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1. STRATEGIES TO AVOID OBVIOUSNESS FINDINGS:
LEGAL ANALYSIS AND PRACTICAL APPLICATIONS
AMERICAN CONFERENCE INSTITUTE
New York, NY
October 10, 2012
Ted J. Ebersole ∙ Lisa B. Pensabene ∙
Sandra A. Bresnick
1

2. Introduction
Sandra A. Bresnick
QUINN EMANUEL URQUHART
& SULLIVAN
2

3. Evolving State Of The Law On
Pharmaceutical Patent Life Cycle Strategies
Prior-Art Obviousness
Obviousness-Type Double Patenting
3

4. Obviousness
In re Kao, 639 F.3d 1057 (Fed. Cir. 2011)
Unigene v. Apotex, 644 F.3d 1352 (Fed. Cir. 2011)
Santarus v. Par Pharms., __ F.3d __, 2012 WL
3797966 (Fed. Cir. Sept. 4, 2012)
4

5. In re Kao, 693 F.3d 1057 (Fed. Cir. 2011)
(Rader, Linn*, Moore)
OPANA ER is an opioid agonist
indicated for the relief of moderate to
severe pain in patients requiring
continuous around-the-clock opioid
treatment for an extended period of
time.
http://www.endo.com/File%20Library/Products/Pre
scribing%20Information/Opana-ER-PI-01-2012.pdf
5

6. In re Kao
Applications related to controlled-release oxymorphone tablets
‘432 application:
Composition with 12-hour dosing interval and in vitro dissolution
profile via USP Paddle Method
‘859 application:
Method of treating pain comprising providing CR oxymorphone
tablet …with Cmax value that is 50% higher when given under fed
vs. fasted conditions
‘740 application:
Method of treating pain comprising providing CR oxymorphone
tablet …and providing information about bioavailability – that it is
increased by 26% in subjects with renal impairment
6

7. In re Kao
The Examiner Rejected All Claims, And The Board Affirmed
Maloney
“Secondary Considerations”
‘432 Application
(Composition)
Replace oxycodone in
Formula 6 with
preferred opioid,
oxymorphone, to yield
claimed composition
Assumed commercial success
and unexpected results WERE
sufficient to overcome prima
facie obviousness BUT NOT
commensurate to claim scope
‘859 Application
(Method with Cmax
limitation)
Sufficient teachings in
Maloney to render
claims obvious
Same
‘740 Application
(Method with
“providing BA info”
limitation)
Sufficient teachings in
Maloney to render
claims obvious
Same
7

8. In re Kao
Federal Circuit re “Secondary Considerations”
When present, must consider them, “though they are not
always dispositive,” 639 F.3d at 1068.
Evidence must be reasonably commensurate with claim scope
‐ “This does not mean an applicant is required to test every
embodiment …If an applicant demonstrates that an
embodiment has an unexpected result and provides an
adequate basis to support the conclusion that the other
embodiments falling within the claim scope will behave
in the same manner, this will generally establish that the
evidence is commensurate with the scope of the claims,”
id.
8

9. In re Kao
Federal Circuit re “Secondary Considerations”
Reiterated importance of nexus – “a fundamental
requirement” before “secondary considerations can carry the
day”
“Where the offered secondary consideration actually results
from something other than what is both claimed and novel in
the claim, there is no nexus to the merits of the claimed
invention,” id.
9

10. In re Kao
Substitution Of
Oxymorphone In
Formula 6
‘432
Application
Unexpected Results
Opana® ER
No substantial
evidence that such
substitution yields
a composition that
falls within the
dissolution profile
of claim 1. Board’s
conjecture is
insufficient.
Unexpected multiple
peaks in oxymorphone
blood concentration
639 F.3d at 1066-67
Board erred in ignoring
this evidence. Board
must determine nexus
between unexpected
result and “aspects of the
claimed invention not
already present in the
prior art,” e.g., claimed
dissolution rate range vs.
prior art rates.
639 F.3d at 1069
Commercial Success
Opana® ER
Board erred in refusing to
credit evidence because it
was not proven across the
entire claimed range of
dissolution rates.
But record silent on nexus.
Directed Board to
determine whether
evidence resulted from
the merits of the claimed
invention as opposed to
prior art or other extrinsic
factors.
639 F.3d at 1069
10

11. In re Kao
Maloney
‘859
Application
“Secondary Considerations”
Unexpected Results, Commercial
Success Of Opana® ER
Held: “Food effects” element is
inherent property of
oxymorphone, in CR or IR forms.
That OSA didn’t recognize this was
irrelevant, stating “This is not a
case where the Board relied on an
unknown property of prior art for a
teaching.” 639 F.3d at 1070.
“Merely discovering and claiming a
new benefit of an old process cannot
render the process again patentable,
so evidence of secondary
considerations was insufficient to
overcome this strong showing of
primary considerations that rendered
the claims at issue invalid.” 639 F.3d at
1072.
Substantial evidence supported
Board on remaining disputed
elements, 12-hour release and
hydrophobic material. 639 F.3d at
1071-72.
11

12. In re Kao
Maloney
’740
Application
“Secondary Considerations”
Unexpected Results, Commercial
Success Of Opana® ER
“Novel contribution” = “providing
information” about correlation
between renal failure and
bioavailability.
Board’s ruling that secondary
considerations were not commensurate
with the scope of claimed invention
was error, but harmless, because no
nexus:
Held: Though the correlation was
not known, “informing someone
of the correlation cannot confer
patentability absent a functional
relationship between informing
and administering steps,” citing
King Pharms. 639 F.3d at 1072.
Held: (1) No evidence that multiple
peaks was related to “informing step;”
and (2) No evidence that Opana ER’s
commercial success is attributable to
the informing step, because “the claim
does not require that the informing
step have any appreciable effect on the
administration of the drug.” 639 F.d at
1074.
12

13. Unigene & Upsher Smith v. Apotex, 655 F.3d 1352
(Fed. Cir. 2011) (Rader*, Moore, O’Malley)
Salmon Calcitonin nasal spray.
Indicated for the treatment of
postmenopausal osteoporosis in
women greater than 5 years
postmenopause with low bone
mass relative to healthy
premenopausal women.
www.fortical.com
13

14. Unigene v. Apotex
Unigene holds 505(b)(2) NDA to Fortical® salmon
calcitonin nasal spay, listing Novartis’ Miacalcin® as
reference drug.
Apotex filed ANDA, Unigene brought suit.
On cross-motions for summary judgment, SDNY
granted summary judgment of non-obviousness, and
the Federal Circuit affirmed.
14

15. Unigene v. Apotex
Fortical was developed as a design-around of Miacalcin.
They have different formulations, among them:
‐ Miacalcin has benzalkonium chloride (BZK) as preservative,
absorption enhancer, surfactant.
‐ Fortical has citric acid, which functions as absorption
enhancer and stabilizer/buffer.
Disputed Claim 19 of ‘812E reissue patent:
‐ Liquid pharmaceutical composition for nasal
administration comprising …salmon calcitonin, about 20
mM citric acid, about 0.2% phenylethyl alcohol, about
0.5% benzyl alcohol, and about 0.1% polyexyethylene (2)
sorbitan monooleate.
‐ Claim 19 does not assign functionality or property to the
components of the formulation, and covers Fortical.
15

16. Unigene v. Apotex
Court: OSA would have had design need and market
demand to create an FDA-approved liquid nasal
composition that delivers salmon calcitonin, 655 F.3d at
1362.
Design need: to achieve a bioequivalent composition.
Market demand: to achieve a composition that treats
the same symptoms as the reference formulation.
OSA would have known that a formulation
bioequivalent to Miacalcin would have the best
chance for FDA approval.
16

17. Unigene v. Apotex
Prior art:
Miacalcin formulation; ‘014 patent; Day Reference.
Found significant differences between prior art and claims, id.:
‘014 patent: citric acid used in liquid injection into rat
duodenum, not for human use in liquid pharmaceutical
formulation, also much higher concentrations.
Day reference: taught away from claimed composition, even
though individual excipients were described, but with different
functionality than used in the asserted claim.
Held: No reasonable juror could conclude that the prior art would
give OSA sufficient reason or motivation to use about 20 mM citric
acid in a liquid nasal salmon calcitonin composition with reasonable
expectation it would work, id. at 1363.
17

18. Unigene v. Apotex
No reasonable expectation of success, even accepting the
design need and market pressure to develop a bioequivalent
to Miacalcin :
‐ “There is no genuine dispute of material fact that OSA
attempting to make a liquid composition to deliver salmon
calcitonin through nasal administration would not have
considered using about 20 mM citric acid with the
narrowly claimed amounts of benzyl alcohol, phenylethyl
alcohol, and polysorbate 80, because the formulation
would not be expected to perform properly to meet the
specificity of a pharmaceutical use.” 655 F.3d at 1363.
18

19. Santarus, Inc. v. Par Pharms., __ F.3d __
2012 WL 3797966 (Fed. Cir. Sept. 4, 2012)
ZEGERID® (omeprazole/sodium
bicarbonate) is an immediate-release oral
proton pump inhibitor (PPI) used in adults
for up to 4 weeks to treat heartburn and
other symptoms that happen with
gastroesophageal reflex disease (GERD).
http://www.santarus.com
19

20. Santarus v. Par
Zegerid® brand omeprazole formulations, non-enteric coated.
Santarus, Inc. is exclusive licensee to 5 patents (“Phillips
patents”) covering specific formulations of PPIs.
Prior PPI formulations required enteric coating to be
bioavailable.
‐ PPIs are extremely acid-sensitive. It was known that
unprotected PPIs do not survive long enough in the
bloodstream to reach parietal cells.
Phillips patents claim specific combinations of uncoated PPI
and buffering agents – allowing administration to people who
are unable to swallow tablets.
20

21. Santarus v. Par
Par filed ANDA, and Santarus sued in Delaware.
D. Del. held, inter alia, all 36 asserted claims obvious.
‐ Also found infringement; no inequitable conduct; and written
description issues with some claims.
Fed. Cir. (Rader, Newman, Moore), per curiam, affirmed invalidity of
some claims and reversed on others, holding them not invalid:
‐ Affirmed: claims relating to ratios of buffers, dosage range,
blood serum concentrations, and powder formulations.
‐ Reversed: claims directed to non-enteric coated conventional
tablets and amounts of buffering agents.
‐ Judge Newman wrote separately regarding written description
and obviousness.
21

22. Santarus v. Par
Each patent in suit was CON or CIP of the ‘737 patent.
Scope and content of prior art differed depending on the
claim’s effective filing date. Held ‘737 patent was prior art to
claims in several patents in suit:
‐ Various claims of ‘346 patent.
‐ Various claims of ‘885 patent.
‐ Claim 29 of ‘988 patent.
22

23. Santarus v. Par
Affirmed obviousness of claims to which the ‘737 patent is prior art,
various claims of the ‘346, ‘885, and ‘988 patents.
Claims 2 and 17 of ‘885 patent, exemplary claims on appeal:
‐ Claim 2: Method of treating gastric disorder … providing PPI
composition, at least one buffering agent, excipients, not enteric
coated, and with specified serum concentrations
‐ Claim 17 depends on claim 2 and requires sodium bicarbonate
as buffering agent in about 1000 mg to about 2000 mg
Argued:
‐ (1) Claims require uncoated PPIs and buffering agents in specific
amounts and ratios not disclosed in the prior art; (2) they
achieved the results using only 1000 mg to 2000 mg sodium
bicarbonate; and (3) they achieve specific blood serum
concentrations not disclosed in the prior art.
23

24. Santarus v. Par
Per curiam court disagreed, holding that the ‘737 patent
discloses, inter alia:
‐ Formulating omeprazole in conventional forms and
aqueous suspensions with buffering agent.
‐ That “omeprazole need not be enterically coated.”
‐ Broad ranges for amounts of sodium bicarbonate that can
be used.
‐ Blood serum concentrations were inherent properties of
the prior art formulation.
Result: Claims to which the ‘737 patent are prior art are
obvious.
24

25. Santarus v. Par
Reversed obviousness of some claims to which the ‘737 patent is
not prior art.
Santarus argued the prior art taught away from all non-enteric
coated omeprazole formulations.
‐ Federal Circuit agreed as to claims to conventional dosage
forms, which were “explicitly ruled out” by Pilbrant, 2012 WL
3797966 at *10.
‐ But disagreed as to powder formulations for use in aqueous
suspensions, which were covered by undisputed claim
constructions, id. at *10-11 (prior art called option “second-best
choice”).
Other claim limitations, such as ratios and ranges of buffers:
‐ Federal Circuit found amounts, ranges broadly disclosed in prior
art, id. at *12.
25

26. Santarus v. Par
Objective Considerations
‐ Skepticism in the industry, unexpected results, long-felt need,
industry recognition, commercial success
‐ Federal Circuit affirmed district court’s finding that objective
evidence was insufficient to overcome obviousness, id. at *13.
• No commercial success – other PPI sales dwarfed Zegerid
• Skeptic’s statement was not subject to cross-exam, not entitled to
weight
In her dissent, Judge Newman disagreed with the ruling that the
‘737 patent is prior art. She also disagreed with Court’s factual
analyses of scope and content of prior art, teaching away, and the
court’s analysis of objective considerations, all of which she
discusses in detail.
26

27. Obviousness Developments
Ted J. Ebersole, Ph.D.
ASSISTANT GENERAL PATENT COUNSEL
ELI LILLY AND COMPANY
27

28. Alcon v. Apotex
(Fed Cir. Aug 8, 2012; Moore*, O’Malley and Prost)
Alcon markets Patanol® (olopatadine), an anti-allergy eye
medication applied topically.
US 5,641,805 (new use of an old compound) listed in the OB
Apotex filed an ANDA
Alcon filed suit under 271(e)(2)(A) asserting claims 1-8
District ct found all claims infringed, enforceable and not
invalid (790 F. Supp. 2d 868 (S. D. Ind. 2011)
Federal Circuit reversed on claims 1-3 and 5-7 finding them
invalid, but affirmed on claims 4 and 8.
28

29. Technology
Anti-allergy medications for eyes encompass two classes of
compounds:
‐ Anti-histamines which block or displace mast cell-released
histamines from binding at the receptors on target tissues
that trigger itching, redness
‐ Mast cell stabilizers which block the release of histamine
and other mediators in the first place from the mast cells
29

30. Known At Time Of Invention
Olopatadine itself.
Olopatadine was an effective antihistamine.
Some drugs in the genus of compounds that included
olopatadine were effective mast cell stabilizers.
Not known
Olopatidine was a mast cell stabilizer in human eyes.
30

31. Claim 1
A method for treating allergic eye diseases in humans
comprising stabilizing conjunctival mast cells by topically
administering to the eye a composition comprising a
therapeutically effective amount of a 11-(3dimethylaminopropylidene)-6,11-dihydrobenz(b,e) oxepin-2acetic acid or a pharmaceutically acceptable salt thereof.
31

32. Kamei Prior Art
Discloses treating eye allergies in guinea pigs using eye drops
with olopatadine in concentrations ranging from 0.0001% 2/v
to 0.01% w/v.
Overlaps with claims 1-3 and 5-7.
It does not overlap with 4/8 (0.1% w/v)
It does not disclose treating allergies in human eyes.
32

33. Did A Motivation To Adapt
The Kamei Formulation Exist?
District court found as a fact: animal tests including guinea pig eyes
models are predictive of a compound’s antihistamine activity in its
topical availability in human eyes, YET it found no motivation
existed to use the concentrations disclosed in Kamei in human eyes.
Clear error by the district court to conclude that no motivation
existed.
District court focused too heavily on the teaching of the patent.
‐ Specification: Mast cells in different species and in different
tissues within the same species exhibit different biological
responses (known as mast cell heterogeneity). = lack of
predictability from one species to another or one tissue within
one species to another tissue in the same species.
33

34. Alcon Argued
No reasonable expectation of success that such modified
formulation would be “safe” in humans.
Panel however noted that “safe” was not a limitation of the
claims AND the data used by the patentee to support the
claims was in vitro data which also did not demonstrate “safe”
Objective indicia of nonobviousness (unexpected results and
commercial success), but panel did not hold it outweighed
strong showing of obviousness.
Claims 1-3 and 5-7 by clear and convincing evidence found
obvious to the skilled artisan.
34

35. Claims 4 And 8
Further directed toward “0.1% w/v”
Apotex acknowledges lack of disclosure in Kamei but argues routine
experimentation would have led the skilled artisan to try this formulation, as
Kamei taught increased antihistamine activity from 0.0001% to 0.01%.
‐ Alcon argues no motivation to try 0.1% because of olopatadine’s biphasic
property, i.e. stabilize mast cells below a certain concentration but destabilize
above that concentration.
‐ Kamei discloses concentrations substantially lower than 0.1% (relied on expert
who stated no reasonable expectation of success with an order of magnitude
higher concentration.).
Apotex also points to prior art that discloses a genus of compounds encompassing
olopatidine (but not exemplified) that has one example teaching an ophthalmic
solution with 0.1% to treat allergies in animals. Substitute this compound with
olopatidine.
‐ Alcon argues cannot simply substitute olopatidine into this solution
‐ Skilled artisan would have known that you cannot substitute one active
ingredient for another without adjusting the concentration.
35

36. Sciele Pharma (Shionogi Pharma) vs. Lupin
(July 2, 2012; Moore*, Prost, Lourie)
Shionogi markets Fortamet® (extended release metformin
HCl).
US 6,866,866 (pharmacokinetics) listed in the Orange Book.
Lupin filed an ANDA.
Shionogi filed suit under 271(e)(2)(A) asserting claims 1, 3-5,
and 25.
Lupin launched at risk before judgments on merits.
Shionogi obtained a preliminary injunction.
Federal circuit vacated injunction and remanded.
36

37. Claims
Directed toward dosage forms with a “mean time to
maximum plasma concentration (Tmax) of the drug which
occurs at 5.5 to 7.5 hours after oral administration on a oncea-day basis to human patients.”
Claim 3 explicitly narrows this range to 5.5 to 7.0.
37

38. Preliminary Injunction (1)
Shionogi filed its 271 suit asserting claims including claim 1 despite
its mistake.
Merits were not resolved prior to 30 month stay expiry; FDA finally
approved Lupin’s ANDA.
Lupin launched at risk.
District court granted injunctive request finding that Shionogi was
likely to prevail on its infringement claim based on Lupin’s proposed
labeling.
District court did not address Lupin’s obviousness argument as part
of its order granting injunctive relief.
Lupin appealed. Fed Cir vacated and remanded to the district court
to make appropriate findings of fact and conclusions of law.
38

39. On Remand…
District court again granted a preliminary injunction concluding:
‐ Deference owed to the PTO
• Prior art references cited by Lupin were before the PTO and therefore
Lupin faced an “added burden of overcoming the deference…”
‐ KSR was not directly applicable to this case because the prior art
was before the PTO when the ‘866 patent issued.
• Prior art discloses a median (not mean) Tmax and such difference is
too great in light of the deference owed to the PTO’s assessment of
the art.
‐ Statements used during prosecution by Shionogi regarding
enablement could not also be used as proof of obviousness.
39

40. Preliminary Injunction (2)
Lupin sought stay. District court denied.
Lupin appealed the grant/moved for stay.
Federal circuit heard arguments and stayed injunction against
Lupin in the interim.
40

41. Presumption Of Validity
Lupin argued the presumption should not attach to the ‘866 patent
because of the erroneous issuance of claims with the higher range
of 7.5.
Shionogi argued it should be a higher presumption because the
references cited here were already considered by the PTO.
Both are wrong. (i4i) Presumption of validity attaches to all issued
patents and the burden of proof remains the same – clear and
convincing evidence (not “extremely clear and convincing” or
“crystal clear and convincing”).
Instead, whether a reference was before the PTO or not or whether
the prosecution history is puzzling and flawed or not can be a factor
to the amount of weight such evidence is given by the fact-finder
making it easier or harder to meet the burden of proof.
41

42. Is There A Substantial Question Of Invalidity?
Lupin argues that asserted claims are obvious over Cheng in
view of Timmins.
‐ Part 1 of obviousness argument: references.
• Cheng discloses all of the limitations of the asserted claims except
for the Tmax range of 5.5 to 7.5 hours (it discloses instead 8 to 12
hours).
• Timmins discloses a Tmax in the claimed range.
‐ Part 2 of obviousness argument: admission.
• Applicant states during prosecution “that one skilled in the art
would be able to manipulate the processes and formulations of
the [prior art] by other methods to obtain the claimed
pharmacokinetic parameters of the present invention by routine
experimentation.”
42

43. Shionogi Argues
Disclosed Tmax range is not recited in Cheng.
Timmins discloses median Tmax not claimed mean Tmax.
There is no motivation to combine the two disclosures.
43

44. Federal Circuit
Timmins discloses raw data to calculate the mean Tmax and also during
oral argument Shionogi’s counsel agreed that Timmins discloses a range of
possible mean Tmax between 4.67 and 6.33 hours based on this data.
Timmins also provides motivation about lowering Tmax to yield more
desirable plasma levels of drug over an extended period of time because
the drug is better absorbed in the earlier phases of the GI tract.
Timmins also provides a reason to lower the Tmax to match the profile of
the standard of care Glucophage.
Also, the panel found the statements by the applicant during prosecution
to be telling (disagreeing with the district court that such statements only
applied to enablement and not to obviousness).
Motivation to lower the Tmax + the applicant’s characterization of
predictability and skill in the art during prosecution = routine and obvious
design choice to pursue an ER with a lower Tmax. (“If a person of ordinary
skill can implement a predictable variation, 103 likely bars patentability.”
KSR 550 U.S. at 417.
44

45. In re Cyclobenzaprine HCl Extended Release
(April 16, 2012; O’Malley, Newman and Reyna)
Cephalon markets Amrix® (cyclobenzaprine HCl), a muscle
relaxant (single dose provides 24 hour treatment) .
U.S. 7,387,793 and 7,544,372 (pharmacokinetic) listed in the
OB.
Mylan (first) and Par filed ANDAs.
Cephalon, who is the parent company of the exclusive
licensee of these patents, filed suit.
District court found infringement but held claims invalid as
obvious. (best mode was also on appeal/written description
concerns were not on appeal).
Federal Circuit reversed.
45

46. Technology
Immediate release
Pharmacokinetics (PK) – study of what person’s body does to
a drug after administration (Tmax, Cmax, AUC)
Pharmacodynamics (PD) – study of the effect that a drug
renders on a body, e.g., muscle spasm relief
Goal: to come up with an ER formulation that would be
therapeutically effective
46

47. Patentee’s Discovery
Co-inventors first estimated PK values of immediate release
formulations using computer models.
Then, using those data, they created models for b.i.d. and
t.i.d. at 10 mg per dose.
And then, they used that data to create a model for 30 mg
QD.
And then, they created in vitro dissolution profile to see how
much drug would be released over time if the formulation
with the model PK data from above.
And then, they tested a formulation with such model PK
values and dissolution profile in a clinic and the results
confirmed it was therapeutically effective.
47

48. Claims
‘793 patent covers modified-release dosage forms of skeletal muscle relaxants; ‘372 is directed to methods of
reliving muscle spasms administering such dosage forms (share same specification)
Claims 1 -3 (of ‘793 patent) combined:
A multi-particulate pharmaceutical dosage form of a skeletal muscle relaxant providing a modified release
profile comprising a population of extended release beads, wherein said extended release beads comprise an
active-containing core particle comprising cyclobenzaprine HCl, and an extended release coating comprising a
water insoluble polymer membrane surrounding said core, wherein said dosage form when dissolution tested
using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37°C exhibits a
drug release profile substantially corresponding to the following pattern: after 2 hours, no more than about
40% of the total active is released; after 4 hours, from about 40-65% of the total active is released after 8
hours, from about 60-85% of the total active is released; wherein said dosage form provides therapeutically
effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful
musculoskeletal conditions when administered to a patient in need thereof; and wherein said water insoluble
polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of
cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on
ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary
ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof; and a
plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl
citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated
mono- and di-glycerides and mixtures thereof, and that provides a maximum blood plasma concentration
(Cmax) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl and an AUC0-168
within the range of about 80% to 125% of about 740 nghr/mL and a Tmax within the range of 80% to 125% of
about 7 hours following a single oral administration a pharmaceutical dosage form comprising 30 mg of
cyclobenzaprine HCl.
48

49. PK/PD Relationship
District court dismissed the lack of this relationship essentially
relying on that a skilled artisan would expect an extended
release formulation to have the same PD effect on the body if
it has the same PK profile of an immediate release.
But, it was undisputed that at the time of the invention a
PK/PD relationship for cyclobenzaprine HCl whether it is an
extended or immediate release was not known.
Court found that without such relationship, a skilled artisan
could not predict with reasonable expectation of success
whether a particular PK profile, including a bioequivalent one,
would produce a therapeutically effective formulation.
49

50. Federal Circuit
It may have been obvious to experiment with the use of the PK profile of
an immediate release when working on an extended release formulation,
no evidence exists to demonstrate that a skilled artisan would have had a
reasonable expectation of success that it would be therapeutically
effective.
The panel contrasts:
“where a skilled artisan merely pursue ‘known options’ from ‘a finite
number of identified, predictable solutions,’ the resulting invention is
obvious under Section 103.” (KSR)
vs.
“where, however, a defendant urges an obviousness finding by ‘merely
throw*ing+ metaphorical darts at a board’ in hopes of arriving at a
successful result, but ‘the prior art gave either no indication of which
parameters were critical or no direction as to which of many possible
choices is likely to be successful,” courts should reject ‘hindsight claim
obviousness.’” (Kubin)
50

51. Federal Circuit
District court cited to the co-inventor’s approach when it
relied on this being nothing more than “routine
experimentation.”
But, the Federal Circuit found this to be impermissible
hindsight analysis and merely retracing the inventor’s steps.
51

52. Federal Circuit
Mylan’s expert stated the following response:
Q: So the idea is that if the blood
levels were similar to Flexeril [a
known immediate release formulation
with PK data], then hopefully the
effect would be similar – the
therapeutic effect would be similar to
Flexeril?
A: Hopefully.
Depends on the
relationship between blood levels and
the therapeutic effect.
52

53. Federal Circuit
FDA guidance document
Panel however stated that “knowledge of the goal does not
render its achievement obvious.” (“Recognition of a need
does not render obvious the achievement that meets that
need…Recognition of an unsolved problem does not render
the solution obvious.”).
It further found it’s not that bioequivalence evidence can
never be used to support obviousness, but when the claimed
invention is limited to pharmacodynamic effect as here, and
such a PK/PD relationship is unknown, such evidence has
limited value.
Otherwise, formulating any and all extended release
formulation would be obvious to try to target bioequivalence.
53

54. Objective Evidence Of Nonobviousness
(Not “Secondary” Factors)
District court found it to be insufficient to rebut Mylan’s
showing of prima facie obviousness.
Federal Circuit explained AT LENGTH this was improper
shifting of the burden of persuasion to Cephalon and the
critical importance of considering objective evidence at the
time of the obviousness assessment to prevent a “judicial
hunch” biased by the patentee’s invention.
54

55. Failure Of Others
ALZA had tried, similarly to the coinventors of the claimed
invention, PK modeling using immediate release cyclobenzaprine
formulations but the approach they took with such models was
materially different. (“Evidence that others were ‘going in different
ways’ is strong evidence that the *inventor’s+ way would not have
been obvious.”
Also, district court improperly disregarded these failures because it
found that ALZA had an additional goal (beyond therapeutically
effective) of reducing side effects, which was not a claimed
limitation of Cephalon’s formulation. And so ALZA’s failure was
directed at a different problem.
The panel disagreed finding that the district court was not required
to disregard the common goal – of achieving a therapeutically
effective formulation - however simply because there was an
additional goal.
55

56. Long-felt Need
This objective consideration is closely related to failure of
others, where the former is related to the demand for such an
invention and the latter to whether others tried and failed.
Patient compliance was a concern because of multiple dosing
with immediate release.
Long delay between marketing of immediate-release and
Cephalon’s Amrix®.
56

57. Practical Considerations
Initial reaction of obviousness for otherwise seemingly simple
inventions is not always right.
Be careful not to present the claimed invention as the next
logical step to the problem.
File narrowly/support the scope.
Diligence upfront with the scientists at understanding the
discovery.
57

58. Recent Developments In
Obviousness-Type Double Patenting
Case Law
Lisa B. Pensabene
FITZPATRICK, CELLA, HARPER &
SCINTO
58

59. Obviousness Type Double Patenting Recent Issues
Same analysis as obviousness?
‐ “Starting point” or “lead”
‐ Objective indicia
‐ Role of the specification
Defenses?
‐ Terminal disclaimer
‐ Restriction requirement and consonance
59

60. Sun Pharm. v. Eli Lilly (Fed. Cir. 2010)
Gemzar®: active ingredient gemcitabine, used to treat cancer.
Earlier ‘614 patent
‐ claims gemcitabine and methods of treating viral infections
with gemcitabine.
‐ Specification (not the claims) disclosed use of gemcitabine
for treating cancer (among other uses)
Patent in suit ‘826 patent claims methods of treating cancer
with gemcitabine. (Expiry Nov. 2012)
60

61. Sun Pharm. v. Eli Lilly (Fed. Cir. 2010)
Claimed compound & disclosed use in prior patent
‐ Case law
• Geneva v. GSK: “*T+o ascertain the scope of the earlier patent’s claim to
the compound itself, we had to examine the specification of the earlier
patent, including the compound’s disclosed utility.” Sun Pharma at 1385.
• Pfizer v. Teva: Earlier patent claimed several compounds and specification
disclosed their use in treating inflammation-associated disorders. Later
patent claimed methods of using these compounds to treat inflammationassociated disorders, and “thus the later patent was invalid for
obviousness-type double patenting.” Id.
‐ Patentee argued that earlier patents in these cases disclosed only one use that
was “necessary to patentability” in terms of meeting the utility requirement,
but Fed. Cir. noted that Pfizer disclosed multiples uses.
61

62. Sun Pharm. v. Eli Lilly (Fed. Cir. 2010)
Claimed compound & disclosed use in prior patent
‐ The holding of Geneva and Pfizer “extends to any and all such
uses disclosed in the specification of the earlier patent.” Sun
Pharma at 1387 (emphasis added).
‐ “It would shock one’s sense of justice if an inventor could receive
a patent upon a composition of matter, setting out at length in
the specification the useful purposes of such composition, … and
then prevent the pubic from making any beneficial use of such
product by securing patents upon each of the uses to which it
may be adapted.” Id. (italics in original)
‐ “*O+ur claim construction precedent establishes that claim terms
must be construed in light of the entire issued patent.” Sun
Pharma at 1388 (emphasis added).
62

63. Otsuka Pharm. v. Sandoz (Fed. Cir. 2012)
Abilify®: an “atypical” antipsychotic
Aripiprazole, the active ingredient in Abilify®, is a carboystril
compound. Other FDA-approved atypical antipsychotics have
different structures (e.g., related to clozapine or risperidone).
The patent in suit claims aripirazole, pharmaceutical
compositions for treating schizophrenia including carboystril
compounds (including ariprazole), and method for treating
schizophrenia with aripirazole.
63

64. Otsuka Pharm. v. Sandoz:
Three Alleged Lead Compounds
All are prior art
One also is claimed in an
earlier Otsuka patent

65. Otsuka Pharm. v. Sandoz (Fed. Cir. 2012)
Alleged lead compound: “Unsubstituted butoxy”
‐ Disclosed and claimed in Otsuka’s earlier ‘416 patent
‐ Earlier ‘416 patent disclosed broad genus of carbostyril derivatives
(nine trillion compounds) having antihistaminic and central nervous
controlling action, including use as anti-psychosis agents.
‐ Most potent compounds had different structures than alleged lead.
• Most potent compound had ethoxy substituent on phenyl ring, and second
compound had unsubstituted phenyl ring.
• Two additional compounds (with 7-propoxy linkers) also proved more potent
than “unsubstituted butoxy” compound.
65

66. Otsuka Pharm. v. Sandoz (Fed. Cir. 2012)
Obviousness
‐ Two part inquiry: (1) whether a POSA would have selected
the asserted prior art compound as a lead; and (2) whether
prior art supplied reason or motivation to modify the lead
compound.
• No teaching towards starting with any of the three alleged leads. A
structure like clozapine or risperidone were more attractive lead
compounds (than defendant’s three alleged leads).
• Only the inventors’ path would have lead to the modification: “The
inventor’s own path itself never leads to a conclusion of
obviousness; that is hindsight.” Id. at 1296.
66

67. Otsuka Pharm. v. Sandoz (Fed. Cir. 2012)
Obviousness Double Patenting
• No lead analysis: the obviousness type double patenting analysis
“must necessarily focus on the earlier claimed compound over
which double patenting has been alleged, lead compound or not.”
Otsuka at 1297.
• BUT . . . analysis still requires “identifying some reason that would
have led a chemist to modify the earlier compound to make the
later compound with a reasonable expectation of success.” Id.
• No motivation to make the particular modifications and a “high
degree of unpredictability in antipsychotic drug discovery as of the
priority date.” Id. at 1298.
67

68. Eli Lilly v. Teva (Fed. Cir. 2012)
Pemetrexed (active ingredient in anti-cancer drug, Alimta®)
claimed in ‘932 patent in suit.
68

69. Eli Lilly v. Teva (Fed. Cir. 2012)
Pemetrexed (claimed
compound) only differs from
‘608 patent compound in the
aryl region.
‘775 patent intermediate
compound: Examples disclosed
in ‘775 patent show how ‘775
patent intermediate can be
used to make many
compounds including
pemetrexed through reduction
or hydrolysis reactions.
69

70. Eli Lilly v. Teva (Fed. Cir. 2012)
Compound argument: Earlier ‘608 patent claimed a compound
that would be modified to invention because “conventional
wisdom” would lead to modifying the region that was different by
substituting a phenyl group in aryl region.
Cannot just look at the differences between the claims
“*D+ifferences cannot be considered in isolation—the claims must
be considered as a whole. Amgen expressly noted that ‘*t+his part
of the [OTDP] analysis is analogous to an obviousness analysis
under 35 USC 103.’ ” Lilly at *4.
“In the chemical context, we have held that an analysis of *OTDP]
‘requires identifying some reason that would have led a chemist to
modify the earlier compound to make the later compound with a
reasonable expectation of success.’” Lilly at *5.
70

71. Eli Lilly v. Teva (Fed. Cir. 2012)
Intermediate Argument: Earlier ‘775 patent claiming an intermediate which the
disclosure indicated could be used to synthesize invention compound pemetrexed
Facts differ from Sun Pharma, Geneva, Pfizer:
‐ “*T+he claims at issue recite two separate and distinct chemical compounds:
the ‘775 Intermediate and pemetrexed.” Lilly at *7.
‐ “*T+he asserted claims of the ‘932 patent do not recite a use of the same
compound, but a different compound altogether.” Id. (italics in original).
Lilly’s successive claims are wholly independent of one another:
‐ Earlier patent offered no protection over pemetrexed.
‐ No requirement to use intermediate: Pemetrexed can be made in several
different ways, “many of which do not involve the ‘775 Intermediate.” Lilly at
*8. Intermediate is a “versatile compound” from which “innumerable final
products beyond pemetrexed” could be derived. Id.
71

72. Eli Lilly v. Teva (Fed. Cir. 2012)
Objective Indicia Evidence
District court refused to hear Lilly’s evidence of nonobviousness because “secondary considerations are not
relevant to the analysis of invalidity for obviousness-type
double patenting.” Lilly at *8.
In a footnote, Geneva had said: “Obviousness requires
inquiry into object criteria suggesting non-obviousness; nonstatutory double patenting does not.” Geneva Pharma. v.
GSK, 349 F.3d 1373, 1378, n.1 (Fed. Cir. 2003).
The Federal Circuit clarified earlier precedent and stated,
“*I+nquiry into secondary considerations is not required in
every obviousness- type double patenting analysis, not that
such evidence is off-limits or irrelevant.” Lilly at *8.
72

73. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Chain of applications relating to Mirapex®, containing pramipexole,
is used to treat Parkinson’s Disease.
‘812 patent claims pramipexole, and is the third in chain of related
patents:
‐ Original ‘947 application (issued as ‘374 patent): In response to
restriction requirement, amended to claim only one group of
compounds and one method of using same to treat Parkinson’s
Disease.
‐ Second ‘197 application (issued as ‘086 patent): divisional
claimed only methods of using compounds except method
claimed in ‘374 patent.
‐ Patent in suit (‘812 patent): divisional to ‘197 appl. claiming only
various groups of compounds except group claimed in ‘374
patent.
73

74. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Terminal disclaimer: On last day of bench trial, applicants
attempted to file terminal disclaimer and then apply the PTE to the
shortened term of the ‘812 patent.
‐ Terminal disclaimer filed after expiration of earlier patent cannot
cure double patenting.
‐ “By permitting the later patent to remain in force beyond the
date of the earlier patent’s expiration, the patentee wrongly
purports to inform the public that it is precluded from making,
using, selling, offering for sale, or importing the claimed
invention during a period after the expiration of the earlier
patent.” Boehringer at 1348 (emphasis added).
‐ “The patentee cannot undo this unjustified timewise extension
by retroactively disclaiming the term of the later patent because
it has already enjoyed rights that it seeks to disclaim.” Id. (italics
in original, bold added).
74

75. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Terminal Disclaimer – Patent Term Extension
‐ Argument of no unjustified time wise advantage because
patent term extension would have been in place
‐ BUT . . . rights granted under PTE are more limited than
rights under patent grant: here, the patent term extension
only applied to claims for treatment of Parkinson’s (i.e., not
claims 5 and 6).
‐ So, a competitor conducting a patent search would have
“wrongly been led to believe that the ‘812 patent
continued to cover” compounds in claims 5 and 6, or use of
pramipexole for uses other than treatment of Parkinson’s.
Boehringer at 1349.
75

76. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Restriction Requirement (Safe-harbor of 35 U.S.C. § 121)
‐ “A patent issuing on an application with respect to which a
requirement for restriction under this section has been made, or
on an application filed as a result of such a requirement, shall
not be used as a reference either in the [PTO] or in the courts
against a divisional application or against the original application
or any patent issued on either of them….”
‐ No requirement that the divisional be a direct divisional of the
original application.
‐ Precedent recognized applicability of the safe-harbor provision
to patents sharing a common lineage with application in which a
restriction requirement was entered. Id. at 1352.
76

77. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Restriction Requirement
‘947 appl.
Select (a) one compound and one use group; or
(b) one making group.
Compound
‘197 appl.
Using
Groups I-V
Divisional
Making
VI-VII
VIII-X
II
‘374 patent
Divisional
‘671 appl.
VIII, X, and
IX (but not II)
‘086 patent
I, III-IV
‘812 patent
IX

78. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Restriction Requirement Safe-harbor
‐ Consonance requires that “the line of demarcation
between the ‘independent and distinct inventions’ that
prompted the restriction requirement be maintained.”
Boehringer at 1354 (emphasis added).
‐ Court determined that in case of subsequent applications,
“consonance requires…that the claims prosecuted in two or
more application having common lineage in a divisional
chain honor, as between applications, the lines of
demarcation drawn by the examiner.” Id. (emphasis added).
‐ Here, consonance met because patents do not claim
inventions that overlap with each other or with ‘374
patent. Id.
78

79. Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)
Dissent – “Consonance not met”
‐ Consonance not met because the later applications claimed
multiple patentably distinct inventions:
• “The ‘197 application (the parent), a divisional of the ‘947
application, was not consonant with the original restriction
requirement, as the applicants combined in a single application
claims that the original examiner determined were drawn to
separate inventions, namely Groups VIII, IX, and X of the ‘947
application.” Boehringer at 1357.
• “The child application (the ‘671 application) was also not consonant
because it contained separate inventions, namely claims
encompassing Groups I, III, IV, and V of the ‘947 application.” Id.
79

80. Conclusion
Thank You
80