Chemical Polymorphs

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Sreeni Padmanabhan
SPE – AU 1617
Tel: 571-272-0629
Email: sreeni.padmanabhan@uspto.gov
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Chemical Polymorphism
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Polymorphism
Polymorphs & Allotrophs
Examples : Elements / Inorganic / Organic
Carbon: graphite & diamond
ZnS: zinc blend and wurtzite
Progesterone: 5 forms
Chloramphenicol: 4 (1 amorphous and 3
crystalline) forms
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Example of a Hexamorphic Crystal System (1)
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Photomicrographs
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Properties
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Various forms
Pseudomorphs
Polymorphs
Different Physical
properties: solubility,
mp, density, hardness,
crystal shape, optical
and electrical
properties, vapor
pressure
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Bioavailability,
dissolution rate,
chemical & physical
stability, color, flow,
filterability, etc.
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Characterization
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Crystallography: Single crystal X – ray diffraction
& X-ray Powder Diffraction
Microscopy: Polarizing Optical Microscopy & Thermal
Microscopy
Thermal Methods of Analysis: Thermogravimetry;
Differential Thermal Analysis and Differential
scanning calorimetry
Vibrational Spectroscopy: Raman & IR Spectroscopy
Chemical Environment: NMR Spectroscopy
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Emphasis on Polymorphism - WHY
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Solid forms are often critical in the development of
Active Pharmaceutical ingredients
Ground state – most stable but least soluble
For optimum bioavailability must balance properties
of stability and solubility
Disappearing act of Polymorphs
New forms leads to Newer Drug Products
New Forms --------- Newer Patents??
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Polymorphism & Patentability
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Patent Strategies often involve first patenting
compounds and then applying for patents on
various polymorphs --- are these polymorphs
separately patentable?
Polymorphs with unexpected properties may
support Patentability
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Patentability – Example 1
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Claim 1: A polymorph of benzocaine
characterized by X-ray diffraction pattern
characterized by a peak having a diffraction
angle (Ø ) of about 21.6°.
Claim 2: A method of treating pain
comprising administering a polymorph of
benzocaine characterized by X-ray diffraction
pattern characterized by a peak having a
diffraction angle (Ø ) of about 21.6°.
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Example 1 (Contd.)
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Specification:
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Benzocaine hydrochloride was crystallized out of
acetone, i.e., Form A
Benzocaine hydrochloride was crystallized out of
toluene, i.e., Form B
Benzocaine hydrochloride was crystallized out of
ethanol/water, i.e., Form C (a hemihydrate)
The compound is useful for treating pain.
X-ray powder diffraction data for each of the
Forms A, B and C is included.
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Example 1 Contd: Prior art
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The prior art teaches Polymorphic form G of
benzocaine hydrochloride, crystallized out of nbutanol, useful for treating headache. X-ray
diffraction data is also given - “d” values: 38.5, 28.4,
21.5 ----.
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Example 1: Patentable Claim?
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Polymorphic form B of benzocaine
hydrochloride having the following X-ray
powder diffraction pattern, expressed in
terms of “d” interplanar spacing and relative
intensities ( I/Imax) “R¹ ”:
“d”spacing: 21.6, 21.6, 20.8, 20.6, 18.5, 17.6.
“R¹” values: 88, 35, 100, 78, 10, 12.
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Patentability – Example 2
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Claim:
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Polymorph form 2 Tricor having the following Xray powder diffraction pattern expressed in terms
of “d” spacing and relative intensities( “R¹”)
 D spacing: 8.95; 6.37; 5.64
 R¹: 15, 28, 100.
Specification:
 Describes the process of making & crystallizing the
polymorph and also the use of the polymorph as a
carbohydrate lowering drug.
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Example 2 (Contd.)
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Prior art: (Reference - A)
 Teaches Polymorph 1 of Tricor, with a similar use
 Does not disclose or suggest that Tricor may
assume distinct, crystalline forms having different
properties
 Does not teach a method to make polymorph 2 of
Tricor.
Prior art (reference - B )
 Lists 16 carbohydrate lowering drug compounds,
including Tricor
 Refers to a pharmaceutically acceptable salt,
hydrate or polymorph thereof, without specifically
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mentioning a polymorph of Tricor.
Example 2 (Contd.)
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The Prior art does not teach that Tricor may assume
distinct, crystalline, polymorphic forms having
different physical properties
Is a rejection under 35 USC 103 over A in view of B
proper?
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Example 2 (Contd.)
Obviousness Considerations:
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Whether the claimed Polymorph would have been
prima facie obvious over Polymorph 1
Polymorph 2 is an additional form of an old product
and both products have similar utility. In general,
changing the form, purity or another characteristic of
an old product in an expected manner that does not
alter its properties, does not result in a new nonobvious product.
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Example 2 (Contd.)
Note:
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This conclusion may change on a case by case basis
depending on the particular facts at issue.
Obviousness considerations include the expectation
that the other polymorphic form would have been
expected to have existed and that one would have
been motivated to have prepared it, and that one
would have known how to have prepared this other
form.
Note that, secondary considerations, such as
unexpected results are always considered. These
might include unexpected increases in activity or
bioavailability.
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Example 2 (Contd.)
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In this case, no prima facie case of obviousness has
been established since the prior art does not
establish that:
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------- Polymorphic form 2 of Tricor was known, and
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------- that there were methods of making
Polymorph 2 of Tricor, known in the prior art.
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Patentability – Example 3
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Claim:
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A synthetic crystalline zeolite molecular sieve
having a composition 0.9+0.1Na2O:Al2O3:2.43.4SiO2 :0.45H2O having an X-Ray diffraction
pattern containing the following d-spacings: 8.5,
7.4 ----
Specification:
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Describes how the X-ray pattern was determined
and how the crystals were prepared
Discloses its use as a desiccant and adsorbant.
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Example 3 (Contd.)
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Prior art:
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Zeolite R with the following chemical formula:
0.9+0.2Na2O:Al2O3:3.4-3.6SiO2:XH2O, X is about 7
for the fully hydrated form having an X-ray
diffraction pattern containing the following d
spacings: 8.55, 7.45 ---- Process conditions for making the claimed zeolite
and the prior art zeolite are similar. Zeolite R is
useful as a desiccant and adsorbant.
Is a rejection under 35 USC 102 or 103 proper?
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Example 3 (Contd.)
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102/103 Rejection:
 Is it proper, if made?
 The claimed zeolite and prior art zeolite appear similar
chemically but from the X-Ray pattern it is found that there
are apparent differences in the “d” values.
 These apparent differences may be insufficient to distinguish
that which is claimed from the prior art since “d” value
measurements are imprecise and the difference in values
between the prior art and the claimed invention are within
the limits of experimental variation.
Conclusion:
 The rejection is proper – there is insufficient difference
between the two zeolites to conclude, absent further
evidence, that the claimed invention is different than that in
the prior art.
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Example 3 (Contd.)
The slight differences in d spacings may be
reasonably attributed to such factors as the
apparatus used for X-Ray study, humidity,
temperature, orientation of powder sample, etc.
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References
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Chemical & Engineering News, “The Right Stuff”, Feb
24,2003, pages 32-34
Journal of Pharmaceutical Sciences, “Pharmaceutical
Applications of Polymorphism” 58, 911-929 (1969)
Polymorphism in Pharmaceutical Solids,”Drugs and
the Pharmaceutical Sciences”;V95 – Brittain, H.G.,
(1999).
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Sreeni Padmanabhan
SPE – AU 1617
Tel: 571-272-0629
Email: sreeni.padmanabhan@uspto.gov
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