2. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 1 The Impact of KSR On Pharma/Bio Patent Obviousness Brian V. Slater C5 Pharma & Bio Patent Litigation, Amsterdam, February 17-18, 2009

3. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 2 Obviousness under 35 U.S.C. § 103  A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, –if the differences between the subject matter sought to be patented and the prior art –are such that the subject matter as a whole would have been obvious at the time the invention was made –to a person having ordinary skill in the art to which said subject matter pertains (“PHOSITA”)

4. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 3 KSR Int’l Co. v. Teleflex, Inc., 127 S.Ct. 1727 (2007)  CAFC erred in finding non-obviousness in a mechanical case by –Being too “rigid” in applying its teaching, suggestion, motivation (“TSM”) test for combining references –Focusing solely on problem motivating the patentee –Assuming PHOSITA led only to prior art elements designed to solve same problem –Concluding that “obvious to try” is always insufficient –Trying too hard to avoid “hindsight bias”

5. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 4 The “New” Flexible Approach Under KSR  Supreme Court rejected rules based approach in favor of “expansive and flexible” approach. KSR at 1739.  Re-affirmed a Graham v. John Deere analysis: 1.Determine scope and content of prior art 2.Ascertain differences between prior art and the claim 3.Resolve level of ordinary skill in the pertinent art 4.Consider secondary considerations, such as commercial success, long felt but unsolved needs, failure of others, etc.

6. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 5 Combining Art After KSR  TSM test still one way to show obviousness but legitimate reasons to combine references may go beyond teachings of the prior art – e.g., common sense, “design need”, “market pressure”  “Obvious to try” may suffice under certain circumstances –“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions....” KSR at 1742.  Still needs to be an articulated reason to combine: –“it can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” KSR at 1741.

7. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 6 Predictability is Key  The combination of old elements or substitution of one element according to known methods must do “more than yield predictable results”. KSR at 1739-40.  BUT predictability depends on technology:  “Following these principles may be more difficult in other cases than it is here because the claimed subject matter may involve more than the simple substitution of one known element for another or the mere application of a known technique to a piece of prior art ready for the improvement.” KSR at 1740.

8. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 7 Post-KSR CAFC Published Decisions  New Chemical Entity  Stereoisomers  Biomolecule  Formulation  Method of Treatment

9. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 8  New Chemical Entity

10. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 9  Claim: Pioglitazone (Actos®)  Prior art: “compound b”  Held: NOT OBVIOUS –No reason to have chosen compound b as a “lead” for antidiabetic research: it was not one of 3 compounds with best properties –Prior art taught away: compound b caused weight gain –Pioglitazone had unexpected property of non-toxicity 1. Takeda v. Alphapharm, 492 F.3d 1350 (Fed. Cir. 2007)

11. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 10 2. Eisai v. Dr. Reddy’s, 533 F.3d 1353 (Fed. Cir. 2008)  Claim: Rabeprazole (Aciphex®)  Prior art: Lansoprazole  Held: NOT OBVIOUS –No reason to substitute fluorine in lansoprazole given that fluorine linked with desirable property of lipophilicity 3.Ortho-McNeil v. Mylan, 520 F.3d 1358 (Fed. Cir. 2008)  Discovery of billion dollar a year anti-epilepsy drug topiramate (Topomax®) during anti-diabetic research held NOT OBVIOUS

12. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 11  Stereoisomers

13. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 12 1. Forest Labs. v. Ivax, 501 F.3d 1263 (Fed. Cir. 2007)  Claim: Escitalopram (Lexapro®)) –S- and (+)- enantiomer  Prior art disclosed –Racemic mixture of escitalopram  Held: NOT OBVIOUS –“undue experimentation” in separating enantiomers (difficulties faced by inventors and failures of others) –unexpected property (S- enantiomer 2x potency of racemate) and secondary considerations supported non-obviousness

14. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 13 2. Aventis Pharma Deutschland v. Lupin, 499 F.3d 1293 (Fed. Cir. 2007)  Claim: Ramipril (Altace®): –SSSSS stereoisomer  Prior art disclosed –Composition containing SSSSS + SSSSR –SSS isomer of similar compound, enalapril, was 700-fold more potent than SSR isomer  Held: OBVIOUS –Prior art taught separation of enantiomers by “conventional” methods –PHOSITA would expect SSSSS to have greater potency and expect potency to vary with absolute amount of SSSSS in a mixture – and that is all it did

15. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 14 3. Sanofi-Synthelabo v. Apotex, 550 F.3d 1075 (Fed. Cir. 2008)  Claim: Clopidogrel bisulfate (Plavix®) — dextrorotatory enantiomer  Prior art disclosed racemic mixture and separation techniques  Held: NOT OBVIOUS –Rejected Apotex “obvious to try” argument – (i) known that enantiomers can have different properties (even if allocation is unpredictable) and (ii) techniques for separating were known and required minor experimentation –Separation of enantiomers was unlikely to be productive (based on prior failures) and was not routine –Unexpected property of “absolute stereoselectivity”: dextrorotatory enantiomer retained all of the potency and none of the toxicity –Art taught away from bisulfate salt of clopidogrel as sulfates could encourage re-racimerization

16. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 15  Biomolecule

17. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 16 In re Sullivan, 498 F.3d 1345 (Fed. Cir. 2007)  Claims: antivenom composition comprising antigen binding regions of antibodies (Fab)  Prior art disclosed –purified whole antibody is effective at neutralizing snake venom –using Fab to detect snake venom in immunoassays –Fab detection yielded similar results as whole antibody  Remanded for proper consideration of rebuttal evidence –Fab are cleared quickly and would not be expected to neutralize venom –Unexpected property = decreased occurrence of adverse reactions –Long-felt need for new antivenom composition

18. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 17  Formulation

19. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 18 1. In re Omeprazole, 536 F.3d 1361 (Fed. Cir. 2008)  Claims: pharmaceutical preparations of omeprazole containing an inert water-soluble subcoating separating drug core and enteric coating  Prior art disclosed –omeprazole salt with an enteric coating –use of subcoatings in various pharmaceutical preparations  Held: NOT OBVIOUS –PHOSITA would not have concluded enteric coating would react negatively with drug core thus requiring a subcoating—not “obvious to try” –Even if PHOSITA had recognized negative interaction, art taught many possible approaches and away from using a water-soluble subcoating

20. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 19 2. Abbott Labs. v. Sandoz, 544 F.3d 1341 (Fed. Cir. 2008)  Claims: extended release polymeric formulations of clarithromycin (an erythromycin derivative) with particular pharmacokinetic profile  Prior art disclosed –erythromycin formulation with HPMC as a hydrophilic matrix –controlled release formulations of azithromycin (another erythromycn derivative) which included HPMC  Held: NOT OBVIOUS –Rejected “obvious to try” argument based on property differences between clarithromycin and azithromycin –PHOSITA would not have predicted which formulation of clarithromycin would provide the required pharmacokinetics

21. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 20  Method of Treatment

22. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 21 1. Daiichi Sankyo v. Apotex, 501 F. 3d 1254 (Fed. Cir. 2007)  Claim: method of treating ear infections with topical ofloxacin (a gyrase inhibitor)  Prior art disclosed –Topical use of ciprofloxacin (another gyrase inhibitor) to safely treat ear infections –Gyrase inhibitors “should be used only in difficult cases and exclusively by the otologist”  Dist. Ct. found patent not obvious; determined PHOSITA = pediatrician or general practitioner  Held: OBVIOUS –PHOSITA = specialist in ear treatments (e.g., otologist) or developing pharmaceutical formulations/treatments for the ear

23. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 22 2. PharmaStem Therapeutics v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007)  Claims: compositions and methods of hematopoietic reconstitution using cryopreserved viable human neonatal or fetal stem cells derived from umbilical cord blood  Prior art –Disclosed idea of using cryopreserved cord blood to effect hematopoietic reconstitution  Held: OBVIOUS –Patentee argued no one in prior art knew that stem cells were present in cord blood, rather they were merely “progenitor cells” –Problem – patentee had acknowledged in the specification that it was known that umbilical cord blood contains stem cells

24. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 23 Post-KSR Landscape  Statistically, KSR does not appear to have increased rate of obviousness Not obvious Obvious  New Chemical Entity 3  Stereoisomers 2 1  Biomolecule Remand  Formulation 2  Method of Treatment 2 TOTAL 7 3

25. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 24 Post-KSR Landscape  CAFC obviousness rulings do not reveal a sea change in approach: –e.g., Daiichi Sankyo (obvious to ear specialist to substitute one closely related antibiotic for the other in absence of evidence of unpredictability) –e.g., Aventis (motivation to separate enantiomers came from related prior art showing SSS 700 times more potent than its SSR isomer)  CAFC careful not to rely exclusively on TSM test, but still requires some articulated reason to modify or combine the prior art: –e.g., Aventis (“It remains necessary to show ‘some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness'") (citing KSR) –e.g., Takeda (“Thus, in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.”)

26. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 25 Post-KSR Landscape  To date, CAFC appears to be resisting over-use of “obvious to try” defense: –Supposed to apply only in limited circumstances:  Where there are “finite number of identified, predictable solutions” KSR at 1742. –CAFC has found “obvious to try” inapplicable where  Multitude of ways of trying to solve problem -- e.g., In re Omeprazole (multiple prior art paths to avoid stability issue not using a subcoating)  Where there is no “reason” to make modification -- e.g., Eisai v. Dr. Reddy’s (no reason to substitute fluorine in prior art compound where it was linked with desired lipophilicity)  Where there is a lack of predictability of success of combination -- e.g., Abbott v. Sandoz (property differences between clarithromycin and azithromycin made substitution unpredictable and non-obvious)

27. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 26 Post-KSR Landscape Newman J.:  “The Court in KSR did not create a presumption that all experimentation in fields where there is already a background of useful knowledge is ‘obvious to try’.... The methodology of science and the advancement of technology are founded on the investigator’s educated application of what is known, to intelligent exploration of what is not known. Each case must be decided in its particular context, including the characteristics of the science or technology, its state of advance, the nature of the known choices, the specificity or generality of the prior art, and the predictability of results in the area of interest.” Abbott at 1352. –Abbott Labs. v. Sandoz, 544 F.3d 1341, 1352 (Fed. Cir. 2008)

28. FITZPATRICK, CELLA, HARPER & SCINTO © 2009 | www.fitzpatrickcella.com 27 Post-KSR Landscape  CAFC still giving substantial weight to powerful rebuttal evidence: –Teaching away  e.g., Takeda (alleged “lead” compound for diabetes research caused weight gain); In re Omeprazole (non-soluble subcoating would have been more logical) –Unexpected results  e.g., Sanofi (claimed enantiomer had absolute stereoselectivity); Ortho-McNeil (anticonvulsant properties of topiramate discovered in search for diabetes drug) –Secondary considerations  e.g., Forest Labs and Sanofi cases (failure of others to separate enantiomers)

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