Polymorphism and Patentsfrom

A Chemist’s Point of View Joel Bernstein

Ben-Gurion University of the Negev

DIVERSITY AMIDST SIMILARITY:

A Multidisciplinary Approach to Polymorphs, Solvates and Phase Relationship

Erice, Sicily

June 19, 2004

Agenda

• Introduction • Some general remarks about patents and patent

litigations• Case studies of four patent litigations

– Ranitidine hydrochloride– Paroxetine hydrochloride– Cefadroxil– Aspartame

• Summary

What is a patent?

• A patent is a social contract– known since middle ages

OED: “…license to manufacture sell or deal in an article or commodity, to the exclusion of other persons”

– First known English patent in 1449 to John of Utyman for a method for making stained glass

– Today, right to exclude– Patent systems give inventor exclusive rights in return

for the cooperation of an inventor to teach the rest of society how to use findings or invention (Maynard & Peters, 1991)

More on patents…• Must be a product of human ingenuity• Must have novelty - not part of the “state of the art”• Must not be obvious; obviousness is construed by hypothetical

person “one skilled in the art” - competent but without imagination• Must have usefulness - must serve some worthwhile practical use.

In some places this includes drugs, but not methods of medical diagnosis or treatment

• Must contain an enabling description - sufficient detail to allow one skilled in the art to make and use invention

• Inventor gains exclusive rights, but is responsible for policing these

Can’t make it, use it or sell it

Patent litigation

• Y infringes Z’s patent• Z tells Y they are infringing and starts proceedings• Y claims that Z’s patent is invalid, unenforceable,

obvious, or not novel (or combinations of these)

• In USA cases heard in Federal District Court or ITC for international cases

• Lots of discovery, limited privilege, many pretrial pleadings, conferences, possibility of jury

Case 1: Ranitidine hydrochloride

• Developed in 1970’s by Allen & Hanburys Ltd., in flurry of activity following identity of histamine H2 receptor (Black; Tagamet [cimetidine]) to treat ulcers

• June ‘77 D. Collin first prepares ranitidine hydrochloride (RHCl)

• US patent 4,128,658 patent (‘658 patent) is granted in 1978

Title Page of ‘658 Patent for RHCl

Case 1: Ranitidine hydrochloride

• Developed in 1970’s by Allen & Hanburys Ltd., in flurry of activity following identity of histamine H2 receptor (Black; Tagamet [cimetidine]) to treat ulcers

• June ‘77 D. Collin first prepares ranitidine hydrochloride (RHCl)

• US patent 4,128,658 patent (‘658 patent) is granted in 1978

• Example 32 gives procedure for preparation of RHCl

Example 32 from ‘658 patent for RHCl

History of RHCl, cont’d

• 15.4.80 Glaxo (serendipitously) discovers new polymorph, designated Form 2

• (US) Patent applied for 10.81; granted 6.85 as patent 4,521,431 (‘431 patent)

• Advantage is ‘favourable filtration and drying characteristics…’

Title page of ‘431 patent of RHCl

History of RHCl, cont’d

• 15.4.80 Glaxo (serendipitously) discovers new polymorph, designated Form 2

• (US) Patent applied for 10.81; granted 6.85 as patent 4,521,431 (‘431 patent)

• Advantage is ‘favourable filtration and drying characteristics…’

• Form 2 since marketed by Glaxo

Market impact of RHCl (Zantac)

Patent History of RHCl (Zantac)

1977 - First preparation of RHCl1978 - Registration of U.S. ‘658 patent1980 - Discovery of Form 2 of RHCl1984 - Zantac first marketed in U.S.1985 - Registration of U.S. ‘431 patent on Form 2 1992 - Sales of Zantac reach $3.44 billion 1995 - U.S. ‘658 patent expires 2002 - U.S. ‘431 patent on Form 2 expires

1990-1991 Events• Genpharm, Novopharm attempt to make Form 1

using ‘recipe’ of Example 32 in ‘658 patent

• Get Form 2

• Genpharm, Novopharm file ANDA with FDA to market Form 2 in 1995

• Claim that Form 2 is inherent in Form 1 patent (Example 32)

• Glaxo sues GenpharmGlaxo sues Novopharm

Issues/Arguments in Glaxo v Novopharm I

• Novopharm admitted infringement of ‘431 patent– Claimed that ‘431 patent is invalid– Form 2 inherent in ‘658 patent– Claimed that Glaxo never performed Ex. 32 exactly as written

• Glaxo argued– Novopharm’s experiments contaminated by seeds of F2– Therefore not faithful replication of Ex. 32– Ex. 32 does not invariably lead to F2

• Comparison with procedure in original notebooks (1976)• Three preparations of F1 at Oxford in 1993

• Sufficient evidence to convince court that Ex. 32 does lead to F1 and ‘431 patent was valid (17 Sept 1993)

Subsequent events

• Novopharm loses appeal

• World Trade Agreement extends ‘658 patent from December 8, 1995 to July 25, 1997

• Glaxo v. Genpharm settled out of court

• Novopharm files ANDA to market F1 (April 1994)

• Glaxo sues Novopharm

Issues/Arguments Glaxo v Novopharm II• Glaxo claimed that Novopharm’s product would contain not pure

F1, but a mixture of F1 and F2

• Novopharm’s original ANDA specified 99% polymorphic purity of F1 (by IR)

• Amended ANDAs would have permitted polymorphic purity as low as 90%

• Novopharm submitted X-ray evidence that its actual samples did not contain detectable F2

• (Same) Court found that Novopharm product would not contain F2, and if it did it would not be as basis for improvement or equivalent (i.e. mixtures allowed)

• Question of polymorphic mixtures dealt with in a later case

Some polymorphism/chemistry issues arising in RHCl cases

• Serendipitous discovery and recognition of polymorphs

• Role of solvent, heating, stirring, etc. to control polymorph obtained

• Development and use of analytical methods for characterization of polymorphic forms

• Relative stability of polymorphic forms

• Phenomenon of disappearing polymorphs

• Role of seeding, intentional and unintentional

• Distinction between polymorphic identity and polymorphic purity

Case 2: Paroxetine hydrochloride: Paxil®, Seroxat®

Antidepressant (serotonin uptake inhibitor)

2001 Worldwide sales ca $3.2 bn

Originally developed by Ferrosan (Denmark) in 1970’s as the (hygroscopic) anhydrate

Transferred to Beecham (now GlaxoSmithKline) ~1980

Late 1984 hemihydrate appeared, apparently serendipitously

Hemihydrate developed and marketed since 1993 by SKB

Hemihydrate patent (‘723) due to expire in 2006

Paroxetine Hydrochloride Developments ~ 1995-2003

1995-1998:Apotex (BCI) develop process for making anhydrate; research starts with Paxil samples (hemihydrate)

1998: Apotex (BCI) apply for ANDA to market anhydrate

1998: SKB sues Apotex for infringing the hemihydrate ‘723 patent, claiming presence of hemihydrate in API and formulation,conversion with time.Apotex claims hemihydrate patent is invalid, and even if valid anhydrate product does not infringe

2003: Trial in Chicago; U.S. Federal Court, Judge Richard Posner

1992: Ferrosan (anhydrate) ‘196 patent expired

Paroxetine Hydrochloride The Judgment-2003

Apotex’s product will not infringe ’723 patent“To summarize:I construe claim 1 of SmithKline’s patent ‘723 to cover crystalline paroxetine hydrochloride hemihydrate in any commercially significant quantity, and so construed the claim is valid against the various attacks on it made by Apotex but clearly will not be infringed by Apotex’s anhydrate product.”

Hemihydrate patent is valid; Claim 1 states: “Crystalline paroxetine hydrochloride hemihydrate.”

Paroxetine Hydrochloride Some of the Legal Reasoning

“Some conversion from anhydrate to hemihydrate is likely to occur in a seeded facility in which the anhydrate is exposed to air; BCI’s plant is seeded; and the anhydrate manufactured there is exposed to nondehumidified air before it leaves the plant. The evidence is sufficient to support an inference that BCI will be making at least tiny amounts of the hemihydrate if it is permitted to manufacture the anhydrate.”

“In sum, I am not persuaded that Apotex will produce an anhydrate that has sufficient hemihydrate to be detectable by the methods in use in 1985.”

Paroxetine HydrochlorideMore of the Legal Reasoning

“The reason for excusing the alleged infringement in this case is not that Apotex stole only a little hemihydrate from SmithKline. It stole nothing from Smithkline. It doesn’t want hemihydrate, and it derives no value from the hemihydrate that it unavoidably creates and “sells”. If it made hemihydrate deliberately, or if it took advantage of 100 percent conversion to obtain a product that had hemihydrate’s superior handling characteristics, that would be theft and it would be nonsense to point out that paroxetine is only 10 percent of the pill by weight. “

Judge Posner’s decision was appealed to the Federal Circuit, which specializes in hearing patent cases.

“…If…claim 1 is valid and will be infringed either by a single crystal of hemihydrate or by a barely detectable amount of it, Apotex has a complete affirmative defense that SmithKline is the cause of the infringement.”

Paroxetine HydrochlorideFederal Circuit Decision April 23, 2004

“In summary, this court reverses the claim construction of the district court and holds that claim 1 covers any amount of crystalline paroxetine hydrochloride hemihydrate without further limitation…affirms the district court’s finding that Apotex’s PHC anhydrate product will infringe claim 1 under that broad construction…”

“…Notwithstanding that conclusion, this court holds, based on the undisputed facts, that SmithKline’s clinical trials constituted a public use under §102(b) rendering claim 1 invalid. Apotex is, therefore, not liable for infringing claim 1 of the ‘723 patent.”

Paroxetine HydrochlorideFederal Circuit Decision April 23, 2004

“’Experimental use negates public use; when proved, it may show that particular acts, even if apparently public in a colloquial sense, do not constitute a public use within the meaning of section 102.’”

“In other words, the claim covers the compound regardless of its use as an antidepressant. The antidepressant properties of the compound are simply not claimed features. Consequently, the clinical tests, which measured the efficacy and safety of the compound as an antidepressant, did not involve the claimed features of the invention. The 1985 tests, therefore, do not qualify as an experimental use to negate the statutory bar.”

Paroxetine Hydrochloride Some of the chemical issues in this litigation

Formal and practical definitions of anhydrate, hemihydrate

Physical and chemical characterization of anhydrate/hemihydrate

Relative stability of anhydrate/hemihydrate

Factors leading to conversion of anhydrate hemihydrate:moisture, seeds, heat, pressure

Characteristics and role of seeds (intentional and unintentional)in crystallization

Analytical methods - qualitative and quantitative - for determining

the composition of mixtures of crystal forms

Case 3: Cefadroxil

• Antibiotic developed by Bristol-Myers (BM), marketed as Ultracef and Duricef

• US Sales 1988 ~ $100m

• Crystalline monohydrate (apparently discovered serendipitously) claimed in US 4,504,657 (‘657 or “Bouzard” patent)

• Characterized by XRPD pattern

• Improvement included greater stability and higher bulk density production of smaller pills

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Cefadroxil: Patent Issues

• Prior art included 1973 patent (‘282 patent) of another crystalline modification (the “Micetich” form)

• Granting of 1987 patent recognized difference between Bouzard and Micetich forms

• As expiration of ‘282 patent approached, attempts to make Micetich form led to Bouzard form, and a number of litigations

• Again claim that Bouzard form was inherent in Micetich patent

• Many issues arose; many experiments performed

Cefadroxil: Some experiments on crystal modification related to litigation

• XRPD of Bouzard indexed to show that every line corresponded to that modification

• Attempts to prepare Micetich form in unseeded environment led to contested results

• Crystallization experiments in bacterial clean room could not eliminate seeds 100’s times smaller

• Series of side-by-side sealed and unsealed experiments; seed-free produced Micetich form, open flasks produced Bouzard form

Cefadroxil: Some polymorphic issues contested (in BM v. Zenith, among many litigations)

• Zenith prepared hemihydrate; BM contended that an NDA, rather than ANDA is required

• BM contended that hemihydrate converted to monohydrate, thus infringing Bouzard patent

• Contention that conversion occurs in stomach after ingestion

– Court found in favor of BM

– On appeal Zenith contended that patent doesn’t cover momentary conversion in stomach

– BM identified 15 of 37 diffraction lines

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Cefadroxil: Some polymorphic issues contested (in BM v. Zenith, among many litigations)

• Zenith prepared hemihydrate; BM contended that an NDA, rather than ANDA is required

• BM contended that hemihydrate converted to monohydrate, thus infringing Bouzard patent

• Contention that conversion occurs in stomach after ingestion– Court found in favor of BM– On appeal Zenith contended that patent doesn’t cover momentary

conversion in stomach– BM identified 15 of 37 diffraction lines– Court found 15/37 insufficient for literal infringement

• Framing of claims using XRPD or IR changed

United States Patent Application 20040019093

Kind Code A1

Aronhime, Judith ;   et al. January 29, 2004

Novel crystal forms of ondansetron , processes for their preparation, pharmaceutical compositions containing the novel forms and methods for treating nausea using them.

AbstractOndansetron crystalline Forms A and B are useful in the treatment of nausea and vomiting. Form B has a uniquely high melting point of about 244 degree C and both forms are stable against thermally induced polymorphic transition from 30.degree. C. up to their melting points.

24. The crystalline form of ondansetron of claim 23 wherein the thermal analysis result is a differential scanning calorimetry thermogram taken at a heating rate of 10.degree. C. min.sup.-1 in a closed pan that exhibits a melting endotherm with a maximum at 230.+-.2.degree. C.

25. The crystalline form of ondansetron of claim 24 wherein the melting endotherm has a magnitude of 324.26 Joules per gram.

United States Patent Application 20040019093

Kind Code A1

Aronhime, Judith ;   et al. January 29, 2004

18. A crystalline form of ondansetron characterized by a powder X-ray diffraction pattern having peaks at 25.4, 26.7 and 27.8.+-.1.0 degrees two-theta.

19. The crystalline form of ondansetron of claim 18 further characterized by strong intensity peaks in the powder X-ray diffraction pattern at 23.2, 25.9 and 27.8.+-.1.0 degrees two-theta and medium intensity peaks at 25.4 and 26.7.+-.1.0 degrees 2-theta.

20. The crystalline form of ondansetron of claim 18 further characterized by peaks in the powder X-ray diffraction pattern at 11.0, 14.8, 15.5, 16.4, 20.6, 21.4, 24.2.+-.1.0 degrees two-theta.

United States Patent Application 20040019093

Kind Code A1

Aronhime, Judith ;   et al. January 29, 2004

21. The crystalline form of ondansetron of claim 18 containing less than or equal to about 5% other crystalline forms of ondansetron.

22. The crystalline form of ondansetron of claim 21 containing less than or equal to about 1% other crystalline forms of ondansetron.

Case 4: Aspartame (crystal habit)

• G.D. Searle (Monsanto) artificial sweetener (Nutrisweet); 100-200x sweeter than sucrose

• “Conventional” manufacturing process:

– Needles w/ diameter 10m

– Fine needles w/ large specific volume

– Problems with filtration & drying

– Formation of scale on reactor surfaces

– High dustability and hygroscopicity of product

– Unsuitable for tabletop use

Aspartame crystals• Five crystal modifications:

– Two hemihydrate polymorphs

– Dihemihydrate

– Other two forms less well characterized

• Many attempts to improve quality of crystals

• Ajimoto (Japan) found that cooling H2O solutions without stirring led to ‘bundle-like’ crystal aggregates

• Improved handling characteristics compared to conventional crystals

Aspartame patent history

• 1985 - European patent for ‘bundle’ crystals granted

• 1992 - Opposition division of EPO concludes that ‘bundle’ are same as conventional crystals

• Same polymorph but different habits

• Ajimoto presented a detailed report on the differences

Aspartame: the Ajimoto reportComparison of bundle and conventional crystals

• Bundle has higher degree of crystal perfection• Bundle has smaller volume; hence higher bulk density• Bundle has significantly less water than conventional• Bundle expected to dissolve more slowly, but opposite is true• Bundle has higher density and lower strain• Slightly different SSNMR spectra• Bundle show sharp optical extinction indicating higher

degree of perfection.• XRPD patterns reflect differences in strain; differences in

calculated XRPD patterns (including mosaic spread, etc.) matched experimental ones.

Measured XRPD’s of Conventional and Bundle Crystals of Aspartame

Aspartame - the decision

1997 - Board of Appeal of EPO set aside the opposition

1998 - New European Patent Specification issued

Summary

• Polymorphism is playing an increasingly important role in establishing and protecting intellectual property rights in the pharmaceutical industry

• As in the analysis and characterization of polymorphs a variety of analytical methods may be used in patent specifications

• The preparation, prosecution and protection of a patent involving polymorphs is a challenging scientific and legal activity

The Economist on Patent Litigation08.03.03

“Forget horse-racing, says one patent lawyer: ‘Patent litigation is the true sport of kings.’”

(Citing Judge Posner’s decision in Paxil case)

The End