patents and the expectation of success...

Patents and the Expectation of Success DoctrineWhat is Reasonable, Tension With Enablement, Best Practices for Patent Drafting and Patent

Prosecution

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WEDNESDAY, JANUARY 8, 2020

Presenting a live 90-minute webinar with interactive Q&A

Alissa K. Lipton, Partner, Finnegan Henderson Farabow Garrett & Dunner, Boston

Jill K. MacAlpine, Ph.D., Partner, Finnegan Henderson Farabow Garrett & Dunner, Washington, D.C.

Leslie A. McDonell, Partner, Finnegan Henderson Farabow Garrett & Dunner, Boston

Sara A. Leiman, Ph.D., Attorney, Finnegan Henderson Farabow Garrett & Dunner, Boston

Lulu Wang, Ph.D., Attorney, Finnegan Henderson Farabow Garrett & Dunner, Boston

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5

Agenda

Reasonable expectation of success doctrine

Obviousness, including OSI v. Apotex

Anticipation

Enablement, utility, and written description

Takeaways and best practices

6

Reasonable Expectation of Success (REOS)

• Courts’ concerns regarding clinical data impact:

– Obviousness

– Anticipation

– Enablement/Utility

– Written Description

7

Reasonable Expectation of Success (REOS)

Obviousness AnticipationEnablement,

UtilityWritten

Description

• Rasmusson v.

SmithKline

• In re ’318

• Lilly v. Actavis

• Impax v. Aventis

• Sandoz v.

Pharmacyclics

• Nuvo v. Dr. Reddy’s • OSI v. Apotex

• Cubist v. Hospira

• Yeda v. Mylan

• Acorda v. Roxane

• Novartis v. West-

Ward

8

Agenda



Anticipation



9

OSI Pharms., LLC v. Apotex Inc.,

939 F.3d 1375 (Fed. Cir. 2019)

• IPR challenge to Orange Book-listed patent (US 6,900,221) with claims

to erlotinib, an epidermal growth factor receptor (EGFR) inhibitor to treat

non-small cell lung cancer (NSCLC). Marketed by OSI as Tarceva®.

• PTAB found patent unpatentable for obviousness, finding reasonable

expectation of success for treating NSCLC with the EGFR inhibitor.

• Federal Circuit found PTAB finding of reasonable expectation of

success not supported by substantial evidence and reversed the

obviousness determination.

10


939 F.3d 1375 (Fed. Cir. 2019)

• “Obviousness determination requires finding that a person of ordinary

skill in the art would have been motivated to combine or modify the

teachings in the prior art and would have had a reasonable expectation

of success [REOS] in doing so.”

11


939 F.3d 1375 (Fed. Cir. 2019)

• High unpredictability in cancer treatments, including EGFR inhibitors for

cancer treatments.

• Asserted prior art disclosed erlotinib as EGFR inhibitor for the treatment

of cancer, “good anti-cancer activity in preclinical models,” Phase I and

II clinical trials without clinical data.

12


939 F.3d 1375 (Fed. Cir. 2019)

• Schnur: discloses 105 compounds, including erlotinib, as EGFR

inhibitors and treatments for 12 different types of cancer; does not

discuss NSCLC.

• Gibbs: review article discussing cancer therapeutics, including erlotinib;

states that erlotinib is in clinical trials and appears to have “good anti-

cancer activity in preclinical models . . . particularly in patients with non-

small cell lung cancer”; did not cite any references with erlotinib data for

NSCLC.

13


939 F.3d 1375 (Fed. Cir. 2019)

• OSI’s 10-K: states:

– “[Erlotinib], which targets a variety of cancers including ovarian,

pancreatic, non-small cell lung and head and neck, achieved a

significant milestone with the completion of Phase I safety trials and

the initiation of Phase II clinical trials in the United States in cancer

patients. [Erlotinib] is a potent, selective and orally active inhibitor of

the epidermal growth factor receptor, a key oncogene in these

cancers.”

14


939 F.3d 1375 (Fed. Cir. 2019)

• PTAB found that the disclosures in OSI’s 10-K that erlotinib targeted a

variety of cancers including NSCLC, and that erlotinib had entered

Phase II clinical trials, would have provided a POSA with a reasonable

expectation of success in view of Schnur’s teachings.

– POSA would understand from the commencement of Phase I studies

that preclinical animal efficacy data had been submitted to FDA.

• PTAB also relied on Gibbs’s statement regarding NSCLC (although

unsupported by any data) as providing a POSA with a reasonable

expectation of success in view of Schnur’s teachings.

15


939 F.3d 1375 (Fed. Cir. 2019)

• Federal Circuit reversed, finding no reasonable expectation of success:

“When the references are properly read, the Board's finding that the

asserted references provide a reasonable expectation of success also

is not supported by substantial evidence. To be clear, the claims

require only treatment of a mammal with erlotinib—efficacy in humans

is not required. But the asserted references do not disclose any data

or other information about erlotinib's efficacy in treating NSCLC. The

record does not contain any clinical (human) data or pre-clinical

(animal) data. It does not even include in vitro (test tube) data

regarding erlotinib's effect on NSCLC. At the same time, it is

undisputed that NSCLC treatment was highly unpredictable with an

over 99.5% rate of failure for drugs entering Phase II clinical studies.”

16


939 F.3d 1375 (Fed. Cir. 2019)

• Federal Circuit reversed, finding no reasonable expectation of success:

- “These references provide no more than hope—and hope that a

potentially promising drug will treat a particular cancer is not

enough to create a reasonable expectation of success in a highly

unpredictable art such as this.”

- “To be clear, we do not hold today that efficacy data is always

required for a reasonable expectation of success.”

17

Cubist Pharms. Inc., v. Hospira Inc.,

805 F.3d 1112 (Fed. Cir. 2015)

• Claims to, inter alia, administering antibiotic daptomycin at an

interval that minimizes skeletal muscle toxicity (4 or 6 mg/kg every

24 or 48 hours) (“dosing patents”).

• District court ruled dosing patents invalid for obviousness.

• Federal Circuit affirmed.

18


805 F.3d 1112 (Fed. Cir. 2015)

• Daptomycin originally developed by Lilly researchers in 1980s.

While daptomycin was effective, 4 mg/kg doses administered every

12 hours resulted in skeletal muscle toxicity in some patients.

• Lilly abandoned development of the drug.

• Cubist researchers discovered that toxic side effects could be

reduced with less frequent administration.

19


805 F.3d 1112 (Fed. Cir. 2015)

• Asserted prior art disclosed preclinical testing of daptomycin and

suggested administration of 4 or 6 mg/kg once per day based on the

drug’s long half-life (Woodworth).

– no disclosure of objective of minimizing skeletal toxicity

• District court relied on known properties of daptomycin including that it

is concentration-dependent, suggesting that less frequent and more

concentrated treatments would be more effective

• District court relied on evidence of aminoglycosides, a group of

antibiotics similar to daptomycin

• Would have been obvious to consider doubling the dosage interval (48

hours) for patients with impaired kidney function

20


805 F.3d 1112 (Fed. Cir. 2015)

• Federal Circuit stated:

“While it is true that the Woodworth reference is predictive in nature, it is

based on extensive laboratory research, and its predictions of the efficacy

of a dosage regimen of 4 mg/kg to 6 mg/kg at daily intervals give rise to a

reasonable expectation that dosages in that amount would be effective in

patients. Moreover, published accounts of Lilly’s clinical trials indicated a

dosage level of 2 mg/kg administered once daily produced no reported

side effects and a dosage level of 3 mg/kg administered twice daily

produced no symptoms of skeletal toxicity, but were not highly effective

against SAE. Those results would have given rise to a reasonable

expectation that somewhat higher doses administered less frequently than

twice daily could be expected to be both safe and effective.”

21


805 F.3d 1112 (Fed. Cir. 2015)

• Federal Circuit found obviousness finding supported by evidence of

aminoglycosides, a group of antibiotics similar to daptomycin

22

Yeda Research & Dev. Co. v. Mylan Pharms., Inc.,

906 F.3d 1031 (Fed. Cir. 2018)

• Claims to dosing regimen of 40 mg glatiramer acetate (GA) in three

subcutaneous injections over seven days for the treatment of relapsing-

remitting multiple sclerosis (RRMS); marketed as Copaxone® 40 mg/mL.

• IPR final written decisions found claims obvious over prior art including

disclosure of dosing regimen of 40 mg GA every other day (Pinchasi).

• Federal Circuit affirmed.

23


906 F.3d 1031 (Fed. Cir. 2018)

• On appeal, Yeda argued that Board erred in finding REOS by

disregarding uncertainties associated with GA, e.g., unknown pk/pd

profile, mechanism of action, optimal dose, active species.

• In In re Cyclobenzaprine, the Federal Circuit held that in the absence of

a known pk/pd profile, bioequivalence alone could not establish

obviousness because “skilled artisans could not predict whether any

particular PK profile, including a bioequivalent one, would produce a

therapeutically effective formulation.” 676 F.3d 1063, 1070 (Fed. Cir.

2012).

24


906 F.3d 1031 (Fed. Cir. 2018)

• Declined to “read [In re Cyclobenzaprine] as establishing a rigid rule

categorically precluding obviousness determinations without pk/pd data.

There, the court's error was relying on bioequivalence alone, without any

evidence in the prior art teaching or suggesting a therapeutically

effective formulation to one skilled in the art, such as pk/pd data. Here,

however, the Board committed no such error; the record is replete with

prior art that would have taught or suggested a therapeutically effective

formulation to a POSITA.”

• Federal Circuit noted that only difference between the claimed invention

and the prior art is one dose per two-week period.

25

Acorda Therapeutics, Inc. v. Roxane Labs., Inc.,

903 F.3d 1310 (Fed. Cir. 2018)

• Claims to dosing regimen for improving walking in multiple sclerosis

patients, by orally administering 10 mg sustained release composition

of 4-aminopyridine (4-AP) twice daily

• Immediate release: 4-AP shown safe and effective for MS treatment at

wide dose range since 1980s (little to no discussion of walking)

• Sustained-release:

• 1997: Elan study with 10 MS patients showed improvements in walking at

17.5 mg 4-AP twice a day

– Also in 1997, Elan licensed their sustained-release formulation to Acorda

• 2002/2003: Acorda study with 25 MS patients showed lower extremity

muscle improvement at 10-40 mg 4-AP twice a day and improvement in

walking at 20-40 mg 4-AP once a day

26

Acorda Therapeutics, Inc. v. Roxane Labs., Inc.,

903 F.3d 1310 (Fed. Cir. 2018)

• Federal Circuit determined prior art dose (e.g., 17.5 mg twice daily,

showing “improvement . . . in walking ability”) rendered claimed dose

(10 mg twice daily) obvious, in light of prior art concerns about toxicity

at high doses

• Contrasting with In re Cyclobenzaprine, Federal Circuit found a skilled

person could “draw reasonable inferences about the likelihood of

success even without a perfectly designed clinical trial showing a

statistically significant difference in efficacy between a specific dose and

placebo.”

• Blocking patent considerations: Federal Circuit held Acorda’s exclusive

license from Elan negated objective indicia of nonobviousness

27

Novartis Pharms. Corp. v. West-Ward Pharms. Int’l Ltd.

923 F.3d 1051 (Fed. Cir. 2019)

• Claims recite a method of inhibiting growth of solid excretory system

tumors (e.g., treating advanced renal cell carcinoma (RCC)) by

administering an effective amount of everolimus.

• West-Ward challenged the claims as obvious in view of references

teaching successful Phase I trials with another mTOR inhibitor

(temsirolimus) and patents claiming everolimus.

• Federal Circuit affirmed the district court’s holding that there was no

reasonable expectation of success that everolimus would effectively

treat RCC. There was high uncertainty in the field, notable

pharmacological differences (e.g., different half-lives, different binding

affinities) between everolimus and temsirolimus, and important

limitations (design, sample size) of the studies on temsirolimus.

28

Novartis Pharms. Corp. v. West-Ward Pharms. Int’l Ltd.

923 F.3d 1051 (Fed. Cir. 2019)

• “Numerous clinical trials investigating a wide range of treatment

strategies for advanced RCC failed. . . . Cancer drugs in general had

high failure rates for treatment of advanced RCC in clinical trials, with

more than 70% of cancer drugs failing during phase II, and a majority of

cancer drugs failing during phase III.” Id. at 1054

• Despite prior art teachings, “[t]here was no data on the efficacy of

everolimus to treat any type of cancer, let alone to treat advanced

RCC.” Id. at 1054-55

• West-Ward’s expert admitted “that a person of skill in the art would not

have reasonably expected a drug to work based only on phase I clinical

trial results, or on the fact that a drug had entered phase II clinical

trials.” Id. at 1058

29

Agenda



Anticipation



30

Impax Labs., Inc. v. Aventis Pharms. Inc.,

468 F.3d 1366 (Fed. Cir. 2006)

• Claims recite a method of treating ALS by administering an effective

amount of riluzole.

• Prior art patent disclosed compounds, including riluzole, and suggested

they may be used to treat ALS.

• Riluzole was not listed as “especially advantageous” in the prior art

patent and the disclosure noted “substantial uncertainty regarding the

effectiveness of treating ALS with glutamate inhibiting compounds.” Id.

at 1380

31

Impax Labs., Inc. v. Aventis Pharms. Inc.,

468 F.3d 1366 (Fed. Cir. 2006)

• Federal Circuit found the prior art patent anticipated the asserted claims

– The enablement requirement for anticipation does not require

utility/effectiveness.

– The proper issue is whether the prior art patent describes the claimed

invention sufficiently to enable an ordinarily skilled person to carry out the

invention

– Found a similar reference was not enabling because it did not identify

riluzole by name from a large genus of compounds. (“[W]ith the large

number of compounds included in formula I and no specific identification of

riluzole . . . [the reference] does not disclose riluzole, and therefore, cannot

enable treatment of ALS with riluzole.” Id. at 1383)

• See also Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325,

1326 (Fed. Cir. 2005) (“A patent claim cannot be anticipated by a prior art

reference if the allegedly anticipatory disclosures cited as prior art are not

enabled”; “a prior art reference need not demonstrate utility in order to serve

as an anticipating reference.”)

32

Sandoz Inc. v. Pharmacyclics LLC,

IPR2019-00865, Patent 9,795,604, Paper No. 8

• Claims recite a method of treating chronic graft versus host disease

(GVHD) by administering a therapeutically effective amount of ibrutinib.

• Sandoz (Petitioner) alleged the claims were anticipated by a prior art

publication that discloses pharmaceutical formulations of ibrutinib and

their uses for treating autoimmune diseases, e.g., GVHD.

• As there are just two forms of GVHD (acute and chronic) and the prior

art publication provided general guidance for therapeutic amounts of

ibrutinib, Sandoz alleged an ordinarily skilled person would have

envisioned treating chronic GVHD.

• The prior art did not include preclinical or clinical data for ibrutinib.

33

Sandoz Inc. v. Pharmacyclics LLC,

IPR2019-00865, Patent 9,795,604, Paper No. 8

• Pharmacyclics (Patent Owner) argued chronic GVHD was “poorly

understood” and “exceedingly difficult to treat, with numerous agents

failing in the clinic,” and thus the prior art publication was not enabled.

• PTAB granted institution of IPR (Sept. 2019)

– Noted that prior art publications and patents are presumed to be enabled.

– “We acknowledge Patent Owner’s argument that cGVHD is difficult to treat,

poorly understood, and lacking in predictive animal models. We further

acknowledge Patent Owner’s argument that numerous treatment agents

have failed in clinic. At this point in the proceeding, however, we are not

persuaded that the alleged failure to develop an effective treatment prior to

ibrutinib is sufficient to rebut the presumptively enabled teaching of the [prior

art] that ibrutinib can be used to treat GVHD.” Id. at 18

34

Agenda



Anticipation



35

Rasmusson v. SmithKline Beecham Corp.,

413 F.3d 1318 (Fed. Cir. 2005)

• Claims to method of treating prostate cancer using finasteride.

• Board held Rasmusson not entitled to priority in interference.

• On appeal to Federal Circuit, Rasmusson argued priority applications

were enabled and that efficacy only pertains to utility under 101 and is

not relevant to enablement

– “[B]oth parties agree that a person of ordinary skill in the art at the

time of Rasmusson’s applications would have recognized that

finasteride was a selective [enzyme] inhibitor, the parties disagree

as to whether a person of ordinary skill in the art would have

believed [as of the priority date] that finasteride would be effective

in treating prostate cancer.”

36

Rasmusson v. SmithKline Beecham Corp.,

413 F.3d 1318 (Fed. Cir. 2005)

• Rasmusson argued that data was not needed and POSA “would

have believed that administering a therapeutically effective amount

of finasteride could be used in treating human prostate cancer”

• Federal Circuit disagreed, finding that enablement requires

sufficient utility as a drug

– “In order to obtain [priority date], Rasmusson needed to provide

experimental proof that his invention could be effective in

treating cancer. Because Rasmusson failed to do so . . . the

Board was correct to find that all applications prior to [later]

application were not enabled, and that Rasmusson is not

entitled to a priority date earlier than the priority date of

SmithKline’s . . . patents.”

37

In re ’318 Patent Infringement Litigation,

583 F.3d 1317 (Fed. Cir. 2009)

• Claims to method of treating Alzheimer’s disease with galanthamine

• One-page specification with no animal or human testing data

• Later, galanthamine efficacy tested, licensed to Janssen, FDA approved

• Federal Circuit upheld finding of invalidity for lack of enablement and utility

38

In re ’318 Patent Infringement Litigation,

583 F.3d 1317 (Fed. Cir. 2009)

• “Typically, patent applications claiming new methods of treatment are

supported by test results. But it is clear that testing need not be conducted

by the inventor. In addition, human trials are not required for a therapeutic

invention to be patentable.”

• “We have held that results from animal tests or in vitro experiments may

be sufficient to satisfy the utility requirement.”

• “Although no case has been called to our attention where utility was

established simply by analytic reasoning, the [MPEP] has recognized that

‘arguments or reasoning’ may be used to established an invention’s

therapeutic utility.”

• “To reiterate: the question here is whether the written description of the

’318 patent would have illuminated to a person of ordinary skill in the art a

credible utility, not whether actual utility was in fact demonstrated.”

39

Eli Lilly and Co v. Actavis Elizabeth LLC,

435 Fed.Appx. 917 (Fed. Cir. 2011)

• Claims recite a method of treating ADHD by administering an effective

amount of tomoxetine.

• Federal Circuit reversed the district court’s finding of lack of

enablement/utility.

• Federal Circuit affirmed the district court’s finding of nonobviousness,

determining no reasonable expectation of success in the prior art that

tomoxetine would safely and effectively treat ADHD.

40


435 Fed.Appx. 917 (Fed. Cir. 2011)

• At the time of filing:

– tomoxetine was a known compound

– tomoxetine had gone through Phase II trials for treating urinary incontinence

and Phase III trials for treating depression

– very little was known about the causes/mechanisms of treating ADHD, and

all drugs used to treat ADHD “exhibited deficiencies” (e.g., adverse events)

– another potent selective norepinephrine reuptake inhibitor (desipramine) was

known to be effective for treating ADHD, but reportedly caused sudden death

in some children

– Suggestion by inventors that tomoxetine might be an effective treatment for

ADHD was met with skepticism

– Experts for both sides in agreement that they would not have expected that

tomoxetine would be a successful treatment for ADHD

41


435 Fed.Appx. 917 (Fed. Cir. 2011)

• Federal Circuit reversed the district court’s finding of lack of enablement/utility.

– “When priority it not at issue, generally the applicant may provide data

obtained either before or after the patent application was filed [to show

utility].” Id. at 925

– Relied on MPEP 2107.03 (8th ed. 2008) for instruction “to give presumptive

weight to the utility for which human trials have been initiated.” Id. at 924

– Presumption of utility depends on context: “The utility of this product to treat

ADHD is not so incredible as to warrant the special procedures that are

authorized for use when the examiner doubts the described utility, as in . . .

subject matter in once notoriously intractable areas such as cures for

baldness or cancer.” Id. at 924 (also noting that claiming “perpetual motion”

would warrant doubt)

42

Agenda



Anticipation



43

Nuvo Pharms. (Ir.) Designated Activity Co. v. Dr. Reddy's

Labs. Inc., 923 F.3d 1368 (Fed. Cir. 2019)

• Claims to composition comprising an acid inhibitor without an

enteric coating and an NSAID with an enteric coating

• D.N.J. found Nuvo’s claims to be nonobvious, enabled, and

adequately described

• Federal Circuit reversed, finding claims invalid for lack of written

description

44



• Tension between nonobviousness and written description

• District court found nonobviousness because “persons of ordinary skill in the

art were discouraged by the prior art from using uncoated PPI and would not

have reasonably expected it to work”

• Dr. Reddy’s argued if it lost on obviousness, “then the claims lack written

description support for the claimed effectiveness of uncoated PPI because

ordinarily skilled artisans would not have expected it to work and the

specification provides no experimental data or analytical reasoning showing

the inventor possessed an effective uncoated PPI.”

• “It is undisputed that there is no experimental data demonstrating the

therapeutic effectiveness of any amount of uncoated PPI and coated NSAID

in a single dosage form.”

45



• Dr. Reddy’s argued “satisfaction of the written description requirement

requires either supporting experimental data, or some reason, theory, or

alternative explanation as to why the claimed invention is possessed by the

inventor, and that mere recitation of claim language in the specification

cannot suffice”

• Specification describing immediate release of uncoated PPI and potential

disadvantages of enteric-coated PPI formulations “in no way provides

support for the claimed efficacy of uncoated PPI”

• “In light of the fact that the specification provides nothing more than the mere

claim that uncoated [drug] might work, even though persons of ordinary skill

in the art would not have thought it would work, the specification is fatally

flawed. It does not demonstrate that the inventor possessed more than a

mere wish or hope that uncoated [drug] would work”

46

Agenda



Anticipation



47

Takeaways and Best Practices

• Properly time patent application filings

– More than a “mere wish” (Nuvo) but less than clinical trial (In re ’318)

– “Analytic reasoning” of utility (In re ’318)

– “Supporting experimental data, or some reason, theory, or alternative

explanation” showing possession (Nuvo)

• Include or exclude characterizations in view of available data and prior art

– Disease characteristics “highly unpredictable” (OSI) or “reasonab[ly]

infer[red]” (Acorda)

– Description of mechanism of action, correlation between animal studies to

human efficacy

48

Takeaways and Best Practices

• Assess scope of claimed subject matter in view of clinical disclosures

– Consider claims of cascading scope

• Monitor clinical data disclosures (e.g., press releases, scientist

presentations)

– Avoid creating own prior art (Acorda)

– Limiting unnecessary subjective statements when disclosure necessary

(In re ’318; Nuvo)

• Balance nonobviousness positions with written description positions in

prosecution and litigation

– Avoid distinguishing prior art based on special features not tested in one’s

own specification (Nuvo)

49

Thank you.

Questions?

Thank You

Sara [email protected]

Alissa [email protected]

Jill [email protected]

Leslie [email protected]

Lulu [email protected]

50

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