1. 1 Sreeni Padmanabhan SPE – AU 1617 Tel: 571-272-0629 Email: sreeni.padmanabhan@uspto.gov

2. 2 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

3. 3 Example of a Hexamorphic Crystal System (1)

4. 4 Photomicrographs

5. 5 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.

6. 6 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

7. 7 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??

8. 8 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

9. 9 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°.

10. 10 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.

11. 11 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 ----.

12. 12 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 ”: “d”spacing: 21.6, 21.6, 20.8, 20.6, 18.5, 17.6. “R¹” values: 88, 35, 100, 78, 10, 12.

13. 13 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.

14. 14 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.

15. 15 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?

16. 16 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.

17. 17 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.

18. 18 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.

19. 19 Patentability – Example 3 Claim: A synthetic crystalline zeolite molecular sieve having a composition 0.9+0.1Na 2 O:Al 2 O 3 :2.4- 3.4SiO 2 :0.45H 2 O 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.

20. 20 Example 3 (Contd.) Prior art: Zeolite R with the following chemical formula: 0.9+0.2Na 2 O:Al 2 O 3 :3.4-3.6SiO 2 :XH 2 O, 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?

21. 21 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.

22. 22 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.

23. 23 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 Sciences”;V95 – Brittain, H.G., (1999).

24. 24 Sreeni Padmanabhan SPE – AU 1617 Tel: 571-272-0629 Email: sreeni.padmanabhan@uspto.gov