1700 frampton chris - rsc.org · prof. chris frampton chief scientific officer pharmorphix

© 2008 SAFC Business confidential

“How to be an effective expert witness”

Prof. Chris FramptonChief Scientific Officer Pharmorphix® (Sigma-Aldrich Company Ltd.)


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Role of the Expert Witness• The Role of the Expert Witness

• In both civil and criminal cases, the opinions of the witnesses are not, in general, admissible. They are normally confined to stating the facts. It is the view of the court that it, that is the judge or judge and jury, are as well equipped as the witness to draw inferences from the facts to which the witness testifies.

• But there are many issues that the court is required to determine which are so far removed from the court’s experience that it needs to obtain the opinion of experts to help it determine the issue in question.

“If matters arise in our law which concern other sciences or faculties, we commonly apply for the aid of that science or faculty which it concerns” Buckley v Rice Thomas (1554)


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• The expert witness is, thus, an exception to the exclusionary rule and is permitted to give opinion evidence. In civil litigation this has statutory authority:

“Where a person is called as a witness in any civil proceedings, his opinion on any relevant matter on which he is qualified to give expert evidence shall be

admissible in evidence” Civil Evidence Act 1972, S.3 (1).

The Expert Witness Institute http://www.ewi.org.uk/

Role of the Expert Witness


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Role of the Expert Witness

• “Expert … witnesses are a crucial resource, without them we (the Judges) could not do our job”

Dame Elizabeth Butler-Sloss, former President of the Family Division

The Expert Witness Institute http://www.ewi.org.uk/


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Outline• Initiation Why when did you become an expert?

• The pivotal telephone call Knowing when to say no!

• Duties of the expert witness Civil procedure rules Part 35

• The 1st written report The thesis

• The 2nd written report The referees from hell

• The trial The viva from hell

• Perspective Pharmaceutical patent disputes

• Performing experiments Laboratory and Personal “GLP”

• Example study Powder diffraction

• Summary


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Civil Procedure Rules Part 35

“………. have explained to me that as an expert witness my overriding duty is to provide an objective and unbiased report to the Court, and that this duty must override any obligation I have towards Company X. I confirm that I understand this duty and have complied with it and will continue to comply with it. In this regard I have read Part 35 of the Civil Procedure Rules, the Practice Direction which supplements Part 35 and the Code of Guidance on Expert evidence.


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• It is your duty as an expert to assist the Court on the matters within your own expertise.

• This duty overrides any obligation you have to Company X, even though they are giving you these instructions and will pay you for your services. This duty encompasses the following…

• The evidence you give must be independent and unbiased.

• You must state the facts or assumptions upon which your opinionsare based, and you should not omit any material facts which could affect your conclusions.

• You must state if any opinion is provisional or requires qualification

Duties of an Expert Witness


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Duties of an Expert Witness

• You must make it clear when a particular issue falls outside of your expertise.

• If at any time you change your view on a particular issue, you must communicate it with out delay, so that is may be communicated to the defendant/claimant and if appropriate, the Patents Court.


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• You will most likely give your evidence in the form of a writtenreport.

• The report must comply with the following requirements…• Your report must be addressed to the Patents Court, not to Company X

or Solicitor Y.• Your report must give details of your qualifications and all relevant

experience.• You must also give details of any literature or other material which you

have relied upon in making your report.• Where there may be a range of opinions on a matter or matters dealt

with in the report, you must summarise the range of opinion and give reasons for your own opinion.

• You must set out a summary of the conclusions you reach• You must state the substance of all material instructions, whether written

or oral, upon which your report was given. This should be an accurate and complete summary of the instructions given.

The Expert’s Written Report


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The Expert’s Written Report• At the end of your report, you must state that you understand you duty

to the Court and that you have complied with that duty.

• Your report must contain a “Statement of Truth” in the following form.

“I believe that the facts I have stated in this report are true and that the opinions I have expressed are correct.”

• You should state if you have had any previous connections with the parties or products or individuals involved.

• It is for the Court rather than the expert or other witnesses to reach legal conclusions based upon the evidence. The expert’s role is to assist the Court in reaching legal conclusions by giving the Court the benefit of the expert’s knowledge and experience.


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It is a contempt of Court to make a false statement in a document which is verified by a “Statement of Truth” without an honest belief in its truth when the statement was made.


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• You may be asked to attend the trial and give oral evidence under oath on the basis of your written report.

• This is probably the first exposure for many of a court and its proceedings.

• You may be asked questions about your report either by the Defendant or the Court.

• This is known as cross examination and is performed by very clever QC’s…it is not a pleasant experience.

• Important to keep your mental concentration at all times.

• Be very sure before answering questions and if necessary make sure your answers are not taken out of context.

• Be very modest about your ability at all times.

The trial


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• Remember at all times that the cross examination is to discredit the evidence you have presented.

• You will find some of the questioning unreasonable…but always keep your head.

• If you begin to feel angry, do not show it, count to 10. The fact that you are finding the questioning unreasonable and you are 100% sure about the evidence you have presented the line of questionswill be probably be recognised as unreasonable.

• Do not fall foul of flattery……

• Be very respectful of the Judge and assist where you can at all times. Remember your function is to assist the Judge and the Court

The trial


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Pharmaceutical Patent DisputesTypical Issues• Bad science

• risk taking

• speed over knowledge

• incorrect experimentation

• Bad data• Wrong data

• misunderstood data

• instrumentation not fit for purpose

• Bad patents• Patents written without consultation of the scientists,

• misinterpretation of data


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• Log in and label all samples that are pertinent to the case and if possible isolate them from all other samples.

• Store, retrieve, return all samples carefully, use a log book and a sensible labelling scheme if a large number of samples are expected.

• Use a new laboratory note book for each case.• Do not use new glassware • Keep all confidential material, confidential.• Keep a record of all the work that you do however trivial.• Do not try to be inventive, do only the work you have been requested to

do.• Maintain close contact with your solicitors.• Always be mindful of the fact that you are there to assist the Court.• Do not get your students to do the work for you.• Consider writing in your own words a simple glossary of terminology

and a lay description of analytical techniques.

Personal GLP….


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• The technique known as X-ray powder diffraction provides a fingerprint of the crystalline state of a material yielding information on the polymorphic form, the quantification of mixtures of polymorphic phases and in some cases the molecular structure of the compound under investigation. An X-ray powder pattern consists of a trace of diffracted beam intensity vs. 2, the diffraction angle. The 2 peak positions of the X-ray powder diffraction pattern relate directly to the unit-cell of the crystalline phase and as such the pattern is unique for each polymorphic form.

Lin

(Cou

nts)

0

100

200

300

400

2-Theta - Scale3 10 20 30

Diffraction Techniques… XRPD


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• Drawbacks…

• Data are most often collected in Bragg-Brentano “Flat Plate”geometry.

• Therefore preferred orientation effects are more than likely to be present.

• If so, then the quoted intensity values are effectively meaningless and cannot be relied on.

• To minimize the effects of preferred orientation researchers are often tempted to grind or manipulate their samples. Both of which canchange the form.

• Single crystal data are not always available by which to construct a theoretical XRD pattern.

• More often than not unable to index the pattern confidently.

• As such the phase purity of the sample cannot be relied upon.

Pharmaceutical patents and XRPD


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• It is a sad fact but…

• X-ray diffractometers are often misaligned or have some form of problem or idiosyncrasy.

• Samples are not always prepared with the love and attention theycrave.

• Organics, [Pharmaceutical materials], are the ugly children of XRPD

• Data is often abused in Patents:

• Intensity values included

• Number of 2 positions can vary [3 up to 37]

• 2 values quoted to a variety of significant figures, (1-3), have also seen 0 and 4.

• Questionable phase purity

• Completely illegible

• Or even worse the wrong pattern!!!

Drawbacks… XRPD


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9.929.916

9.224.315

28.323.214

28.720.513

38.819.912

44.518.811

10.717.710

16.917.49

12.217.08

9.915.97

9.615.56

30.714.95

29.412.64

31.511.03

20.89.02

1007.71

% Intensity2 (degree)Number

29 peaks to 3 decimal places

16 peaks to 1 decimal place

Drawbacks… XRPD


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37 peaks to 2 decimal places

Drawbacks… XRPD


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• Make sure your instrument is aligned, calibrated and a record of the calibration kept.

• Do not grind or adulterate the sample in any way. Try to use it “as received”.

• Run blank sample holder(s) and use holder(s) specifically for this project.

• Prepare the sample with care.

• Read all Patents/documentation carefully especially any suppliedexperimental methodology.

• Check for any previously reported patterns and single crystal structures.

• If you are GLP/ISO/UCAS compliant….make it known and use it.

• Suggest running the sample in different geometries to eliminate issues with preferred orientation

• Suggest attempting to index the experimental patterns whenever possible to yield proof of phase and phase purity.

“GLP”… XRPD


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Is Paroxetine Hydrochloride Anhydrate Form A referred to in GB 2,297,550 is the same material as Paroxetine Hydrochloride Anhydrate referred to in UK Patent Application GB 8526407.

Example: Paroxetine Hydrochloride


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• A search of the literature revealed two crystal structures for Paroxetine Hydrochloride Hemihydrate and one for Paroxetine Hydrochloride Isopropanol solvate.

• The two hemihydrate structures were of excellent quality with R-factors not exceeding five percent. The two structures differed only in the temperature of the data collection; 295 K and 153 K.

• The structure of the isopropanol solvate contained one molecule of paroxetine hydrochloride and one molecule of isopropanol in the asymmetric unit leading to the mono isopropanol solvate stoichiometry. The isopropanol molecule was disordered over two crystallographic sites. The disorder is reflected in the slightly poorer R-factor of 6.5 percent.

Paroxetine hydrochloride hemihydrate

J.A. Ibers., Acta Cryst., C55, (1999), 432-434.

Structure Analyses of Two Crystal Forms of Paroxetine Hydrochloride

M. Yokota, H. Uekusa, Y. Ohashi., Bull. Chem. Soc. Japan, 72, (1999), 1731-1736.

Any Single Crystal Structures available ?


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Paroxetine Hydrochloride Hemihydrate


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Physical data…407Melting point 118°CNo habit givenIR Trace only. Qualitatively matches 403XRPD As below, The first 5 peaks are listed as:6.627, 7.908, 9.460, 11.195 and 13.055°


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Melting point 121°CNeedlesIR, 888, 1194, 1493, 3402 and 3631 cm-1

XRPD As below,The first 4 peaks are listed as:6.6, 8.0, 11.2 and 13.1°

Physical data…550


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Form 2 from 407… Form A from 550…

1

2

3 45

1

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4

6.627, 7.908, 9.460, 11.195 and 13.055° 6.6, 8.0, 11.2 and 13.1°

Qualitative comparison


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Simulated XRD from the hemihydratestructure


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Full Qualitative Comparison


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Personal GLP• Problems can arise if you do not do the work yourself, for example


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Summary• Know when to say no, time, expertise etc.

• The volume of work can be very high, especially as you approach the trial date

• Keep personal and experimental GLP in your mind at all times

• Swear by your data and opinions, not at them….(S. Tarling 1999)

• You are not in Court to make legal decisions

• Always be mindful that your function as an expert witness is to assist the Judge and the Court

1700 frampton chris - rsc.org · prof. chris frampton chief scientific officer pharmorphix

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