Sreeni%20Padmanabhan

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Sreeni Padmanabhan

• SPE AU 1617
• Tel [phone]
• Email sreeni.padmanabhan_at_uspto.gov

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Chemical Polymorphism

• 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

• Various forms
• Pseudomorphs
• Polymorphs
• Different Physical properties solubility, mp,
  density, hardness, crystal shape, optical and
  electrical properties, vapor pressure

• Bioavailability, dissolution rate, chemical
  physical stability, color, flow, filterability,
  etc.

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Characterization

• 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

• 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

• 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

• 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.)

• Specification
• 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

• The prior art teaches Polymorphic form G of
  benzocaine hydrochloride, crystallized out of
  n-butanol, 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?

• 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
• dspacing 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

• Claim
• Polymorph form 2 Tricor having the following
  X-ray 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.)

• 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 mentioning a polymorph of Tricor.

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Example 2 (Contd.)

• 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
• 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 non-obvious product.

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Example 2 (Contd.)

• Note
• 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.)

• In this case, no prima facie case of obviousness
  has been established since the prior art does not
  establish that
• ------- Polymorphic form 2 of Tricor was known,
  and
• ------- that there were methods of making
  Polymorph 2 of Tricor, known in the prior art.

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Patentability Example 3

• Claim
• A synthetic crystalline zeolite molecular sieve
  having a composition 0.90.1Na2OAl2O32.4-3.4SiO2
  0.45H2O having an X-Ray diffraction pattern
  containing the following d-spacings 8.5, 7.4
  ----
• Specification
• 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.)

• Prior art
• Zeolite R with the following chemical formula
  0.90.2Na2OAl2O33.4-3.6SiO2XH2O, 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.)

• 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

• 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 SciencesV95 Brittain,
  H.G., (1999).

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Sreeni Padmanabhan

• SPE AU 1617
• Tel [phone]
• Email sreeni.padmanabhan_at_uspto.gov