Ted J. Ebersole ∙ Lisa B. Pensabene ∙ Sandra A. Bresnick

STRATEGIES TO AVOID OBVIOUSNESS FINDINGS: LEGAL ANALYSIS AND PRACTICAL APPLICATIONS

AMERICAN CONFERENCE INSTITUTE

New York, NY

October 10, 2012

1

Sandra A. Bresnick

QUINN EMANUEL URQUHART & SULLIVAN

Introduction

2

Evolving State Of The Law On

Pharmaceutical Patent Life Cycle Strategies

Prior-Art Obviousness

Obviousness-Type Double Patenting

3

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

In re Kao, 693 F.3d 1057 (Fed. Cir. 2011) (Rader, Linn*, Moore)

5

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/Prescribing%20Information/Opana-ER-PI-01-2012.pdf

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

In re Kao

7

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

The Examiner Rejected All Claims, And The Board Affirmed

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

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

In re Kao Federal Circuit re “Secondary Considerations”

In re Kao

10

Substitution Of Oxymorphone In

Formula 6

Unexpected Results Opana® ER

Commercial Success Opana® ER

‘432 Application

No substantial evidence that such substitution yields a composition that falls within the dissolution profile of claim 1. Board’s conjecture is insufficient. 639 F.3d at 1066-67

Unexpected multiple peaks in oxymorphone blood concentration 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

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

In re Kao

11

Maloney “Secondary Considerations” Unexpected Results, Commercial

Success Of Opana® ER

‘859 Application

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. Substantial evidence supported Board on remaining disputed elements, 12-hour release and hydrophobic material. 639 F.3d at 1071-72.

“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.

In re Kao

12

Maloney “Secondary Considerations” Unexpected Results, Commercial

Success Of Opana® ER

’740 Application

“Novel contribution” = “providing information” about correlation between renal failure and bioavailability. 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.

Board’s ruling that secondary considerations were not commensurate with the scope of claimed invention was error, but harmless, because no nexus: 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.

13

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

Unigene & Upsher Smith v. Apotex, 655 F.3d 1352 (Fed. Cir. 2011) (Rader*, Moore, O’Malley)

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

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

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

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

Unigene v. Apotex

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

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

Santarus, Inc. v. Par Pharms., __ F.3d __ 2012 WL 3797966 (Fed. Cir. Sept. 4, 2012)

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

Santarus v. Par

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

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

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

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

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

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

Santarus v. Par

Ted J. Ebersole, Ph.D.

ASSISTANT GENERAL PATENT COUNSEL

ELI LILLY AND COMPANY

Obviousness Developments

27

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

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

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

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-(3-dimethylaminopropylidene)-6,11-dihydrobenz(b,e) oxepin-2-acetic acid or a pharmaceutically acceptable salt thereof.

31

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

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

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

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

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

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 once-a-day basis to human patients.”

Claim 3 explicitly narrows this range to 5.5 to 7.0.

37

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Federal Circuit

Mylan’s expert stated the following response:

Q : S o t h e i d e a i s t h a t i f t h e b l o o d

l e v e l s w e r e s i m i l a r t o F l e x e r i l [ a

k n o w n i m m e d i a t e r e l e a s e f o r m u l a t i o n

w i t h P K d a t a ] , t h e n h o p e f u l l y t h e

e f f e c t w o u l d b e s i m i l a r – t h e

t h e r a p e u t i c e f f e c t w o u l d b e s i m i l a r t o

F l e x e r i l ?

A : H o p e f u l l y . D e p e n d s o n t h e

r e l a t i o n s h i p b e t w e e n b l o o d l e v e l s a n d

t h e t h e r a p e u t i c e f f e c t .

52

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

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

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

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

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

Lisa B. Pensabene

FITZPATRICK, CELLA, HARPER & SCINTO

Recent Developments In Obviousness-Type Double Patenting

Case Law

58

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

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

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 inflammation-associated 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.

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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).

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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.

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Otsuka Pharm. v. Sandoz: Three Alleged Lead Compounds

All are prior art

One also is claimed in an earlier Otsuka patent

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.

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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.

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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.

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Eli Lilly v. Teva (Fed. Cir. 2012)

Pemetrexed (active ingredient in anti-cancer drug, Alimta®) claimed in ‘932 patent in suit.

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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.

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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.

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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.

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Eli Lilly v. Teva (Fed. Cir. 2012)

Objective Indicia Evidence

District court refused to hear Lilly’s evidence of non-obviousness 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; non-statutory 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.

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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.

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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).

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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.

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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.

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Boehringer Ingelheim v. Barr Labs. (Fed. Cir. 2010)

‘947 appl.

‘374 patent

‘197 appl.

‘086 patent

‘671 appl.

‘812 patent

Restriction Requirement

Compound Making Using

Groups I-V VI-VII VIII-X

Select (a) one compound and one use group; or (b) one making group.

II IX

VIII, X, and IX (but not II)

I, III-IV

Divisional

Divisional

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.

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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.

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Conclusion

Thank You

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