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Killing One Bird with Two Stones:

Pharmaceutical Patents in the Wake of Pfizer v Apotex and KSR v Teleflex

Janis K. Fraser, Ph.D., J.D.

June 5, 2007

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• The pre-apocalypse obviousness world • Pfizer v. Apotex• KSR v. Teleflex• Pharmaceutical patents newly at risk• Obviousness criteria, post-Pfizer/KSR• Keys to overcoming obviousness challenges• Consequences to pharma industry

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The Pre-Apocalypse World• Graham Factors

- scope and content of the prior art- differences between the prior art and the claims- level of ordinary skill in the art

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The Pre-Apocalypse World• Graham’s secondary (“objective”) indicia of

nonobviousness- unexpected results- commercial success- long-felt but unsolved needs- prior effort and failures- willingness of others to license- copying by others- skepticism of experts- tribute by experts

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The Pre-Apocalypse World• Federal Circuit’s 25-year-old obviousness test

- All limitations are found in the art- Teaching, suggestion or motivation to combine (“TSM

test”) is found in the art or in the nature of the problem to be solved

- Expectation of success is found in the art - “Obvious to try” is not the standard- “Teaching away”- “Objective indicia”

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• Pfizer v. Apotex, 480 F.3d 1348, 82 U.S.P.Q.2d 1321 (Fed. Cir. 2007)

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Pfizer v. Apotex: Facts• amlodipine and salts thereof: US 4,572,909 (1982

priority date)

• maleate salt- selected 1982- problems (instability and stickiness) noted April 1984- clinical trials with capsule form

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Pfizer v. Apotex: Facts• 7 alternatives identified and tested in 1984

• Besylate salt- Selected October 1984- In clinical trials by 1985- Filed priority application in 1986: US 4,879,303- Launched as product (Norvasc®) in 1992

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Pfizer v. Apotex: District Court• ‘303 claims not obvious

• No motivation in the art- ‘909 discloses amlodipine salts, but not amlodipine besylate- Berge lists many salts and says besylate is rarely used (0.25%)

• No expectation of success: “no reliable way of predicting the influence of a particular salt species on the behavior of a parent compound”

• Surprising results: better properties than maleate

• Other “ objective consideration” : Pfizer’s switch to besylatesalt

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Pfizer v. Apotex: Federal Circuit• Reversed District Court

• Claims are obvious over ‘909, Berge, and references disclosing besylate salts of other compounds

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Pfizer v. Apotex: Federal Circuit• Motivation to combine

- Does not have to be found explicitly in prior art references sought to be combined

- Can be in “ any number of sources”¾ common knowledge¾ prior art as a whole¾ nature of the problem itself

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- Can be gleaned “ from the nature of the problems encountered with the amlodipine maleate tablet formulations sought to be solved by the inventors”

! Based on undisclosed problems discovered by inventors??

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- Fact that Berge says besylate is rarely used (0.25%) doesn’t matter

¾ “ Irrefutable evidence shows that a skilled chemist at the time would simply make known pharmaceutically-acceptable salts of whatever active ingredient with which he or she was working at the time”

¾ Number of acceptable anions was “ not unlimited”

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- Fact that the art showed only unrelated compounds prepared as besylate salts doesn’t matter

¾ Art described besylate salt as useful in promoting stability, solubility, etc.

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Pfizer v. Apotex: Federal Circuit• Reasonable expectation of success

- Fact that there was no reliable way to predict the influence of a particular salt species doesn’t matter

¾ Need only a reasonable probability of success

¾ Inventor expected that each of the 7 on his list would form a salt with improved characteristics compared to maleate

! Inventor’s own expectations used as evidence of what constitutes “reasonable expectation of success”

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Pfizer v. Apotex: Federal Circuit• “Obvious to try” (not obvious if motivation is

merely to vary all parameters, where the prior art gave no direction)• Here not “ numerous parameters” —only one

• Here the “ art” (inventor?!!) expected besylate salt would form

• Other art “ clearly directed” the artisan to choose besylatesalts

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Pfizer v. Apotex: Federal Circuit• “Obvious to try”

– Required only routine experimentation to confirm the properties

¾ Distinguished routine experimentation used to discover a new compound

¾ Analogized to optimization of a range

¾ Dismissed significance of salt’s effect on properties of the drug because did not affect therapeutic effectiveness

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Pfizer v. Apotex: Federal Circuit• Secondary considerations

– Pfizer’s switch to besylate

¾ No evidence to support Dist. Court’s conclusion

¾ Pharmaceutical companies are in the business of R&D

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Pfizer v. Apotex: Federal Circuit• Secondary considerations

– Unexpectedly superior results (on stability and stickiness)¾ No evidence that the properties were unexpected¾ Pfizer says properties are not predictable, so can’t say art

“ expected” lesser results ¾ Inventor expected an improvement

! So inventor’s own expectations used against him

¾ “ Art” (inventor??) would have expected all 7 salts to work and that one would show up as the best after “ routine optimization”

¾ Even if unexpectedly superior results, doesn’t overcome the “ strong case” of obviousness

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Pfizer Foreshadows KSR• “ Flexible” TSM test• Motivation can be derived from problem to be

solved• “ Obvious to try” can mean obvious

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• KSR v. Teleflex, 550 U.S. ____ (2007)

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KSR v. Teleflex: Facts• Teleflex patent claimed adjustable automobile

pedal with electronic sensor to control throttle

• prior art - adjustable pedal with mechanical throttle control- non-adjustable pedal with electronic sensor to control

throttle

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KSR v. Teleflex: District Court• summary judgment of obviousness

- Graham Factors¾ found “ little difference” between art and claim

- TSM test ¾ hypothetical motivation different from patentee’s

- commercial success of invention insufficient to override obviousness conclusion

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KSR v. Teleflex: Federal Circuit• non-precedential opinion

• reversed summary judgment of obviousness and remanded for trial

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KSR v. Teleflex: Federal Circuit• said District Court did not apply TSM test strictly

enough- lacked findings as to the specific motivation- “ nature of the problem” was insufficient basis here

because the problems addressed by prior art were different from that addressed by Teleflex

• “ obvious to try” does not constitute obviousness

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KSR v. Teleflex: Supreme Court

• Unanimous decision

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• Reaffirmed Graham’s “ expansive and flexible”approach

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KSR v. Teleflex: Supreme Court• Rejected “ rigid approach” of Federal Circuit’s TSM

test- Reason to combine need not be in the prior art—can be

in “ common sense” of a POSITA of ordinary creativity

- Problem to be solved need not be the patentee’s problem

- Obviousness can be based on “ obvious to try,” if there is a design need or market pressure to solve a problem, combined with a limited number of predictable solutions

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• Reaffirmed that “ teaching away” is evidence of nonobviousness (citing United States v. Adams, 383 U.S. 39 (1966))

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• Reaffirmed that “ unexpected results” are evidence of nonobviousness (citing Adams)

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• Reaffirmed that conclusory statements re motivation are insufficient– “ must be some articulated reasoning with some rational

underpinning”– “ important to identify a reason that would have

prompted one of ordinary skill in the relevant field to combine the elements”

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KSR v. Teleflex: Supreme Court• Theme #1: “ common sense”

• Common sense teaches, however, that familiar items may have obvious uses beyond their primary purposes, and in many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.

• If [pursuing a finite number of known options] leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.

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KSR v. Teleflex: Supreme Court• Theme #1: “ common sense”

• Rigid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it.

• Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.

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KSR v. Teleflex: Supreme Court• Theme #2: “ predictable”

• The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.

• [When] a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.

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KSR v. Teleflex: Supreme Court• Theme #2: “ predictable”

• If a person of ordinary skill can implement a predictablevariation, Section 103 likely bars its patentability.

• A court must ask whether the improvement is more than the predictable use of prior art elements according to their established functions.

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Pharmaceutical patents newly at risk• “ Follow-on” patents

– Salts¾ Pfizer v. Apotex

– Enantiomers– Controlled release

¾ Alza v. Mylan, 464 F.3d 1286 (Fed.Cir. 2006)

– Formulations– Delivery route or regimen– Combinations of old drugs– New indications for old drugs

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Pharmaceutical patents newly at risk

• “ Primary” patents– Second or subsequent drug in a class– Minor modification of a known compound

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Obviousness criteria, post-Pfizer/KSR

• Were all elements present in the art?

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• Was there a common-sense reason to combine?– In the art– In the nature of the problem addressed by patentee (even

if that problem was known only to the patentee???)– In the nature of any problem that existed in the art– Has to be articulated (S.Ct. and USPTO)– “ Teaching-away” may neutralize at least some of such

reasons

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Obviousness criteria, post-Pfizer/KSR • Obvious-to-try can in some cases be adequate to

supply the motivation to combine– When varying a single parameter (not multiple), using

routine experimentation and a finite number of known variations

– Less likely when used to discover a new compound as opposed to selecting a variant with improved characteristics

– Less likely when the improved characteristic is therapeutic effectiveness as opposed to physical properties such as stability or stickiness

– Variations must have been within the capabilities of POSITA (…but when aren’t they?)

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• Was there a lack of expected success in the art?– Need only a “ reasonable probability” of success– Undermined by proof that inventor expected the

invention to work (This (from Pfizer) seems wrong, so may not hold)

– “ Teaching away” is best evidence

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• Were the results surprisingly good?– Need to prove what the art would have expected– Undermined by arguing that the field was unpredictable– Undermined by proof that inventor expected at least one

of tested variations to be better than the prior art (Again, seems wrong to use inventor’s expectations as proof of what the art expected)

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• Other objective indicia of nonobviousness– Won’t help if the court is convinced the prima facie

obviousness case is strong

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Keys to overcoming obviousness challenges

• Find a “ teaching away” in the art

• Establish surprising results

• (In litigation) show that the inventor did not predict the invention would work until it did work

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• Argue that problems discovered and solved by inventor are part of the invention, not part of the prior art

• Argue that the asserted motivation lacks “ common sense”

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• Emphasize benefits in terms of therapeutic effectiveness rather than physical properties

• Characterize the invention in terms of discovery rather than mere optimization

• Emphasize non-routine nature of the experimentation needed to discover the invention

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Consequences to pharma industry

• Pro-competitive effect: For existing drugs, it will be harder to block generic entry into market after primary patent expires– Earlier generic entry– However, shorter period of exclusivity may change the

calculation of whether to move forward with developing the NCE in the first place, so may turn out to be anti-competitive

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• Anticompetitive effect: Some promising NCE’s or new formulations or new indications will not be developed because no patent protection at all– No patent means development cost can’t be recouped, so

no one will be willing to develop the drug– Fewer marketed drugs means less choice for consumers– Even generics will suffer because fewer drugs to copy

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• Unlikely to be much counterbalancing benefit to pioneers– Broad “ platform” patents that block new drug

development not as vulnerable to obviousness attack ¾ Research tools¾ Broad genus of novel compounds with new activity

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Janis K. Fraser, Ph.D.

Fish & Richardson P.C.225 Franklin StreetBoston MA 02110

Fone: 617 521 7037Fax: 617 542 [email protected]

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