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Comparing Three Life Cycle Management Approaches *Redacted for public/non-client distribution Adalat Tiazac Cefadroxil.

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Presentation on theme: "Comparing Three Life Cycle Management Approaches *Redacted for public/non-client distribution Adalat Tiazac Cefadroxil."— Presentation transcript:

1 Comparing Three Life Cycle Management Approaches *Redacted for public/non-client distribution Adalat Tiazac Cefadroxil

2 The Path to Success Economic Biases Traps The Path to Success Economic Biases Traps 3 case studies to illustrate 3 Life Cycle Management principles

3 How To Get A Formulation Patent 3 Key Steps: 3 Key Steps: Formality Formality Useful Useful New New

4 Formalities A patent application looks like a paper or thesis A patent application looks like a paper or thesis Abstract; Introduction Abstract; Introduction Materials & Methods; Conclusions may be speculative Materials & Methods; Conclusions may be speculative Results, Data not required (cf. Crick & Watson) Results, Data not required (cf. Crick & Watson) incorrect Conclusions = useless patent incorrect Conclusions = useless patent vague Methods = invalid patent vague Methods = invalid patent legal Claims legal Claims

5 Usefulness The patent application must assert a usefulness The patent application must assert a usefulness Assert : "I suspect this will work." Assert : "I suspect this will work." Clinical data not required. Clinical data not required. Exception : if government has data showing invention does not work Exception : if government has data showing invention does not work cf. throwaway uses cf. throwaway uses a : just one, not "all," nor even "best" a : just one, not "all," nor even "best" usefulness : "made or used in any industry usefulness : "made or used in any industry e = mc 2 e = mc 2

6 ADALAT® CC Bayer's sustained-release nifedipine Bayer's sustained-release nifedipine insolubility impedes absorption into blood insolubility impedes absorption into blood increased solubility makes blood level spike and decreases sustained bioavailability increased solubility makes blood level spike and decreases sustained bioavailability Alternative approaches: large-size tablets, expensive and light-sensitive liquid formulations Alternative approaches: large-size tablets, expensive and light-sensitive liquid formulations

7 Bayer's solution - increase the specific surface area (SSA). Bayer's solution - increase the specific surface area (SSA). Prior art teaches SSA less than 0.5 square meter s/gramPrior art teaches SSA less than 0.5 square meter s/gram SSAs < 0.5 : no special bioavailability advantagesSSAs < 0.5 : no special bioavailability advantages Bayer patent : nifedipine with SSA > 1Bayer patent : nifedipine with SSA > 1 –improved bioavailability Patent Office disputed that this actually worksPatent Office disputed that this actually works –Decision: cooperate with government, or argue? Cost to cooperate : a round-trip business-class ticket from San Diego to ParisCost to cooperate : a round-trip business-class ticket from San Diego to Paris Cost to argue : maybe ticketsCost to argue : maybe tickets What is the value of patent on "nifedipine with SSA greater than 1 when the product is not yet even launched?What is the value of patent on "nifedipine with SSA greater than 1 when the product is not yet even launched?

8 Bayer cooperated, filing clinical pharmacokinetic data Bayer cooperated, filing clinical pharmacokinetic data Dr. Eduard Porges:Dr. Eduard Porges: "plateau-like effect in dissolution testing of... crystals having a SSA of 1 to 4 m 2 /g," "plateau-like effect in dissolution testing of... crystals having a SSA of 1 to 4 m 2 /g," SSA below 1 or above 4 m 2 /g has "a decreasing dissolution rate." SSA below 1 or above 4 m 2 /g has "a decreasing dissolution rate." Dr. Klemens Leopold Lustig:Dr. Klemens Leopold Lustig: blood plasma level in dogs is higher "when using [] crystals between 0.99 to 4.05 m 2 /g. blood plasma level in dogs is higher "when using [] crystals between 0.99 to 4.05 m 2 /g. Data shows: Data shows: x < 1 does not work x < 1 does not work 1< x <4 works the best 1< x <4 works the best x >4 works, but not as well x >4 works, but not as well

9 ADALAT® CC Patent (continued) Patent Office concedes that Bayer high-SSA invention works, and grants patent to Bayer Patent Office concedes that Bayer high-SSA invention works, and grants patent to Bayer Patent covers SSA > 1.0 Patent covers SSA > 1.0 Inexpensive & easy solutionInexpensive & easy solution THE END THE END

10 ADALAT® CC Patent (continued) Elan files a "Paragraph (iv)" ANDA on Adalat CC with API having an SSA of > 5.0 m 2 /g. Bayer sues. Elan files a "Paragraph (iv)" ANDA on Adalat CC with API having an SSA of > 5.0 m 2 /g. Bayer sues. Prior art discloses SSA < 0.5 Prior 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 Lustig) said that SSA over 4 does not work wellElan says Bayer's researchers (Drs. Porges and Lustig) said that SSA over 4 does not work well Elan says it's not fair for the patent to cover versions which Bayer said do not work well Elan says it's not fair for the patent to cover versions which Bayer said do not work well Rule : The patent must assert a use, not the best use Rule : The patent must assert a use, not the best use

11 Court concluded that Bayer data waived protection for any range > 4 Court concluded that Bayer data waived protection 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 conference, plus tickets for the family, plus a houseBenefit to argue : tickets for everyone at this conference, plus tickets for the family, plus a house Analysis : What will be the value of product?Analysis : What will be the value of product?

12 ADALAT® CC Patent (continued) Providing clinical data showing usefulness Providing 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 SSA > 2 at all? Studied ignorance : What if Bayer neglected to test SSA > 2 at all? What happened to patent attorney? Dr. Porges? What happened to patent attorney? Dr. Porges?

13 How To Get A Formulation Patent Formalities Formalities Usefulness Usefulness Newness Newness

14 Newness Exactly or substantially the same Exactly or substantially the same Exactly the same : simple, but rare Exactly the same : simple, but rare Your own work can damage your patent application Your own work can damage your patent application cf. If Dr. Eduard Porges had published his data cf. If Dr. Eduard Porges had published his data Informal disclosures are relevant Informal disclosures are relevant Graduate theses, posters, academic department seminars Graduate theses, posters, academic department seminars

15 Newness (continued) solution - file patent application on work you suspect might be commercially valuable, before public disclosure solution - file patent application on work you suspect might be commercially valuable, before public disclosure risk - waste money on dead-end filings risk - waste money on dead-end filings What if Bayer had aggressively invested in a broad patent... and the product failed? What if Bayer had aggressively invested in a broad patent... and the product failed?

16 Newness (continued) "substantially" similar to "substantially" similar to How much is substantially? How much is substantially? It depends. It depends. e.g., difference between 1.0 m 2 /g SSA for nifedipine e.g., difference between 1.0 m 2 /g SSA for nifedipine What effect does la difference have? What effect does la difference have? lots of negotiation with Patent Office on this point lots of negotiation with Patent Office on this point Examples - Tiazac SR, cefadroxil, tacrine Examples - Tiazac SR, cefadroxil, tacrine

17 Tiazac® SR (Biovail 1-a-day diltiazem) diltiazem hypertensive / angina diltiazem hypertensive / angina wetting agent (e.g., sugar) to preserve in vivo solubilitywetting agent (e.g., sugar) to preserve in vivo solubility Prior art (old Debregeas patent) teaches coating sugar core with API to build up solid dosage form, then seal with porous membrane Prior art (old Debregeas patent) teaches coating sugar core with API to build up solid dosage form, then seal with porous membrane API coating Sugar Core membrane

18 Tiazac® SR Mixing wetting agent (e.g., sugar) with diltiazem improves SR profile Mixing wetting agent (e.g., sugar) with diltiazem improves SR profile Biovail applies for patent on SR formulation Biovail applies for patent on SR formulation Patent Office disputed this is new and demanded proof of newness Patent Office disputed this is new and demanded proof of newness homogenous blend Sugar + API

19 Tiazac SR Biovail filed a Declaration Biovail filed a Declaration Biovail said they are different from earlier Debregeas patent. Biovail said they are different from earlier Debregeas patent. Patent Office agreed that a homogenous dosage form is substantially different from earlier Debregeas coated-core dosage form. Patent Office agreed that a homogenous dosage form is substantially different from earlier Debregeas coated-core dosage form. Patent Office allowed the patent. Patent Office allowed the patent. – THE END

20 Tiazac SR Andrx files ANDA for generic diltiazem SR, made per Debregeas coated-core patent: Andrx files ANDA for generic diltiazem SR, made per Debregeas coated-core patent: sugar core built up with API + ethylcel + polyvinylpyrrolidone; membrane jacket sugar core built up with API + ethylcel + polyvinylpyrrolidone; membrane jacket Biovail sues for patent infringement ( Biovail v. Andrx, Federal Circuit (13 Feb 2001) ) Biovail sues for patent infringement ( Biovail v. Andrx, Federal Circuit (13 Feb 2001) ) Patent covers homogenous sugar + API Patent covers homogenous 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???

21 Tiazac SR Recall that in Patent Office, Biovail said its homogenous mix is different from earlier Debregeas coated-core patent. Recall that in Patent Office, Biovail said its homogenous mix is different from earlier Debregeas coated-core patent. In court, however, Biovail says Andrx product dissolves in vivo to make homogenous sugar + API in stomach In court, however, Biovail says Andrx product dissolves in vivo to make homogenous sugar + API in stomach Court demanded proof of in vivo homogenous mixture Court demanded proof of in vivo homogenous mixture

22 Tiazac SR Biovail lacked any scientific data showing that Andrx's generic product in vivo makes the patented homogenous mixture. Biovail lacked any scientific data showing that Andrx's generic product in vivo makes the patented homogenous mixture. Court did not invalidate Biovail's patent as not new Court did not invalidate Biovail's patent as not new Court concluded that no data show that Andrx actually infringes patent. Court concluded that no data show that Andrx actually infringes patent.

23 Cefadroxil polymorph cefadroxil monohydrate (bioactive form) - BMS cefadroxil monohydrate (bioactive form) - BMS monohydrate, Bouzard form - BMS : monohydrate, Bouzard form - BMS : Patent Office disputed this actually works is new and demanded proof of efficacy newness Patent Office disputed this actually works is new and demanded proof of efficacy newness BMS provided data showing the Bouzard form is easier to handle / fill capsules BMS provided data showing the Bouzard form is easier to handle / fill capsules Patent Office agreed Bz monohydrate is new - it is not substantially similar to prior art monohydrate Patent Office agreed Bz monohydrate is new - it is not substantially similar to prior art monohydrate

24 cefadroxil hemihydrate - Gema, Zenith cefadroxil hemihydrate - Gema, Zenith is 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 question? How much does it cost to resolve this question?

25 Federal Court litigation : 2003 = $4,995,000.00Federal Court litigation : 2003 = $4,995, Patent Office litigation : 2003 = $375,000.00Patent Office litigation : 2003 = $375, Patent prosecution : 2003 = $80,000.00Patent prosecution : 2003 = $80, – a generic manufacturer obtaining its own patent may be an inexpensive "insurance policy"

26 Cefadroxil patents (continued) BMS sues. BMS says the hemihydrate transitions in vivo into the Bouzard monohydrate form, before conversion into bioactive monohydrate. BMS sues. BMS says the hemihydrate transitions in vivo into the Bouzard monohydrate form, before conversion into bioactive monohydrate. Judge concludes, "there is no known way to actually sample the contents of patients' stomachs at the precise moment and conduct x-ray diffraction analysis" Judge concludes, "there is no known way to actually sample the contents of patients' stomachs at the precise moment and conduct x-ray diffraction analysis"

27 Cefadroxil patents (continued) no evidence of infringement no 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 stomachs of past patients taking prior-art bioactive form of cefadroxil intimates that Bz monohydrate was made in stomachs of past patients taking prior-art bioactive form of cefadroxil if Bz monohydrate is not new, then the Bz monohydrate patent must be revoked if Bz monohydrate is not new, then the Bz monohydrate patent must be revoked

28 Next Steps 1Identify third-party patents BEFORE investing in R&DBEFORE investing in R&D e.g., landscaping studye.g., landscaping study 2Identify bars to patentability BEFORE investing in R&DBEFORE investing in R&D e.g., in-house paper researche.g., in-house paper research 3 Identify your competitor's strengths...

29 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.

30 An newsletter on pharmaceutical patent law is available by providing your address: Mark POHL, Esq., Patent Attorney (C) 2010 Pharmaceutical Patent Attorneys, LLC 55 Madison Avenue, 4th floor Morristown, New Jersey USA Certain information has been redacted from this presentation to make it suitable for distribution to the public. Clients may obtain an unredacted copy on request.


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