prior date invention date can beused to �antedate� the referenceduring examination at the PTO.22)

19) MPEP x 2107.01.20) 51 F.3d at 1367.

21) 35 U.S.C. x 102(a).22) The PTO will assume that the date of filing is

the date of invention absent evidence to thecontrary. Thus, a relevant publication pub-lished prior to thefiling date will act as section102(a) prior and will be identified as such inan official communication sent to the appli-cant termed an �office action.� In replying to

the office action, the applicant may use lab-oratory notebook pages with an affidavitshowing that the invention occurred prior tothe publication. There are other reasons forkeeping good laboratory records in a patentcontext. For example, in an interference, twoparties are trying to claim the same invention.With some exceptions, the party who canprove prior invention will be entitled to thepatent.


Amore nefarious provision of the novelty section of the Patent Act is section 102 b):

A person shall be entitled to a patent unless (b) the invention was patented ordescribed in a printed publication in this or a foreign country or in public useor on sale in this country, more than one year prior to the date of theapplication for patent in the United States.23)

Under section 102(b), novelty is referenced from the date that is exactly one yearprior to thefiling date of the application (the �critical date�). Like section 102(a), in 102(b), patents or publications can defeat novelty. Note, however, these actions are notlimited to third parties. The applicant�s own actions can doom him. For example,suppose the applicant was to publish his or her work in a journal on August 1, 2010,the publication date starts a one-year clock. If the applicant has not filed a patent byAugust 1, 2011, the patent rights will be forfeited.24) Section 102(b) also introducesthe concepts of public use and �on sale,� which are beyond the scope of this chapter.

It is not enough for a reference to meet the timing requirements of section 102; itmust also be relevant to the claimsof the patent. To anticipate (i.e., render not novel), areferencemust teach all of the limitations of the claim at issue. For example, whereasthe chemical structure of aspirin is certainly older than any claim currently on filewith the PTO, it is hardly relevant to a claim on a new protein drug. Thus, the analysisof the �prior art� is important. Consider the following generic chemical compound:

R

Assume that an applicant has claimed such a structure and defined R as a C1�C6

alkyl. Thus, the applicant would be defining a genus of compounds as opposed to asingle compound. A prior art reference teaching toluene would anticipate that claimfor lack of novelty. Suppose there was a second claim in the application to the samestructure, but where R is a C3�C6 alkyl. In that case toluene would not be anticipatoryart against this claim.Thus, whenpreparing a patent application forfiling, claim scopebecomes a strategic consideration because prior art acts on patent claims, not on theentire patent. Accordingly, patent claims often look like a funnel in terms of scope.Very broad claims are supported by narrower and narrower claims. If it is laterdetermined that a broad claim is held invalid for lack of novelty, a narrower claimmight still survive. Therefore, whereas a broad claim captures more intellectualproperty space thananarrower claim, it alsopresents a bigger target forprior art attack.Returning to the example where toluene is disclosed in the prior art, practitioners

23) 35 U.S.C. x102(b).24) Very few countries have such a grace period. In Europe, for example, there is no grace period. Thus,

failure to file a patent application by the publication date results in loss of patent rights. In the erawhere publications appear on the Internet long before print, pharmaceutical companies mustemploy vigorous and robust systems for reviewing publications prior to journal submission.


would say that the anticipation is express in that there is a reference that expresslyteaches the compound. In some circumstances, however, that teaching ismore subtle.

Consider the following claim: Crystalline Form B of Compound I exhibiting X-raypowder diffraction peaks at about 5.7, 7.9, 10.0, and 11.5 degrees two-theta. In thisclaim, applicants have prepared a purportedly new polymorph of Compound I andwish to obtain patent coverage. As is sometimes the case in the polymorph world,prior art may exist as to the chemical entity. In this case, let us suppose that there is aprior art reference teaching Compound I that fails to teach anything regarding thecrystalline form of the compound. Instead, the patent provides a synthetic examplewith the formation of a �crystalline white powder.� Confirmation of structure is givenby the usual techniques: NMR, IR, and elemental analysis for instance. Thus, thereference has no express teaching of the crystalline form because there is noindication of which crystalline form was produced. During patent prosecution, theexaminer will want to know whether that crystalline form was Form B or anotherform andwill likely reject the claim. If the crystallinematerial was in fact FormB, it isnovelty-defeating prior art. The material that was never analyzed in the prior art is ofno concern. The examiner will invite the applicants to reproduce the reference andreport the results.25)

Inherent anticipation also plays amajor role in patents directed tometabolites andprodrugs. In Schering Corp. v. Geneva Pharmaceuticals,26) Schering had received twopatents covering antihistamines: the �233 patent and the �716 patent. The earlierpatent, the �233 patent, claimed loratadine, the active ingredient in the blockbusterdrug Claritin�. After obtaining the �233 patent, Schering obtained another patentrelated to loratadine, the �716 patent, which claimed a metabolite of loratadine calleddescarboethoxyloratadine or DCL.27) DCL differs from loratadine in that whereloratadine has a carboxyethyl group or a ring nitrogen, DCL has a hydrogen atom(Figure 3.1).28) Although the �233 patent did not expressly disclose DCL, the lowercourt found that �DCL was necessarily formed as a metabolite by carrying out theprocess disclosed� in the patent.29)That rulingwas based on teachingswithin the �233patent where patients had ingested loratadine. Such ingestion would necessarilyform the anticipatory metabolite.30) The Federal Circuit agreed with the lower courtand invalidated Schering�s �716 patent on grounds of inherent anticipation eventhough at the time the �233 patent was filed, there was no recognition within thereference that DCL would form.31)

25) This fact pattern is common in the solid-statearts. In not all cases does the examiner suc-ceed in requiring the reproduction of prior artreferences. See, for example, Ex Parte Reguri,Board of Patent Appeals and InterferencesAppeal No. 2007-0313 (September 6, 2007).

26) 339 F.3d 1373 (2003).

27) Id. at 1375.

28) Id.

29) Id. at 1376. Inherency requires that theanticipated feature �necessarily andinevitably� occur. See id. at 1378.

30) Id. at 1380.

31) See id. at 1378.


Inherent anticipation profoundly affects pharmaceutical patent strategies. Typi-cally, as pharmaceutical companies improve their marketed product, be it byadvanced formulations or by better manufacturing practices, they seek to patentthose improvements. Under the Schering case, a company may have to identify anypotentially active metabolites earlier in a drug development process than they wouldhave otherwise. The mere act of disclosing administering a drug to a human mighttrigger the one-year clock under section 102(b). Many in the pharmaceutical patentcommunity were critical of the Schering case. It eliminated the notion that theinherent limitation had to be recognized in the prior art.

In the case of Continental Can Co. USA, Inc. v. Monsanto,32) a patent claimed acontainer having various technical features that provided it with added strength andimpact resistance.33) Monsanto argued that a prior art reference, the �443 patent,anticipated the claimat issue under section 102(a). The claimat issue required hollowribs in a container, and according to testimony presented by Monsanto, although the�443 patent did not state that that the ribs were hollow, by practicing the manufactur-ing process of the �443 patent, one would necessarily obtain hollow ribs. Moreover,the court ruled the following:

To serve as anticipation when the reference is silent about the assertedinherent characteristic, such gap in the reference may be filled with recourseto extrinsic evidence. Such evidence must make clear that the missingdescriptive matter is necessarily present in the thing described in thereference, and that it would be so recognized by persons of ordinary skill.34)

N

Cl

N

OO

N

Cl

HN

1 2

Figure 3.1 Structures of loratadine (1) and its metabolite descarboethoxyloratadine (2).

32) 948 F.2d 1264 (Fed. Cir. 1991).

33) Id. at 1266.

34) Id. at 1268 (emphasis added, citations omitted).


In this case, an article of manufacture contained a characteristic that by inspectioncould tell it readily possessed. It just so happened that the reference teaching themanufacture was silent on the issue. By comparison, in Schering, there was norecognition that the �233 patent could serve as an anticipatory reference because theentire molecule was simply missing from the prior art reference. It was only afterSchering spent significant resources isolating and identifying themetabolite that theidentity of the molecule was revealed. Nevertheless, the courts have not carved outany exception for cases such as Schering and these new lines of inherency casesshould be considered in any pharmaceutical patent strategy involving prodrugs ormetabolites.

3.3.3Nonobviousness

The most subjective of the three attributes an invention must possess prior toqualifying for patent protection is that it must be nonobvious. Section 103 of thePatent Act states in part the following:

Apatent may not be obtained though the invention is not identically disclosedor described as set forth in section 102 of this title, if the differences betweenthe subject matter sought to be patented and the prior art are such that thesubject matter as a whole would have been obvious at the time the inventionwas made to a person having ordinary skill in the art to which said subjectmatter pertains. Patentability shall not be negatived by the manner in whichthe invention was made.35)

Imagine Smith is the first person to invent a lamp attached to a reclining chair.Thus, by assumption, it is novel. It is certainly useful since it allows people to read inthe dark while reclining. Imagine now that the prior art consists of a substantialamount of chair art and lampart. Smith is thefirst person, however, to bring these twodisparate arts together into a unitary invention. Is the invention obvious? The statuteis of little guidance since it, perhaps ironically, does not define what is meant byobvious. That task has been left to the courts and over the years, several definitionsand tests have emerged. In the seminal case of Graham v. John Deere, the SupremeCourt laid out a four-part test to aid in the determination onwhether an inventionwasobvious over the prior art. Under that test, the following four factors are examined:

1) The scope and content of the prior art2) Differences between the prior art and the claims at issue3) The level of ordinary skill in the art4) Secondary considerations such as commercial success, long felt but unsolved

needs, failures of others,36) and the like.

35) 35 U.S.C. x 103(a).36) See Graham v. John Deere Co. 383 US 1, 17 (1966).


The so-called Graham factors also do not define obviousness but instead describethe criteria to use in an obviousness analysis. The Federal Circuit attempted to clarifyby adopting the �TSM� test. TSM stands for �teaching–suggestion–motivation� andunder this test, one looks at a combination of prior art and asks whether there isenough of a connection in the art, which would lead one of ordinary skill in the art toconnect the art in such a way as to come up with the claimed invention. In otherwords, it seeks to determine �whether a person of ordinary skill in the art possessedwith the general problem facing the inventor, would have been led to make thecombination recited in the claims.�37) The TSM test may come explicitly from theprior art or may be implicit.38)

Under the TSM test, one might, or might not find Smith�s invention obvious.What the test would require would be some sort of suggestion, motivation, orteaching which would enable one of ordinary skill in the art to combine the prior artreferences to achieve Smith�s invention at the time Smith filed for his patent. Ifsome sort of TSM could be found, the invention would be obvious. A weakness ofthis test is that in areaswhere there is little prior art, it is difficult tofind an inventionobvious. This criticism was levied against the test in the early days of Internetpatents when the paucity of prior art led the PTO to grant many patents despite thefeelings of professionals in the industry that the patented inventions would havebeen obvious to make even without prior art teachings. Perhaps partly in response,in 2007, the Supreme Court revisited the Federal Circuit�s obviousness analysis inthe case of KSR v. Teleflex39) and although it did not eliminate the TSM test, it didremove it as the sole arbiter of whether an invention is obvious. In a now oft-quotedpassage, the Supreme Court ruled the following:

When there is a design need or market pressure to solve a problem and thereare a finite number of identified, predictable solutions, a person of ordinaryskill has good reason to pursue the known options within his or her technicalgrasp. If this leads to the anticipated success, it is likely the product not ofinnovation but of ordinary skill and common sense. In that instance the factthat a combination was obvious to try might show that it was obvious underx 103.40)

Turning back to Smith, it is clear that under theKSR approach, a patent applicationdirected to the lamp–chair combination would not be valid. Presented with a chairand a lamp, one could readily argue that the combinationwould be obvious to trywitha reasonable expectation of success without having to worry about the teachings orsuggestions to combine from the prior art.

37) Alza Corp. v. Mylan Loboratories, 464 F.3d 1286, 1290 (Fed. Cir. 2006, citations omitted).

38) Id.

39) 550 U.S. 398 (2007).

40) Id. at 421.


In the pharmaceutical arts, KSR lowers the bar for finding an invention obvious.Yet, regardless of which test is employed, whether the prior art or an obvious to tryargument prevails, the unpredictability of the claimed invention plays an importantrole in the analysis.When presentedwith a new compound to examine, the PTO (andthe courts) apply a �lead compound� analysis as it relates to the third Graham factor,namely the differences between the claimed invention and the prior art. This analysis�often turns on the structural similarities and differences between the claimedcompound and the prior art compounds.�41) The examiner or court compares theclaimed invention to the closest prior art compound (the lead compound) anddetermines whether it would have been obvious, at the time the application wasfiled, to transform the lead compound into the claimed compound with a reasonableexpectation of success. The greater the differences between the lead compounds andthe claimed compounds, the harder it is to mount a successful obviousness attack.

This lead compound analysis has particular relevance in the area of prodrugs andmetabolites as a recent lower court decision illustrates.

In Daiichi Sankyo v. Mylan,42) a trial court rule that Sankyo�s patent covering theactive ingredient in Benicar� was not obvious in view of the prior art presented at trialfor failing the obviousness prong of patentability. Claim 13 of the 133 page U.S.Patent No. 5,616,599 was directed to olmesartan medoxomil, the active ingredient inBenicar. Benicar is an antihypertensive agent that works by blocking the angiotensinreceptor and is within the class of angiotensin converting enzyme inhibitors (�ACEInhibitors�). Mylan�s only challenge to the patent was a lack of obviousness based onseveral prior art references: DuPont�s �069 and �902 patents and 13 scientific articlesrelating to work done in this field by DuPont.

The first ACE inhibitor introduced to the market was DuPont�s losartan(see Figure 3.2) that later was marketed by Merck as Cozaar�

Sankyo�s research led it to develop a compound with greater activity than losartan,called olmesartan. Poor oral absorption led Sankyo to form the ester derivative as aprodrug that became known as olmesartan medoxomil (Figure 3.2).

In addition to the �069 patent, DuPont had filed an additional patent application,which matured into the �902 patent, which discloses a number of other relatedstructures with varying lower alkyl substituents at the 4-imidazole position and the5-position being either an aldehyde or a carboxylic acid.

In a complex trial, Mylan argued that the six compounds disclosed in the �902patent constitute lead compounds fromwhich it would have been obvious to developolmesartan medoxomil.43) �Here, lead compound is defined as a compound withknown properties that a medicinal chemist uses as a starting point for drugdevelopment.�44) The court, however, disagreed and found that a medicinal chemistwould not have used any of the compounds disclosed in the �902 patent as a leadbecause numerous other second-generation ACE inhibitors existed at the time of

41) Eisai Co. Ltd. v. Dr. Reddy�s Laboratories, Ltd., 533 F.3d 1353, 1356-7 (Fed. Cir. 2008).

42) 670 F. Supp. 2d 359 (O. N. J. 2009).

43) Id. at 375, �6.

44) Id at 375.


filing which exhibited better efficacy than the six compounds identified in the �902patent.45) The court further found that even if the compounds disclosed in the �902patent were considered lead compounds, the structural differences between thepurported leads and the claimed compound at the 4 and 5 ring positions of theimidazole ring were substantial. For example, at the 4-position, the court found thatolmesartan medoxomil�s use of hydrophilic isopropyl alcohol imparted �criticalstructural differences� on themolecule as comparedwith the lipophilic small alkylsin the �902 patent. At the 5-position, the court found that the prodrug functionalitywas key in distinguishing olmesartanmedoxomil from theMylan leads. Turning todocuments showing that DuPont had failed to make a successful medoxomilproduct with one of the examples, the court found that this �highlights thesignificant differences in overall structure between olmesartan medoxomil andthe �902 patent compounds.�46)

The court then looked at whether there was any motivation or suggestion in theprior art to achieve the claimed invention.47) Finding that a medicinal chemist ofordinary skill would not wish to have a hydrophilic substituent at the 4-position in thering, the court ruled that there would be no motivation to make that substitution. Asfor the 5-position in the ring, the court found thatMylan failed to establish that �sucha person would have been motivated to transform the �902 patent compounds into aprodrug.�48) Citing trial testimony, the court found that innovators ��avoid prodrugs�because �there are problems in determining whether the prodrug itself haspharmacology� and �whether the conversion of the prodrug to the active form isreproducible.� Indeed, the court went on to state that as of 1991, the date the

Cl

N

N N

NN

NHOH

O

OO

O

O

N

N N

N N

NH

OH4

5

3 4

Figure 3.2 Structures of losartan (3) and olmesartan medoxomil (4).

45) Mylan presumably argued that the �902 pat-ent compounds were leads most likelybecause they were closer in structure toolmesartan medoxomil than any otherpotential leads.

46) Id at 378.

47) Interestingly, the court cites KSR earlier in itsopinion, but not during this analysis. The

Court of Appeals for the Federal Circuit,however, affirmed and explicitly cited KSR.See Mylan u. Matrix, 2010 WL 3504 759 atþ 4 (September 9, 2010 Fed. Cir.)

48) Id. at 380.


patent application that matured into the �599 patent was filed, �medicinal chemistsapproached the creation of a prodrug as a �last resort,� �a desperation, last-ditchapproach� that was unpredictable.�49) Focusing on the facts of the particularcase, the court also found that the medoxomil moiety would not have beenconsidered a viable ligand due to failures by DuPont to make medoxomilderivatives of one of the compounds cited in the �902 patent.50) Thus, the lackof a motivation to make olmesartan medoxomil by combining the prior artreferences was unable to convince the court that the patent was obvious andshould be declared invalid.

The Federal Circuit has carried the lead compound analysis further and appliedthe KSR test in other cases. For example, Ortho-McNeil Pharmaceutical, Inc. v.Mylan Laboratories Inc.,51) the court found in favor of Ortho-McNeil and rejectedMylan�s argument that the patent covering Topomax� was invalid for lack ofnonobviousness. Mylan advanced the argument that one of ordinary skill in the artwhen faced with designing an antidiabetes drug would �necessarily design anFBPase inhibitor.�52) Applying the KSR test, the court ruled that �contrary toMylan�s characterization, [the invention of Topomax does not present a finite (andsmall in the context of the art) number of options easily traversed to showobviousness�53) as indicated by KSR. The court cited the numerous decisions andalternative paths a skilled artisan would have to face in the road to developing sucha drug and concluded that the range of options is not a �small and finite number ofalternatives that KSR suggested might support an inference of obviousness.�54)

The court ruled that Mylan�s expert arrived at his incorrect conclusion by merelyretracing the inventor�s path with the benefit of hindsight. In doing so, he�discounted the number and complexity of the alternatives.�55) This type ofhindsight reasoning runs counter to the clear dictate of section 103 that requiresthat obviousness be determined �at the time the invention was made.�56) Thus, away to counter both the TSM test and the more liberal KSR standard is to show thatthe prior art is unpredictable thus making it difficult to state that the invention isobvious.

A further example of this unpredictability was discussed in Sanofi-Synthelabo v.Apotex, Inc.57) In that case, Sanofi asserted the patent covering the active enantiomerin Plavix� against Apotex, who countered that the patent was invalid for severalreasons including obviousness. A central theme of Apotex�s attack was that as theracemate was known in the prior art, it would have been obvious to separate theracemate, which has only one chiral center, into the two enantiomers. The FederalCircuit, however, relying on testimony and evidence advanced at trial ruled that �the

49) Id. (citations omitted).

50) Id.

51) 520 F.3d 1358 (Fed. Cir. 2008).

52) Id. at 1364.

53) Id.

54) id.

55) Id.

56) 35 U.S.C. x 103(a); see also id.

57) 550 F.3d 1075 (Fed. Cir. 2008).


result of this separation of enantiomers was unpredictable�58) and affirmed the lowercourt�s decision that the patent was not invalid for being obvious.

In an obviousness analysis, a court will determine whether a prima facie case ofobviousness has been met. The discussions above focus on whether there isenough evidence that, at first glance, appears to suggest that the patented inventionmay be obvious which, if so, establishes a prima facie case. In the chair/lampanalogy, one can readily assume that the rich prior art makes a good case that,under an initial observation, that combination is obvious. Assuming that to be true,it is still possible, however, that the invention survives an obviousness attack. Forexample, suppose that the chair–lamp combination is a smashing commercialsuccess. Such sales data could be used to rebut the prima facie case by suggestingthe despite the fact that the invention appears obvious, robust sales suggest that theinvention fits a niche or need that was absent in the market. In other words, had itbeen obvious, someone else should have come up with the invention but failed todo so. Such facts as commercial success and long-felt need are called �secondaryconsideration of nonobviousness.�59) In addition to these secondary considera-tions, applicants often rely on unexpected results to rebut a prima facie case ofobviousness. Patent applications for combination products often get initial obvi-ousness rejections during examination at the PTO. A common way to refute theserejections is to present data that the combination product provides a synergisticrather than an additive effect.60) The PTO assumes that an additive effect is to beexpected whereas a synergistic effect is unexpected and, depending on themagnitude and quality of the data, can be successfully employed to rebut theprima facie case of obviousness.

In the Sankyo case, the court found that �olmesartan medoxomil exhibits unex-pected results as compared to the �901 patent compounds in terms of potency,drug–drug interaction, insurmountable antagonism, inverse agonism, and otherrehabilitative properties.�61) The court compared the unexpected results to the �902patent compounds because �the resultsmust be shown as unexpected comparedwiththe closest prior art.�62) Thus, at trial, the facts supported Sankyo�s position that the�599 patent was rightly awarded by the PTO which was confirmed on appeal.63)

Over the past several years, courts have focused significant energy on evaluatingthe strengths of pharmaceutical patents fromanobviousness perspective. Acommonthread both from the TSM test and from the less restrictive KSR standard is that themore unpredictable the invention, the less likely that the PTO or a court or jury willfind the invention obvious. For example, in the area of polymorph patents, a speaker

58) Id. at 1090.

59) See Graham 383 U.S. at 17.

60) The courts have ruled that in order to beunexpected, the properties or results claimedmust show differences in �kind and notmerely in degree� from the prior art results.In re Huang, 100 F.3d 135, 139 (FederalCircuit 1996).

61) 670 F. Supp. 2d at 382.

62) Id.

63) The case was affirmed on September 9, 2010.The opinion currently is available at 2010WL3504 759.


representing the PTO gave a presentation recently stating that it would almost neverbe appropriate to issue an obviousness rejection for a polymorph claim because theart is so unpredictable.64) It may help to view this as the gold standard for trying toprotect prodrug patent claims from inevitable obviousness attacks. A caveat onunpredictability, however, it is not enough to say that the field of prodrugs orpharmaceuticals leads to unpredictable behavior. More specific arguments arenecessary. A recent case from the Federal Circuit makes that clear.

In In re Kubin,65) Amgen appealed a ruling by the Patent Office administrative lawboard66) (hereafter �Board�) that upheld an examiner�s determination that a bio-technology patent application sought by Amgen was invalid for failing the non-obviousness requirement. The application at issue claimedDNAmolecules encodingNatural Killer Cell Activation Inducing Ligand (NAIL). The court evaluated arepresentative claim as follows:

An isolated nucleic acid molecule comprising a polynucleotide encoding apolypeptide at least 80% identical to amino acids 22-221 of SEQ ID NO: 2,wherein the polypeptide binds CD48.67)

The Board rejected the claim as obvious primarily over two references: U.S. Patent5,688,690 (Valiante) and a laboratory manual (Sambrook).68) According to the Board,Valiante taught a receptor protein called �p38� that Amgen agreed is the same proteinas NAIL.69) Valiante also taught that �[t]he DNA and protein sequences for thereceptor p38may be obtained by resort to conventional methodologies known to oneof skill in the art.�70) Turning to Sambrook, the Board found that conventionaltechniques, such as the ones disclosed in Sambrook, were used by Amgen to �isolateand sequence the gene that codes for NAIL.�71) Finally, the Board determined thatdue to NAIL�s important immunochemical role, a scientist of ordinary skill wouldhave been motivated to apply the conventional methodologies of Sambrook andValiante to isolate NAIL cDNA as required by the claims.72) Thus, citing KSR, theBoard ruled that it would have been obvious to isolate NAIL cDNAunder the obvious-to-try rubric.73)

Onappeal, the court agreedwith the examiner andheld the invention to fail for lackof nonobviousness.74) The court largely followed the reasoning of the Board, and also

64) Presentation by PTO at Biotechnology/Chemical/Pharmaceutical PartnershipMeeting on September 2, 2009 on PolymorphPatents.

65) 561 F.3d 1391 (Fed. Cir. 2009).

66) This administrative body is called the Boardof Patent Appeals and Interferences and wasdiscussed earlier in this chapter.

67) Id. at 1353.

68) Sambrook J. et al. (1989).Molecular Cloning: ALaboratory Manual, 2nd ed, pp. 43–84.

69) 561 F.3d at 1354.

70) Id. quoting Valiante at column 7, lines 49–51.

71) Id. at 1355.

72) Id.

73) See id.

74) Id. at 1361.


held that under KSR, no special rules exist for examining biotechnology patentapplications.75) In other words, general arguments about the unpredictability ofpharmaceutical or biotechnology applications will not defeat obviousness attacks.

So what kinds of methods exist for attacking obviousness challenges? Commonpatent claims in the pharmaceutical arts include method of treatment claims in theUnited States. For example, suppose a prodrug is shown to have a particulareffectiveness against a bacterial strain. If the minimum dose is much less than thatof a corresponding compound in the prior art, that dosage could be the basis of anunexpected results argument. Even for patent compound claims, in vivo tests inanimals can be used to show results that are much better than those of the prior art.The concept of a �teaching away� can also be powerful. Suppose a prior art referencesteaches a potential lead compound and discusses thatwater solubility is important forthe compound to act. In this instance, if the claimed compound has a lower watersolubility and is nevertheless effective, however, the prior art teaches away from theclaimed invention. Accordingly, one of ordinary skill in the art would not have usedthe reference in order to try and achieve the invention. This strategy could also beused under an �obvious to try� KSR approach by arguing that it would not have beenobvious to try if researchers in the field at the time that an application for patent wasfiled would have not thought that the approach used in the invention was workable.

3.4Conclusion

Strategies for procuring and defending patents in the pharmaceutical arts are by theirvery nature fact specific. Good patent practitioners rely on solid scientific results tocraft a patent strategy. This practitioner believes that it is in the best interest ofpharmaceutical companies to have patent attorneys who understand the sciencedriving the company and to have scientists who understand the importance of patentprotection and appreciate the rudimentary basics of inventorship, patentability, FDAapproval process, and how patent law and FDA intersect under the Hatch-WaxmanAct. Prodrug and/or metabolite patents add an extra level of complexity because ofscientific and regulatory challenges as well as the inherency niche, discussed above,that acts as a trap for the unwary. As if these challenges were not enough, the recentcourt decisions in obviousness have made it even more difficult to insulate phar-maceutical patents from attacks. This is not to say it is time to give up. It does meanthat scientists and patent attorneys need to work closely together to understand andappreciate the prior art, determine what is and what is not predictable about theinvention, and evaluate how and when it is best to protect the invention.

75) Id. at 1360.


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