Comparing Three Life Cycle Comparing Three Life Cycle Management ApproachesManagement Approaches

*Redacted for public/non-client distribution*Redacted for public/non-client distribution

Adalat Adalat ● ● Tiazac Tiazac ● ● CefadroxilCefadroxil

The Path to Success The Path to Success ● ● Economic Biases Economic Biases ● ● Traps Traps

3 case studies to illustrate 3 Life 3 case studies to illustrate 3 Life Cycle Management principles Cycle Management principles

How To Get A Formulation How To Get A Formulation PatentPatent

3 Key Steps:3 Key Steps:FormalityFormalityUsefulUsefulNewNew

FormalitiesFormalitiesA patent application looks like a paper or thesisA patent application looks like a paper or thesis

Abstract; IntroductionAbstract; IntroductionMaterials & Methods; Conclusions may be Materials & Methods; Conclusions may be “speculative”“speculative”

Results, Data not required (Results, Data not required (cfcf. Crick & Watson). Crick & Watson)incorrect Conclusions = useless patentincorrect Conclusions = useless patentvague Methods = invalid patentvague Methods = invalid patent

legal Claimslegal Claims

UsefulnessUsefulnessThe patent application must The patent application must assertassert aa usefulnessusefulnessAssertAssert : : "I suspect this will work.""I suspect this will work."

Clinical data Clinical data notnot required. required.Exception : if government has data showing Exception : if government has data showing

invention does not work invention does not work cf.cf. throwaway uses throwaway uses

aa : just one, not "all," nor even "best" : just one, not "all," nor even "best" usefulnessusefulness : "made or used in any industry” : "made or used in any industry”

e = mce = mc22

ADALAT® CCADALAT® CCBayer's sustained-release nifedipineBayer's sustained-release nifedipine

insolubility impedes absorption into bloodinsolubility impedes absorption into bloodincreased solubility makes blood level spike and increased solubility makes blood level spike and

decreases sustained bioavailabilitydecreases sustained bioavailabilityAlternative approaches: large-size tablets, Alternative approaches: large-size tablets,

expensive and light-sensitive liquid formulationsexpensive and light-sensitive liquid formulations

Bayer's solution - increase the specific surface Bayer's solution - increase the specific surface area (SSA).area (SSA).–Prior art teaches SSA less than 0.5 square meterPrior art teaches SSA less than 0.5 square meters/grams/gram

–SSAs < 0.5 : no special bioavailability advantagesSSAs < 0.5 : no special bioavailability advantages–Bayer patent : nifedipine with SSA > 1 Bayer patent : nifedipine with SSA > 1

–improved bioavailability improved bioavailability –Patent Office disputed that this actually worksPatent Office disputed that this actually works

–Decision: cooperate with government, or argue?Decision: cooperate with government, or argue?–Cost to cooperate : a round-trip business-class ticket Cost to cooperate : a round-trip business-class ticket

from San Diego to Parisfrom San Diego to Paris–Cost to argue : maybe 12-15 ticketsCost to argue : maybe 12-15 tickets–What is the value of patent on "nifedipine with SSA What is the value of patent on "nifedipine with SSA

greater than 1” when the product is not yet even greater than 1” when the product is not yet even launched?launched?

Bayer cooperated, filing clinical pharmacokinetic Bayer cooperated, filing clinical pharmacokinetic data data –Dr. Eduard Porges: Dr. Eduard Porges:

"plateau-like effect in dissolution testing of ... "plateau-like effect in dissolution testing of ... crystals having a SSA of 1 to 4 mcrystals having a SSA of 1 to 4 m22/g," /g,"

SSA below 1 or above 4 mSSA below 1 or above 4 m22/g has "a decreasing /g has "a decreasing dissolution rate."dissolution rate."

–Dr. Klemens Leopold Lustig: Dr. Klemens Leopold Lustig: blood plasma level in dogs is higher "when using [] blood plasma level in dogs is higher "when using [] crystals between 0.99 to 4.05 mcrystals between 0.99 to 4.05 m22/g.“/g.“

Data shows:Data shows: x < 1 does not workx < 1 does not work 1< x <4 works the best1< x <4 works the best x >4 works, but not as wellx >4 works, but not as well

ADALAT® CC Patent ADALAT® CC Patent (continued) (continued)

Patent Office concedes that Bayer high-SSA Patent Office concedes that Bayer high-SSA invention works, and grants patent to Bayerinvention works, and grants patent to BayerPatent covers “SSA > 1.0”Patent covers “SSA > 1.0”–Inexpensive & easy solutionInexpensive & easy solution

THE ENDTHE END

ADALAT® CC Patent ADALAT® CC Patent (continued) (continued)Elan files a "Paragraph (iv)" ANDA on Adalat CC Elan files a "Paragraph (iv)" ANDA on Adalat CC with API having an SSA of > 5.0 mwith API having an SSA of > 5.0 m22/g. Bayer sues./g. Bayer sues.

Prior art discloses SSA < 0.5Prior art discloses SSA < 0.5–Bayer says patent covers any SSA > 1Bayer says patent covers any SSA > 1–Elan says Bayer's researchers (Drs. Porges and Elan says Bayer's researchers (Drs. Porges and

Lustig) said that SSA over 4 Lustig) said that SSA over 4 does not work welldoes not work wellElan says it's not fair for the patent to cover Elan says it's not fair for the patent to cover versions which Bayer said versions which Bayer said do not work welldo not work well

Rule : Rule : The patent must assert The patent must assert aa use, not “the best” use, not “the best” useuse

Court concluded that Bayer data Court concluded that Bayer data waivedwaived protection protection for any range > 4 for any range > 4 –Cost to cooperate : one ticketCost to cooperate : one ticket–Cost to argue : maybe 15 ticketsCost to argue : maybe 15 tickets–Benefit to argue : tickets for everyone at this Benefit to argue : tickets for everyone at this

conference, plus tickets for the family, plus a houseconference, plus tickets for the family, plus a house–Analysis : What will be the value of product?Analysis : What will be the value of product?

ADALAT® CC Patent ADALAT® CC Patent (continued) (continued)Providing clinical data showing usefulnessProviding clinical data showing usefulness

–government must prove that invention does not workgovernment must prove that invention does not work–providing data to PTO may speed patent approvalproviding data to PTO may speed patent approval–providing data to PTO may damage patentproviding data to PTO may damage patent

"No good deed goes unpunished.” "No good deed goes unpunished.” Studied ignorance : What if Bayer neglected to test Studied ignorance : What if Bayer neglected to test SSA > 2 at all?SSA > 2 at all?

What happened to patent attorney? Dr. Porges? What happened to patent attorney? Dr. Porges?

How To Get A Formulation How To Get A Formulation PatentPatentFormalitiesFormalitiesUsefulnessUsefulnessNewnessNewness

NewnessNewnessExactly or substantially the sameExactly or substantially the same

Exactly the same : simple, but rareExactly the same : simple, but rareYour own work can damage your patent Your own work can damage your patent applicationapplicationcf.cf. If Dr. Eduard Porges had published his data If Dr. Eduard Porges had published his data

Informal disclosures are relevantInformal disclosures are relevantGraduate theses, posters, academic department Graduate theses, posters, academic department seminarsseminars

NewnessNewness (continued) (continued)

solution - file patent application on work you solution - file patent application on work you suspect might be commercially valuable, suspect might be commercially valuable, beforebefore public disclosure public disclosurerisk - waste money on dead-end filingsrisk - waste money on dead-end filingsWhat if Bayer had aggressively invested in a What if Bayer had aggressively invested in a

broad patent ... and the product failed?broad patent ... and the product failed?

NewnessNewness (continued) (continued)

"substantially" similar to"substantially" similar toHow much is substantially? How much is substantially? ““It depends.”It depends.”

e.g.e.g., difference between <0.5, difference between <0.5 m m22/g SSA and /g SSA and

>1.0 m>1.0 m22/g SSA for /g SSA for nifedipinenifedipineWhat effect What effect does la difference have?does la difference have?lots of negotiation with Patent Office on this lots of negotiation with Patent Office on this pointpoint

Examples - Tiazac SR, cefadroxil, tacrineExamples - Tiazac SR, cefadroxil, tacrine

Tiazac® SR Tiazac® SR (Biovail 1-a-day diltiazem)(Biovail 1-a-day diltiazem)

diltiazem hypertensive / diltiazem hypertensive / anginaangina–wetting agent (wetting agent (e.ge.g., sugar) ., sugar)

to preserve to preserve in vivo in vivo solubilitysolubility

Prior art (old Debregeas Prior art (old Debregeas patent) teaches coating patent) teaches coating sugar core with API to sugar core with API to build up solid dosage build up solid dosage form, then seal with form, then seal with porous membraneporous membrane

API coating

Sugar Core

membrane

Tiazac® SRTiazac® SRMixing wetting agent (e.g., Mixing wetting agent (e.g., sugar) with diltiazem sugar) with diltiazem improves SR profileimproves SR profile

Biovail applies for patent on Biovail applies for patent on SR formulationSR formulation

Patent Office disputed this Patent Office disputed this

is new is new and demanded and demanded

proof of proof of newnessnewness

homogenous blendhomogenous blend

Sugar + APISugar + API

Tiazac SRTiazac SR

BiovailBiovail filed a Declaration filed a Declaration Biovail said they are different from earlier Biovail said they are different from earlier

Debregeas patent.Debregeas patent.Patent Office agreed that a homogenous Patent Office agreed that a homogenous

dosage form is substantially different from dosage form is substantially different from earlier Debregeas coated-core dosage form. earlier Debregeas coated-core dosage form.

Patent Office allowed the patent.Patent Office allowed the patent.–THE END THE END

Tiazac SRTiazac SRAndrx files ANDA for generic diltiazem SR, Andrx files ANDA for generic diltiazem SR, made per Debregeas coated-core patent: made per Debregeas coated-core patent:

sugar core built up with API + ethylcel + sugar core built up with API + ethylcel + polyvinylpyrrolidone; membrane jacketpolyvinylpyrrolidone; membrane jacket

Biovail sues for patent infringement (Biovail sues for patent infringement (Biovail v. Biovail v.

AndrxAndrx, Federal Circuit (13 Feb 2001), Federal Circuit (13 Feb 2001)))Patent covers Patent covers homogenoushomogenous sugar + API sugar + API Andrx makes an old-fashioned coated core.Andrx makes an old-fashioned coated core.How could there possibly be infringement???How could there possibly be infringement???

Tiazac SRTiazac SR

Recall that Recall that in Patent Office, Biovail said its in Patent Office, Biovail said its homogenous mix is different from earlier homogenous mix is different from earlier Debregeas coated-core patent.Debregeas coated-core patent.

In court, however, Biovail says Andrx In court, however, Biovail says Andrx product product dissolves in vivo dissolves in vivo to make to make homogenous sugar + API in stomachhomogenous sugar + API in stomach

Court demanded proof of Court demanded proof of in vivoin vivo homogenous homogenous mixturemixture

Tiazac SRTiazac SR

Biovail lacked any scientific data showing Biovail lacked any scientific data showing that Andrx's generic product that Andrx's generic product in vivoin vivo makes makes the patented homogenous mixture. the patented homogenous mixture.

Court did not invalidate Biovail's patent as not Court did not invalidate Biovail's patent as not newnew

Court concluded that no data show that Andrx Court concluded that no data show that Andrx actually infringes patent. actually infringes patent.

Cefadroxil polymorphCefadroxil polymorphcefadroxil monohydrate (bioactive form) - BMScefadroxil monohydrate (bioactive form) - BMSmonohydrate, Bouzard form - BMS : monohydrate, Bouzard form - BMS :

Patent Office disputed this Patent Office disputed this actually worksactually works is new is new and demanded proof of and demanded proof of efficacyefficacy newness newness

BMS provided data showing the Bouzard form is BMS provided data showing the Bouzard form is easier to handle / fill capsuleseasier to handle / fill capsules

Patent Office agreed Bz monohydrate is new - it is not Patent Office agreed Bz monohydrate is new - it is not substantially similar to prior art monohydratesubstantially similar to prior art monohydrate

cefadroxil hemihydrate - Gema, Zenithcefadroxil hemihydrate - Gema, Zenithis hemihydrate "substantially" similar to :is hemihydrate "substantially" similar to :

the (non-patented) prior art monohydrate? the (non-patented) prior art monohydrate? the (patented) Bouzard monohydrate?the (patented) Bouzard monohydrate?

How much does it cost to resolve this How much does it cost to resolve this question? question?

• Federal Court litigation : 2003 = $4,995,000.00Federal Court litigation : 2003 = $4,995,000.00

• Patent Office litigation : 2003 = $375,000.00Patent Office litigation : 2003 = $375,000.00

• Patent prosecution : 2003 = $80,000.00Patent prosecution : 2003 = $80,000.00

– a generic manufacturer obtaining its own patent a generic manufacturer obtaining its own patent may be an inexpensive "insurance policy" may be an inexpensive "insurance policy"

Cefadroxil patentsCefadroxil patents (continued) (continued)

BMS sues. BMS says the hemihydrate BMS sues. BMS says the hemihydrate transitions transitions in vivoin vivo into the Bouzard into the Bouzard monohydrate form, before conversion into monohydrate form, before conversion into bioactive monohydrate. bioactive monohydrate.

Judge concludes, "there is no known way to Judge concludes, "there is no known way to actually sample the contents of patients' actually sample the contents of patients' stomachs at the precise moment and conduct stomachs at the precise moment and conduct x-ray diffraction analysis" x-ray diffraction analysis"

Cefadroxil patentsCefadroxil patents (continued) (continued)

no evidence of infringementno evidence of infringement* cautionary note on patent drafting ** cautionary note on patent drafting *

if evidence exists, if evidence exists, intimates that Bz monohydrate was made in intimates that Bz monohydrate was made in stomachs of past patients taking prior-art stomachs of past patients taking prior-art bioactive form of cefadroxil bioactive form of cefadroxil

if Bz monohydrate is not new, then the Bz if Bz monohydrate is not new, then the Bz monohydrate patent must be revokedmonohydrate patent must be revoked

Next StepsNext Steps

1 Identify third-party patentsIdentify third-party patents–BEFORE investing in R&D BEFORE investing in R&D –e.g., landscaping study e.g., landscaping study

2 Identify bars to patentabilityIdentify bars to patentability–BEFORE investing in R&DBEFORE investing in R&D–e.g., in-house “paper” research e.g., in-house “paper” research

3 Identify 3 Identify your competitor'syour competitor's strengths... strengths...

Mark Pohl, Understanding Patent Issues for Formulation Development, Proceedings of Emerging Trends and Technologies in Formulation and Dosage Form Selection for Drug Delivery (18-20 April 2005) (International Quality & Productivity Center, publ.)

ABSTRACT:

New technology – even in such ostensibly mundane areas such as formulation technology - may determine clinical and commercial success. Developing new technology can, however, require significant funding. To protect researchers' access to adequate funding in the future, it may be necessary to commercially protect the innovations made today.

We will discuss how to commercially protect new biopharmaceuticals technology using patents. We will review the various requirements to obtain a patent, and focus more closely on the more difficult requirements. We will also discuss several actual examples of pharmaceutical companies' problems and successes in seeking patent protection.

An email newsletter on pharmaceutical patent law is available by providing your email address:

Mark POHL, Esq., Patent AttorneyMark POHL, Esq., Patent AttorneyMark.Pohl@LicensingLaw.NetMark.Pohl@LicensingLaw.Net

(C) 2010 Pharmaceutical Patent Attorneys, LLC(C) 2010 Pharmaceutical Patent Attorneys, LLC55 Madison Avenue, 4th floor55 Madison Avenue, 4th floor

Morristown, New Jersey 07960-7397 USAMorristown, New Jersey 07960-7397 USAwww.LicensingLaw.Netwww.LicensingLaw.Net

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copy on request.