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Parties Involved:
Constantin Efthymiopoulos
Appellant

Document Text:

United States Court of Appeals 

for the Federal Circuit ______________________ 

IN RE: CONSTANTIN EFTHYMIOPOULOS,

Appellant

______________________ 

2016-1003

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. 08/737,141.

______________________ 

Decided: October 18, 2016

______________________ 

LYNNE A. BORCHERS, Myers Bigel Sibley & Sajovec, 

PA, Raleigh, NC, argued for appellant. Also represented 

by PETER DANIEL SIDDOWAY, ANTHONY P. DEROSA,

SHAWNA CANNON LEMON. 

FARHEENA YASMEEN RASHEED, Office of the Solicitor, 

United States Patent and Trademark Office, Alexandria, 

VA, argued for appellee Michelle K. Lee. Also represented 

by THOMAS W. KRAUSE, SCOTT WEIDENFELLER, KAKOLI 

CAPRIHAN, LORA DRISCOLL. 

______________________ 

Before PROST, Chief Judge, NEWMAN and BRYSON, Circuit 

Judges.

Opinion for the court filed by Chief Judge PROST. 

Dissenting opinion filed by Circuit Judge NEWMAN. 

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2 IN RE: EFTHYMIOPOULOS

PROST, Chief Judge. 

This appeal arises from the examination of a number 

of claims of U.S. Patent Application No. 08/737,141 (“’141 

application”). The examiner rejected all pending claims 

as obvious and the United States Patent and Trademark 

Office, Patent Trial and Appeal Board (“Board”) affirmed 

all of those rejections. Appellant Constantin Efthymiopoulos (“Efthymiopoulos”) then requested rehearing, 

which the Board denied. For the following reasons, we 

affirm the Board’s decision. 

BACKGROUND

The ’141 application relates to methods of treating or 

preventing influenza by administering the drug 

zanamivir1 by oral inhalation. On appeal, Efthymiopoulos challenges the rejection of claims 14-30, 32, 34-38, and 

43-65. Independent claim 14 is representative:

14. A method for treating a human suffering from 

an infection by an influenza virus, wherein the 

method comprises administering to the human an 

effective amount of [zanamivir], wherein the 

[zanamivir] is administered by inhalation through 

the mouth alone.

J.A. 1697.

 The examiner rejected the pending claims as obvious 

over Australian Patent No. AU-A1-27242/92 (“Von Itzstein II”), in view of WIPO Publication WO 91/16320 

(“Von Itzstein I”) and a number of other references. Like 

the ’141 application, Von Itzstein I discloses that 

 

1 The ’141 application uses the chemical name of

zanamivir: 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-Dglycero-D-galacto-non-2-enopyranosonic acid. For ease of 

reference, we refer to the compound as zanamivir 

throughout the opinion. 

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IN RE: EFTHYMIOPOULOS 3

zanamivir can be administered to treat and prevent 

infections by the influenza virus. Von Itzstein I only 

discloses intranasal administration (and not oral inhalation) of zanamivir. Von Itzstein II discloses the administration of a compound similar to zanamivir by 

“inhalation” for the treatment and prevention of influenza. The examiner concluded that Von Itzstein II disclosed 

all of the limitations of the challenged claims except that 

it did not teach zanamivir specifically and did not expressly teach inhalation only by mouth of its compounds. 

The examiner found, however, that Von Itzstein I taught 

zanamivir and suggested administering that compound to 

the respiratory tract to treat or prevent influenza. The 

examiner further determined that zanamivir and the 

compound disclosed in Von Itzstein II are “adjacent 

homologues” (meaning they are part of a series of compounds that differ in structure only by a single substituent) and thus concluded that using zanamivir in the 

method disclosed in Von Itzstein II would have been 

obvious. 

Finally, the examiner noted that, with respect to administration, there are only two possible inhalation 

methods: through the mouth (oral) or through the nose 

(nasal). In view of the other prior art references that 

taught the well-known availability of inhalers, that oral 

inhalation delivers more drug to the lungs than nasal 

inhalation, and the fact that influenza infects the lungs, 

the examiner concluded that treating influenza by oral 

inhalation of zanamivir would have been obvious. 

The Board agreed with and extensively cited the examiner and affirmed all of the rejections. The Board 

found that Von Itzstein II’s disclosure of “inhalation” for 

treating influenza with its compounds “is reasonably 

understood to disclose inhalation by either the nose alone, 

mouth alone, or both” and thus concluded that Von Itzstein II in view of Von Itzstein I’s disclosure of zanamivir 

rendered the claims obvious. J.A. 12-13. The Board also 

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4 IN RE: EFTHYMIOPOULOS

considered Efthymiopoulos’s evidence of secondary considerations—namely of unexpected results—but found it 

to be unpersuasive. 

Efthymiopoulos sought rehearing, but the Board denied its request. Efthymiopoulos then timely appealed 

the Board’s decision to us. We have jurisdiction under 28 

U.S.C. § 1295(a)(4)(A) (2012).

DISCUSSION

We review the Board’s legal determinations de novo 

and its underlying factual determinations for substantial 

evidence. Rambus Inc. v. Rea, 731 F.3d 1248, 1251 (Fed. 

Cir. 2013). Obviousness is a legal question based on 

underlying fact findings. In re DBC, 545 F.3d 1373, 1377 

(Fed. Cir. 2008). 

Efthymiopoulos argues that the Board erred in rejecting the pending claims as obvious. Efthymiopoulos contends that none of the prior art references, alone or in 

combination, teach administration of zanamivir by inhalation through the mouth. Moreover, Efthymiopoulos 

says that a person of ordinary skill would not have expected that the administration of zanamivir through 

inhalation by mouth only would be effective. That is

because oral inhalation delivers more drugs to the lower 

respiratory tract, and, at the time of the invention, it was 

thought that delivery of anti-influenza drugs to the upper 

respiratory tract was required to be effective. Finally, 

Efthymiopoulos faults the Board for failing to consider its 

evidence of unexpected results. 

We conclude that the Board did not err in its obviousness determination. There is no dispute that Von Itzstein I discloses the use of zanamivir to treat and prevent 

influenza. There is also no dispute that Von Itzstein II 

discloses several pages of different administration methods for an adjacent homologue of zanamivir to achieve the 

same result—treating or preventing influenza. In particCase: 16-1003 Document: 34-2 Page: 4 Filed: 10/18/2016
IN RE: EFTHYMIOPOULOS 5

ular, Von Itzstein II expressly discloses administration 

through “oral,” “nasal,” or other forms “suitable for administration by inhalation,” among other methodologies. 

The Board’s finding then, that a skilled artisan would be 

motivated to use zanamivir in the methods disclosed by 

Von Itzstein II, is supported by substantial evidence. 

The Board also agreed with the examiner’s conclusion

that Von Itzstein II’s disclosure of administration through 

“inhalation” includes oral inhalation. That finding is 

supported by substantial evidence. As the Board noted, 

“[I]nhalation can only be carried out via the nose or the 

mouth. Since Von Itzstein II does not limit its disclosure 

to nasal inhalation, it is reasonably understood to disclose 

inhalation by either the nose alone, the mouth alone, or 

both.” J.A. 12-13.

The Board’s conclusion is further supported by the 

fact that both Von Itzstein references teach that the 

compounds may be administered in many forms, including as a dry powder through an inhaler. And, as the 

Board noted, the state of the art at the time of invention 

established that dry-powder compositions were often used 

specifically for oral inhalation. 

Efthymiopoulos’s argument that a skilled artisan 

would not reasonably expect zanamivir to be effective if 

administered through oral inhalation is also unpersuasive. As the examiner noted, it was known in the art at 

the time that, although the influenza virus primarily 

attacks the upper respiratory tract, certain strains of the 

virus also attack the lower respiratory tract and that 

young children in particular were more susceptible to

lower respiratory tract infections from the virus. And as 

the examiner observed, oral inhalation delivers more 

drugs to the lungs as compared to nasal inhalation. Thus, 

substantial evidence supports the determination that a 

skilled artisan would have a reasonable expectation of 

success in combining the Von Itzstein references. 

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6 IN RE: EFTHYMIOPOULOS

Finally, Efthymiopoulos contends that the Board disregarded its evidence of unexpected results, namely the 

testimony of Dr. Hayden. We disagree. The record shows 

that the Board thoroughly considered and discussed 

Dr. Hayden’s declaration in its decision and found that 

Dr. Hayden’s testimony insufficient to overcome the 

prima facie case of obviousness. For example, the Board 

found that a study by Dr. Hayden did not show unexpectedly superior results between oral and intranasal inhalation. That finding is supported by substantial evidence. 

As the Board observed, Dr. Hayden himself conceded that 

the conclusion of the study he conducted was that “adding 

intranasal administration of zanamivir did not obviously 

improve” the results of using oral administration alone for 

the treatment of influenza. J.A. 1706. Thus, after considering Dr. Hayden’s testimony and the manner in which it 

was conducted, the Board properly concluded that the

claimed method would not necessarily yield an unexpectedly superior result. 

Dr. Hayden also cited the Kaiser study which involved 

preventing influenza and showed that the rate of influenza was “substantially although not statistically significantly reduced” in patients treated with orally inhaled 

zanamivir compared to those treated with intranasal 

zanamivir. J.A. 1458. But, as the Board found, the 

Kaiser study is also unpersuasive because it did not 

disclose superior results, its findings were admittedly not 

statistically significant, and it dealt only with prevention

of influenza, while the claims are directed to the treatment of influenza. 

The Board therefore properly considered Efthymiopoulos’s evidence of unexpected results and simply found 

it lacking. That finding is supported by substantial 

evidence. We thus conclude that the Board correctly 

affirmed the examiner’s rejection of all pending claims as 

obvious. 

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IN RE: EFTHYMIOPOULOS 7

CONCLUSION

For the foregoing reasons, we affirm the Board’s decision.

AFFIRMED

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United States Court of Appeals 

for the Federal Circuit ______________________ 

IN RE: CONSTANTIN EFTHYMIOPOULOS,

Appellant

______________________ 

2016-1003

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. 08/737,141.

______________________ 

NEWMAN, Circuit Judge, dissenting. 

This litigation concerns the influenza drug zanamivir, 

marketed under the trademark Relenza®. The PTAB and 

now this court rule that it was obvious to administer this 

drug by oral inhalation, although there is no reference, no 

prior art, no suggestion, proposing that this mode of 

application might succeed, or that it should be tried. 

There was evidence of skepticism even as oral inhalation 

was evaluated. There was no contrary evidence. The 

evidence on which the Board and now this court rely is 

the evidence in the patent application itself, describing 

oral inhalation, its benefits, and its effectiveness. Upon 

learning this information from this inventor’s disclosure, 

the Board found that it was obvious, and my colleagues 

agree that it is obvious to them. 

Zanamivir was a known drug for treatment of influenza, administered by nasal inhalation, for the influenza 

virus was believed to infect the upper respiratory tract. 

The PTAB recognized that “the Examiner acknowledges 

that Von Itzstein II does not specifically teach inhalation 

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2 IN RE: EFTHYMIOPOULOS

of the compound through the mouth.” PTAB Op. 7. Nor 

does any other reference teach or suggest treatment of 

influenza by oral inhalation of this compound or any 

related compound. My colleagues nonetheless deem this 

treatment of influenza obvious on the ground that inhalation occurs only through the nose or the mouth. Thus the 

court rules that the discovery of effective treatment by 

oral inhalation is obvious to the court, although not 

obvious to experts, and not suggested in the prior art.

The applicant provided the expert opinion of Dr. Hayden, who discussed a large international study in which 

he participated, and concluded that the “effectiveness of 

orally inhaled zanamivir as compared with nasal administration . . . could be considered an unexpected result”: 

In part because uncertainties existed regarding 

the transmission and pathogenesis of influenza as 

of the effective filing date of the present application, it was unclear whether oral inhalation of 

zanamivir with the dry powder inhaler device utilized in the studies would be clinically effective

alone for prevention or treatment of naturally occurring uncomplicated influenza. In view of this 

uncertainty, the clinical effectiveness of orally inhaled zanamivir as compared to nasal administration for prevention of naturally occurring 

uncomplicated influenza above could be considered an unexpected result. Similarly, the effectiveness of orally inhaled zanamivir without 

intranasal zanamivir for treatment of naturally 

occurring uncomplicated influenza alone could be 

considered an unexpected result.

Decl. of Frederick G. Hayden, M.D. at 7 (filed in U.S. 

Patent Application No. 08/737,141 Mar. 12, 2013). Both 

the Board and the court discount Dr. Hayden’s opinion 

because these experiments were not conducted for patent 

purposes but for scientific purposes, and were not direct 

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IN RE: EFTHYMIOPOULOS 3

comparisons with the Board’s view of the closest prior art. 

Dr. Hayden explained that: 

Although this study was not designed to compare 

directly the effects of zanamivir administration by 

oral inhalation alone to the effects of zanamivir 

administration by intranasal administration 

alone, it nonetheless found that the oral inhalation route alone provided unexpectedly significant 

activity without requiring intranasal administration for effective treatment of influenza virus illness . . . .

Id. at 3. Dr. Hayden explained that it was unexpected 

that this study “demonstrated the therapeutic value of 

drug delivery by the oral inhalation route to the posterior 

oropharynx (throat) and lower respiratory tract to treat

naturally occurring influenza virus infection.” Id. at 4.

Dr. Hayden also discussed a study that showed that 

the rate of influenza infection during 5 days of prophylaxis treatment was 6% for nasal inhalation alone – the same 

as for the placebo group – but was 2-3% for the group that 

received zanamivir “both by oral inhalation and intranasally.” Id. at 4, citing Kaiser et al. Short-Term Treatment 

with Zanamivir to Prevent Influenza: Results of a PlaceboControlled Study, 30 CLINICAL INFECTIOUS DISEASES 587–

89 (2000). Dr. Hayden concluded that “[t]he results of 

this study supported a difference in protection between 

intranasal zanamivir and orally inhaled zanamivir” and 

“suggest the importance of delivering zanamivir to the 

posterior oropharynx and/or lower respiratory tract for 

the prevention of naturally acquired influenza virus 

illness.” Id. at 4–5. As quoted supra, Dr. Hayden stated 

that this result was unpredictable and unexpected. Id. at 

7.

As stated in In re Dihrendra Ranchhoddas Merchant, 

575 F.2d 865, 868 (CCPA 1978), “The Board’s basic error 

resides in its determination that Pring was the closest 

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4 IN RE: EFTHYMIOPOULOS

prior art and that absent comparative tests vis-à-vis 

Pring, there was no rebuttal of what the Board considered 

a prima facie case.” The Board erred in refusing to consider Dr. Hayden’s results and in criticizing his tests as 

not in accordance with the Board’s design of patentoriented directly comparable experiments. The Board 

disregarded that Von Itzstein I only evaluated administration by nasal administration of a solution. See International Patent Application No. WO91/16320 at 54 (Oct. 

31, 1991) (“Von Itzstein I”) (describing intranasal administration of aqueous solution). The fact that scientific 

studies did not compare oral inhalation to liquid nasal 

administration does not mean the comparative evidence 

can be disregarded entirely. Dr. Hayden explained his 

conclusions; the Board should have considered them.

The Board did not hold that the result here was expected. However, the Board held that the claimed subject 

matter was obvious, on a rationale akin to “obvious to 

try.” However, in the unpredictable arts such as medicinal treatment, for a method to be obvious to try, there 

must be some suggestion in the prior art that the method 

would have a reasonable likelihood of success.

There is no suggestion in the prior art to pursue oral 

inhalation, for the teachings of Von Itzstein II must be 

taken in context. It is noteworthy that there is extensive

discussion in Von Itzstein II directed to all of the known 

forms of oral administration of this product—plus parenteral, topical, rectal, vaginal, and intranasal administration—but Von Itzstein II lacks any mention of oral 

inhalation. The Von Itzstein II reference, which is the 

primary reference relied on by the Board, states: 

Pharmaceutical formulations include those 

suitable for oral, rectal, nasal, topical, (including 

buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for 

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IN RE: EFTHYMIOPOULOS 5

administration by inhalation or insufflation. The 

formulations may, where appropriate, be conveniently presented in discrete dosage units and may 

be prepared by any of the methods well known in 

the art of pharmacy. All methods include the step 

of bringing into association the active compound 

with liquid carriers finely divided solid carriers or 

both and then, if necessary, shaping the product 

into the desired formulation.

Pharmaceutical formulations suitable for oral 

administration may conveniently be presented as 

discrete units such as capsules, cachets or tablets 

each containing a predetermined amount of the 

active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active 

ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients 

such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be 

coated according to methods well known in the 

art. Oral liquid preparations may be in the form 

of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixers, or may be presented as a dry product for constitution with 

water or other suitable vehicle before use. Such 

liquid preparations may contain conventional additives such as suspending agents, emulsifying 

agents, non-aqueous vehicles (which may include 

edible oils), or preservatives.1

 

1 This is the text on which the panel majority appears to rely for the statement that “Von Itzstein II 

expressly discloses administration through ‘oral,’ ‘nasal,’ 

or other forms ‘suitable for administration by inhalation.’” 

Maj. Op. at 5. 

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6 IN RE: EFTHYMIOPOULOS

Australian Patent No. AU-A-27242/92 at 8–9 (April 4, 

1993). The description of suitable formulations continues 

for almost three more pages, but does not mention or 

suggest oral inhalation. No disclosure of administration 

of zanamivir by oral inhalation can be found here or 

anywhere else in the prior art. One wonders how it can 

nonetheless be obvious, particularly in view of the specific 

teaching in Von Itzstein I that nasal administration is the 

mode for administering zanamivir. To make a prima facie

case, the prior art must provide, and the Board must 

identify, a reason or motivation to depart from the prior 

art; no reference or combination of references has been so 

identified—even in hindsight.

It cannot be “obvious to try” the only form of oral administration that is absent from the Von Itzstein recitations. In KSR v. Teleflex the Court explained that 

“obvious to try” may arise “where there is a design need or 

market pressure to solve a problem and there are a finite 

number of identified, predictable solutions, a person of 

ordinary skill has good reason to pursue the known options within his or her technical grasp.” 550 U.S. 398, 416 

(2007). The Board’s conclusion relies on a general finding 

that “inhalation can only be carried out via the nose or 

the mouth.” PTAB Op. 11. But this is a flawed rationale, 

for Von Itzstein II teaches a totality of “oral, rectal, nasal, 

topical (including buccal and sub-lingual), vaginal or 

parenteral (including intramuscular, sub-cutaneous and 

intravenous) administration or in a form suitable for 

administration by inhalation or insufflation.” Von Itzstein II at 8. The omission of oral inhalation from this 

compilation of all the “known options” for this drug makes 

conspicuously clear that oral inhalation was not an “identified predictable solution.” The Board’s ruling that oral 

inhalation was nonetheless obvious is not supported by 

substantial evidence. See In re Huai-Hung Kao, 639 F.3d 

1057, 1067 (Fed. Cir. 2011) (“The Board’s own conjecture 

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IN RE: EFTHYMIOPOULOS 7

does not supply the requisite substantial evidence to 

support the rejections . . . .”).

It was undisputed that, at the time of this invention, 

it was believed that the influenza virus infected primarily 

the upper respiratory tract, that is, the nasal passages. It 

was undisputed that there was not a reasonable expectation that administration to the lower respiratory tract by 

oral inhalation would be effective. The Von Itzstein

references do not show or suggest oral inhalation, either 

for zanamivir or for any related compounds. The Board’s 

statement that inhalation is “reasonably understood” to 

include oral inhalation, PTAB Op. 12, is without authority. There was no record showing or supporting such an 

understanding. There was no suggestion or hint in any 

reference that treatment by oral inhalation would have a 

reasonable expectation of success. 

This mode of therapy is taught only by this inventor. 

There was not substantial evidence to support the Board’s

ruling of obviousness. From the court’s flawed analysis 

and unsupported conclusion, I respectfully dissent.

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