Transcript Slide 0 - Fitzpatrick, Cella, Harper & Scinto

The Impact of KSR On Pharma/Bio Patent
Obviousness
Brian V. Slater
C5 Pharma & Bio Patent Litigation, Amsterdam, February 17-18, 2009
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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”)
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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”
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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.
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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.
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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.
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Post-KSR CAFC Published Decisions
 New Chemical Entity
 Stereoisomers
 Biomolecule
 Formulation
 Method of Treatment
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 New Chemical Entity
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1. Takeda v. Alphapharm, 492 F.3d 1350 (Fed. Cir. 2007)
 Claim: Pioglitazone (Actos®)
C2H5
N
 Prior art: “compound b”
H3C
 Held: NOT OBVIOUS
N
CH2CH2
CH2CH2
– 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
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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
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 Stereoisomers
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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
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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
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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
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 Biomolecule
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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
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 Formulation
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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
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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
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 Method of Treatment
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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
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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
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Post-KSR Landscape
 Statistically, KSR does not appear to have increased rate of
obviousness
Not obvious
 New Chemical Entity
3
 Stereoisomers
2
 Biomolecule
1
Remand
 Formulation
2
 Method of Treatment
2
TOTAL
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Obvious
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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.”)
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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)
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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)
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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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