Ip strategies for crystaline forms london dec. 2010
1. Stefano Turchetta - R&D Manager
ITALFARMACO Group
IP Strategies for Crystalline Forms 2010
London, December 7 th 2010
2. Overview
• A couple of key points when dealing with novelty of
crystalline forms: prior art documents and difference
from prior art practice
• The first key point. Structural studies via single
crystal X-rays diffraction in prior art documents.
– Case studies on API 1 and API 2
• The second key point. Exact reproduction of prior art
practice.
– Case study on API 3.
• Take home lessons to help the assessment of
novelty of a newly found crystalline form
3. A basic feature for a
patentable crystalline form:
NOVELTY
We will be concentrating on NOVELTY,
under two particular aspects:
– Prior art documents
– Difference from prior art practice
4. The first key concept for
the assessment of the
novelty of a crystalline
form
Demonstration that no prior
art exists regarding that
particular crystalline form.
5. This assessment is usually done by
reviewing
• Databases
• Literature
• Patents
• Acts of congresses
6. Do crystalline forms have
peculiar literature sources ?
Apart from the traditional Organic
Chemistry Journals, Publications of studies
generating and using single crystal X-rays
diffraction are a very wide and powerful
source of information for crystalline forms.
They are an often
overlooked source of prior
art for crystalline forms
7. What kind of information do
these documents contain ?
Usually they do not contain the
typical data used for Crystalline
forms characterization (no PXRDs,
DSCs TGAs, ssNMRs, Ramans).
Most often they report the
results of single crystal
diffraction studies
8. The skilled in the crystalline
form science knows that
• It is straightforward to calculate
the PXRD from single crystal data
• Softwares are available on the
web that can make this job. For
example…
9. The Cambridge Crystallographic
Data Centre (CCDC) offers a
web-based search interface to
the Cambridge Structural
Database (CSD)
This interface allows to retrieve
data such as bibliographic sources
of its stored data and the
calculated Powder X-Ray
diffraction profiles
13. Calculated PXRD in CSD for API 1
(reporting as source J. Med. Chem. 1992)
Experimental PXRD claimed in 2003 Patent
14. CCDC software allows also to retrieve the peak
positions (2Theta) and Miller indexes for each
calculated PXRD peak position
15. Recognizing the relevance of
prior art on single crystal X-ray
diffraction helps the discoverer
of a supposed new crystalline
form to determine if it is really
new or not.
17. A key prior art document
Journal of Medicinal Chemistry 1993
Reports the results of experiments of
X ray diffraction on single crystal of
the API 2
21. So an important action to do
in order to know if a newly
found crystalline form of an
API is novel is:
look for literature dealing with
single crystal X-rays diffraction
data relative to that API.
Then work out the simulated or
calculated PXRD and compare it
with your experimental data.
22. The second key concept
for assessing the novelty
of a crystalline form
Demonstration that Practice of the
prior art teachings do not end up in
yielding the supposed new
crystalline form
28. The key point is the pH at
which API 3 is precipitated
• US ‘932: “neutralized with HCl”
• US ‘211: “neutralized at pH 5 with 6 N
HCl”
• Org. Proc. Res. Dev. 1999: “adjust at
pH 3 with aqueous hydrochloric acid”
29. What happens when the prior art teachings
are applied to prepare API 3 ?
• US ‘932 “neutralized
with HCl”
• US ‘211 “neutralized at
pH 5 with 6 N HCl”
• Org. Proc. Res. Dev.
1999 “adjust at pH 3
with aqueous
hydrochloric acid”
The teaching of OPRD yields a
crystalline API 3.
3
30. In the first two cases there is
no complete conversion into
the acid form and the product
precipitates as amorphous,
while in the third case the
product precipitates as pure
acid form and it is crystalline.
31. PXRD described
in a WO2008
Experimental PXRD
on material obtained
by application of
OPRD
32. A careful investigation and
reproduction of the prior
art methodologies
described to obtain API 3
allows to understand if our
newly found crystalline
form is novel.
33. To summarize
1. Single crystal X-rays studies are
a main source of prior art for
crystalline forms. Care should
be taken with newly found
crystalline forms to compare
calculated PXRD from single
crystal data, with experimental
PXRD. If experimental PXRD
and calculated PXRD are
different, there is a strong case
in favour of novelty of the form.
34. To summarize
2. Practice of prior art teachings
can be a strong tool in favour of
novelty, when it is possible to
demonstrate that a supposed
new crystalline form is not
produced when following those
teachings.
