# United States **Court of Appeals**  **for the Federal Circuit**

______________________

LOS ANGELES BIOMEDIC AL RESEARCH INSTITUTE AT HARBOR

- UCLA MEDICAL CENTER, Appellant

v.

ELI LILLY AND COMPANY, Appellee

______________________

2016

- 1518

______________________ Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board

, in No. IPR2014

- 00752.

______________________ Decided: February 28 , 2017

______________________

E WA M. D AVISON , Fenwick & West LLP, Seattle, WA, argued for appellant. Also represented by D AVID K EITH T ELLEKSON , E LIZABETH B. H AGAN ; V IRGINIA K AY D E M ARCHI , A MY H AYDEN , Mountain View, CA.

M ARK J. F ELDSTEIN , Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, argued for appellee. Also represented by J OSHUA G OLDBERG , Y IEYIE Y

ANG ; C HARLES E. L IPSEY , Reston, VA; M ARK S TEWART , Eli Lilly and Company, Indianapolis, IN.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 2

______________________

Before N EWMAN , B RYSON , and M OORE , Circuit Judges.

Opinion for the court filed by Circuit Judge B RYSON

. Opinion c oncurring in part, d issenting from the jud gment filed by Circuit Judge N EWMAN

. B RYSON , Circuit Judge.
Appellant Los Angeles Biomedical Research Institute at Harbor

- UCLA Medical Center (“ LAB”) seeks review of a decision of the Patent Trial and Appeal Board h olding all claims of U.S. Patent No. 8,133,903 (“the ’903 patent”) unpatentable as obvious. We vacate the Board’s order and remand for further proceedings.

I

A

The ’903 patent claims a method of “arresting or r egressing” a condition known as penile fibrosis . The met hod entails the long

- term, daily administration of drugs known as type 5 phosphodiesterase (“PDE5”) inhibitors. The drugs function by inhibit ing the enzymatic action of PDE 5, which is found in the human penis. See ’903 patent, col. 6, line 51, through col. 7, line 15.

The penis contains two cylindrical chambers called the corpora caverno sa . Those chambers fill with blood during an erection. The corpora cavernosa are sur ro un ded by a membrane called the tunica albuginea. Penile f ibrosis is characterized by the buildup of excess collagen

. It includes two conditions : penile tunical fibrosis , which results from the buildup of excess collagen in the tunica albuginea, and corpo ral tissue fibrosis , which results from

a buildup of excess collagen in the corpora cavernosa

. See ’903 patent, col. 68, ll. 22

- 32, 37

- 39; see also id. , col. 9, ll. 45

- 46

.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 3

The two fibrotic conditions can cause erectile dysfun ction , although they do not always do so

. Tunical fibrosis can manifest itself as Peyronie’s disease

, a condition that

“ usually leads to penile deformation (curved penis during erection), pain, and quite frequently erectile dysfunction.” ’903 patent, col. 1, ll. 33

- 34

. Corporal ti ssue fibrosis, which results from the death of smo oth muscle cells in the

corpora cavernosa and a corresponding buildup of coll agen, can cause dysfunction of the mechanism that retains blood in the corpora cavernosa during an erection. In a healthy male, the relaxation of the smooth muscle cells in the penis increases the flow of blood to the corpora cave rnosa . The flow of blood into the corpora cavernosa in turn

compress es the veins of the penis against the tunica albuginea to block the flow of blood fro m the penis. The compression of those veins is known as the veno

- occlusive mechanism . Disruption of that mechanism, known as corporal veno

- occlusive disorder (“ CVOD ”)

, can lead to erectile dysfunction. Id. , col. 2, ll. 23

- 31.

In addition to the two types of penile fibrosis , there

are many other causes of erectile dysfunction

. Some

ca u ses of erectile dysfunction

, such as those of psycholog ical origi n, are entirely unrelated to fibrosis.
In the early 2000s

, PDE5 inhibitors such as sildenafil ( Viagra) and tadalafil (Cialis) were well known and co mmonly used for the on- demand treatment of erectile dysfunction. See ’903 patent, col. 10, line 59

, through col. 11, line 3. The use of sildenafil and tadalafil for that

purpose was not restricted to cases of erectile dysfunction resulting from penile fibrosis

. In dividuals with erectile dysfunction of varying causes were instructed to take PDE5 inhibitors before sexual activity in order to obtain an erection at the desired time

. As the ’903 patent e xplains, that use of PDE5 inhibitors was “ not addressed to the long

- term cure of underlying tissue fibrosis.” Id. , col. 10, line 67

, through col. 11, line 3.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 4

At th at time

, according to the patent, there was a need for adequate non

- surgical treatment s for Peyronie’s disease and other fibrotic conditions

. ’903 patent , col. 2, ll. 2-7 (noting that surgery was “the only option” available in most cases of Peyronie’s disease)

. E rectile dysfunction resulting from t ho se conditions could be treated sympt omatical ly with on

- demand PDE5 inhibitors, but there was “[n]o effective method of treatment . . . directed towards the molecular pathways underlying excessive collagen deposition” to address penile fibrosis. Id. , col. 2, ll. 4 4- 46

. The ’903 patent , owned by LAB

, claims such a trea tment. Claim 1, the only independent claim, re cites:

1. A method comprising: a) administering a cyclic guanosine 3’, 5’

- monophosphate (cGMP) type 5 pho sphodiesterase (PDE5) inhibitor accor ding to a continuous long

- term regimen
to an individual with at least one of a penile tunical fibrosis and corporal ti ssue fibrosis; and b) arresting or regressing the at least one of the penile tunical fibrosis and co rporal tissue fibrosis, wherein the PDE

5 inhibitor is administered at a dosage up to 1.5 mg/kg/day for not less than 45 days.

’ 903 patent, col. 68, ll. 2 3-32

. The remaining four claims depend from c laim 1 and concern the type of drug ( c laim 2), the type of fibrotic condition ( c laim 3), the mode of administration ( c laim 4),LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 5

and the durati on of treatment ( c laim 5). Id. , col. 68, ll. 33

- 45. 1

B

In 20 1 3, LAB filed an infringement action in the United States District Court for the Central District of California against Eli Lilly & Company (“Lilly”), alleging that Lilly’s marketing of the drug Cialis induced i nfringement of the ’903 patent

. Los Angeles Biomed. Research Inst. v. Eli Lilly & Co. , No. 2:13

- cv

- 08567

- JAK

JCG (C.D. Cal

. filed Nov. 20, 2013 ). Lilly subsequently filed multiple petitions requesting that the Patent Trial and Appeal Board conduct inter partes review of the ’903 patent. The Board instituted inter partes review on the petition in which Lilly contend ed that all the claims of the ’903 patent were unpatentable as obvious in light of three references . The cited references were: Francesco Montorsi et al., The Ageing Male and Erectile Dysfunction , 20 World J

. Urology 28

- 53 (2002) (“Montor si”) ; International Patent Application No. WO 01/80860 (published Nov. 1, 2001) (John S. Whitaker et al., applicants) (“Whitaker”); and Hart mut Porst et al., Daily IC351 Treatment of ED

, 12 Int ’ l J

. Impotence Research (Supp. 3) S76, B13 (2000 ) (“Porst”)

. 2

1 LAB has not presented separate arguments for the patentability of any of the dependent claims.

2 The Board also instituted inter partes review on the petition in which Lilly argu ed that all the claims of the ’903 patent were unpatentable as anticipated by Whitaker . The Board conducted that inter partes review in a separate proceeding, No. IPR2014

- 00693. At the conclusion of that proceeding, the Board ruled that the claims were not anticipated. Th at decision

, which Lilly appealed

, is addressed in the related case, Eli Lilly & Company v. Los Angeles Biomedical Research Institute atLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 6

T he ’ 903 patent claims priority from Provisional A pplication No. 60/420,281, which was filed on October 22, 2002

. ’903 patent, col. 1, ll. 12

- 15. The Board rejected LAB’s argument for the earlier priority date and determin ed that the specification of the provisional application did not disclose the dosage limitation of “up to 1.5 mg/kg/day ,” i.e., a dosage of up to 1.5 milligrams of PDE5 inh ibitor per kilogram of the patient’s body weight each day.

The Board also construed several claim limitations that are now at issue on appeal . First, the Board co nstrued the phrase “a n individual with at least one of penile tunical fibrosis and corporal t issue fibrosis ” to

mean an “ individual hav[ing] symptoms that may be associated with penile fibrosis, such as [erectile dysfun ction] , but not that the patient be specifically diagnosed as having penile tunical fibrosis or corporal tissue fibrosis.”
Second, the Board construed the phrase “a rresting or regressing the at least one of the penile tunical fibrosis and corporal tissue fibrosis ” as having no limiting role, but merely stating the intended result of administering a PDE5 inhibitor at a dosage o f up to 1.5 mg/kg/day for at least 45 days.
Third, in the Decision on Institution, the Board co nstrued the term “continuous long

- term regimen” to mean “the administration of drug over a certain period of time without intermission such that the treatment is therape utically effective.” In its final decision, t he Board conclu ded that the claim limitation requiring the delivery of a dosage of up to 1.5 mg/kg/day for at least 45 days “would meet the claim requirement of a continuous, long

- term regimen.”

Harbor

- UCLA Medical Center

, No. 2016

- 1547 , decided together with this case but in a separate opinion

.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 7

The B oard then addressed the three prior art refe rences: Montorsi, Whitaker, and Porst

. Montorsi is a review article that addresses the trea tment of erectile dysfunction in the aging male population. Montorsi state s that male erectile dysfunction is associa ted with aging ; that atherosclerosis (the buildup of plaque in the arteries) is common in the elderly; and that ather osclerosis is associated with CVOD and corporal fibrosis, which can cause erectile dysfunction. Montorsi at 28, 30

- 31. Montorsi conclude s th at “it seems reasonable to hypothesi s e that the [erectile dysfunction] from ageing is the result of atherosclerosis

- induced cavernosal ischaemia leading to caver nosal fibrosis and [CVOD].” Id. at 31.

Montorsi discusses several relevant studies of erectile dysfunction

. It beg ins by reviewing a group of studies on sildenafil as a treatment for erectile dysfunction in elderly patients . The patients in that study were instructed to take up to 100 mg of sildenafil on demand (one hour before sexual activity) but no more than once daily over a 12 week to 6 month period. Those studies showed that sildenafil was well tolerated and that it ameliorated the treated condition. Montorsi at 32

- 33. Another study reported that administering a 100 mg dose of sildenafil at bedtime to male patients between 40 and 68 years old with erectile dysfunction produced an increase in nocturnal erections. Id. at 31 (citing Francesco Montorsi et al.

, Sildenafil Taken at Bedtime Significantly Increases Nocturnal Erections: Results of a Placebo

- Controlled Study , 56 Urology 906, 907 (2000) ). Montorsi conclude s that th is stud y “opened the door to further study invest igating the possible dosage of sildenafil to be administered daily at bedtime to prevent or treat [erectile dy sfunction] in the elderly patient.” Montorsi at 31.
Whitaker is an abandoned pat ent application that claims the chronic use of low

- dose PDE5 inhibitors to treat erectile dysfunction

. Whitaker define s “chronic” asLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 8

“the regular administration of the [PDE 5 inhibitor] in intervals unrelated to the onset of sexual activity,” and
state s that “chronic administration generally refers to regular administration for an extended period, preferably daily for three or more days, and still more preferably daily for as long as the patient suffers from erectile dy sfunction (in the absence of therapy).” Whitaker at 7. Whitaker define s “daily” as “administration of the [PDE5 inhibitor] one or more times, generally one to three times, still more preferably one time, per a bout 24

- hour period.” Id.
Example 6 of Whitaker combine s data from five clin ical studies to show that chronic administration of low dose s (5 mg or 10 mg) of tadalafil improved erectile fun ction in a population of patients with male erectile dy sfunction. Whitaker at 34. The study population included four subgroups, in which tadalafil was taken (1) less than 30% of the time, (2) 30

- 50% of the time, (3) 50

- 70% of the time, and (4) more than 70% of the time. Id. Example 6 states that tadalafil “was adminis tered ‘daily’ to [these] patients.” Id. ; accord id. at 35 (“The Study Drug was administered in 5 mg and 10 mg doses, ‘daily’ and not more than once every 24 hours.”). Whitaker note s “a trend toward better response with increased frequency of dose.” Id. at 36 (referring to results showing better ere ctile function in subgroups 3 and 4 than in subgroups 1 and 2). In Example 7, tadalafil was administered daily for three weeks to men 21

- 72 years old with erectile dysfunction, in subgroups receiving either a placebo or one of four dosages (10, 25, 50, and 100 mg). The results showed that “[a]dverse events [side effects] were dose

related, and attenuated with continued daily treatment.” Id. at 38.

Whitaker states that “[t]he enhanced efficacy demo nstrated by low daily dosing of a PDE5 inhibitor in treating erectile dysfunction . . . results from improved vascular responsiveness when the PDE5 inhibitor is present co n-LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 9

tinuously, or essentially continuously, in plasma.” Whi taker at 12. Whitaker term s that effect “vascular cond itioning,” an effect that ha d not been reported or observed in treatments with PDE inhibitors generally, nor more specifically in the case of on- demand dosing of PDE5 inhibitors. Id. Whitaker conclude s that “[i]t is expected that vascular conditioning occurs after chronic admi nistration of the PDE5 inhibitor, for example, after about three daily doses of up to 10 mg, preferably after five days of daily dosing, and more preferably after seven days of daily dosing. In addition, after about three days of daily dosing, intermittently missing one chronic dose may lead to a reduction in vascular conditioning, but not a complete loss of conditioning.” Id. at 13. Whitaker then posit s : “It is theorized, but not relied upon herein, that vascular conditioning is caused by a partial or complete reversal of circulatory dysfunctions in penile circulation arising from conditions such as diabetes, atherosclerosis, smoking, hypertension, or a combination of such factors.” Id. at 13. Porst is a published abstract of a study showing that 100 mg of tadalafil administered daily for three weeks to men with erectile dysfunction having a mean age of 52.4 years was safe and well tolerated, and that it improved erectile f unction

. The Board found that Montorsi and Whitaker t aught administering a PDE5 inhibitor to an individual with erectile dysfunction, as required by its construction of “an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis.” The Board also found that Montorsi t aught that erectile dysfunction in the aging male is associated with atherosclerosis , which in turn is associated with the development of corporal fibrosis , and that Whitaker t aught that l ong

- term treatment with a PDE5 inhibitor can cause reversal of circulatory dysfun ctions caused by diabetes, atherosclerosis, smoking, hype rtension, or a combination of such factors.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 10

The Board further found that the three references together t aught daily do sing of up to 1.5 mg/kg/day for at least 45 days , and therefore met the “continuous long

term regimen” limitation of the ’903 patent

. In particular, the Board found that Montorsi t aught dosing of up to 100
mg of sildenafil per day . A ccording to the ’903 patent, col. 45, ll. 7

- 12, a dosage of 100 mg per day is roughly equiv alent to 1.5 mg/kg for an average weight adult male

. Although the Board acknowledged that Whitaker’s E xample 6 d id not specifically disclose dosing every day

, it

no ted that Whitaker t aught that better results are o btained with increased frequency of dos ing, that adverse effects are attenuated with daily administration , and that treatment should continue for as long as the erectile dysfunction persists. Finally, t he Board found that Porst taught that a dosage of 100 mg of tadalafil per day is safe and well tolerated.
In response to Lilly’s arguments based on the prior art references, LAB argued that its treatment method produced unexpected results, because at the time of the invention the scientific community believed that PDE5 inhibitors would exacerbate fibrosis , not treat it. That belief, according to LAB, was based on the understanding that the enzyme inductible nitric oxide s y nthase (“iNOS”) and its product, nitric oxide, which have a mechanism of action similar to that of PDE5 inhibitors, were profibrotic. The Board rejected that argument on the ground that the claims of the ’903 patent do not require a particular mechanism o f action and that any antifibrotic effect resulting from the administration of PDE5 inhibitors, whether expected or not, is inherent.
The Board ultimately concluded that the combination of references satisfies each of the limitations of the ’903 patent
, as construed, and that the combination provides a reasonable expectation of success in treating erectile dysfunction.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 11

On appeal, LAB argues that the Board erred (1 ) in denying LAB’s claim of priority to the October 2002 filing date of the inventors’ provis ional application

, (2) in co nstruing the three disputed claim terms, (3) in deciding that claim 1 of the ’903 patent would have been obvious based on incorrect claim constructions, and (4) by failing to adequately consider the prevailing belief s in the fie ld and the unexpected results achieved by the inventors

. II

A
In order for a patent to be entitled to priority based on an earlier application or chain of applications, each pr ev ious application in the chain must comply with the written description requirement of 35 U.S.C. § 112(a)

. Bradford Co. v. Conteyor N. Am., Inc. , 603 F.3d 1262, 1269 (Fed. Cir. 2010). To satisfy the written description requir ement, the disclosure in each application must “reasonably convey[]” to those skilled in the art that a s of the claimed priority date the inventor was in possession of the later claimed subject matter. Vas

- Cath Inc. v. Mahurkar , 935 F.2d 1555, 1563 (Fed. Cir. 1991). A disclosure in a parent application is not sufficient if it “merely renders the later

c laimed invention obvious . . . ; the disclosure must d escribe the claimed invention with all its limitations.” Tronzo v. Biomet, Inc. , 156 F.3d 1154, 1158 (Fed. Cir. 1998).
In this case, t he inventors filed a provisional applic ation in October 2002 to which the ’903 patent claims priority. Lilly argues on appeal that the three prior art references w ere published before the provisional applic ation was filed and are thus prior art under 35 U.S.C. § 102(a) even with the priority date of October 2002. LA B responds that Lilly asserted Whitaker and Montorsi as prior art only under 35 U.S.C. § 102(b) before the Board and that Whitaker and Montorsi do not qualify as prior art under that provision. We decline to address theLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 12

question of Lilly’s waiver, as we c onclude on the merits that the ’903 patent is not entitled to the priority date of the provisional application because of a lack of adequate written description

. The provisional application does not explicitly disclose a dosage of “up to 1.5 mg/kg/day.” LAB, however, co ntends that the dosage level is disclosed by a rat study described in the provisional application . In that study, rats were provided with 100 mg/L ( milligrams per liter ) of sildenafil in drinking water . LAB argues that a person of skill i n the art would be able to calculate the correspon ding human dosage according to a conversion method devised by E. J. Freireich, and that the result of that computation would be a dosage of approximately 1.5 mg/kg/day. See Emil J. Fr e ir e ich, Quantitative Compar ison of Toxicity of Anticancer Agents in Mouse, Rat, Ha mster, Dog, Monkey, and Man

, 50 Cancer Chemother apy Reports 219

- 44 (1966).
LAB’s argument depends on several assumptions r egarding the knowledge of a person of skill in the art

. Such a person wo uld have to know the average daily water intake of the rat model used in the ’903 patent, the average weight of the rat model used in the ’903 patent, the average weight of an adult human male, and the average height of an adult human male . Moreover, that person would need to know of the Freir e ich method for calculating the rat

- to

- human interspecies dosage conve rsion and have a reason to apply it

. The Board held that the first four variables were not knowable from the discl osure in the application, but would at best require persons of skill to look to the prior art and make assumptions

. Th at is not enough to establish priority. See Lockwood v. Am. Airlines, Inc. , 107 F.3d 1565, 1572 (Fed. Cir. 1997) (“It is not sufficient for purposes of the written de scription requirement of § 112 that the disclosure, when combined with knowledge in the art, would lead one to speculate as to modifications that the inventor might have envisioned,LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 13

but failed to disclose.”). Moreover, the underlying a ssumptions for LAB’s expert’s derivation were themselves faulty. For example, LAB’s expert assumed an adult male weight of 86.1 kg to calculate the 1.5 mg/kg/day human dosage from the rat study. He relied on an uncited, non

prior art reference for th at data . Lilly’s expert showed that the dosage would have been approximately 1.7 mg/kg/day if 67 kg

— the weight disclosed in the ’903 patent

— had been used instead. 3

As for the fifth assumption, LAB presented no ev idence as to why a person of skill would choose to rely on the Fr eire ich method to calculate a human dosage for therapeutic treatment of fibrosis with PDE5 inhibitors. That reference was not disclosed in the provisional appl ication, is nearly half a century old, and was based on measurements of toxicity of anticancer agents

. More importantly, LAB cannot rely on standalone references that it failed to incorporate in the provisional application in order to make out its priority claim. “[I]t is the discl osures of the [provisional] application[] t hat count,” not those of uncited references. Allergan , Inc. v. Sandoz Inc.

, 796 F.3d 1293, 1309 (Fed. Cir. 2015) ( holding that it was error to rely on a clinical protocol to show earlier posse ssion because the protocol was not disclosed in the specificati ons of the asserted patents)

. Because proof of priority requires written description disclosure in the parent application, not simply info rmation and inferences drawn from uncited references, the Board correctly held that LAB’s expert’s calculation d id
not satisfy the requirements for priority and that the ’903

3 The patent states that “1 .5 mg/kg . . . is about the dose ingested by men with an on demand single 100 mg tablet.” ’903 patent, col. 45, ll. 7

- 12. That passage a ssumes that an adult man weighs approximately 67 kg.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 14

patent was therefore not entitled to the October 2002 priority date of the provision al application

. B

In an inter partes review proceeding, the Board giv es claims their broadest reasonable interpret ation consistent with the specification

. In re Cuozzo Speed Techs., LLC

, 793 F.3d 1268, 1276, 1279 (Fed. Cir. 2015), aff’d , 136 S. Ct. 2131, 2142 (2016). We review the Board’s claim construction de novo except for subsidiary fact findings, which we revie w for substantial evidence. Id. at 1280.

1. The broadest reasonable i nterpretation of the phrase “a n individual with at least one of penile tunical fibrosis and corporal tissue fibrosis ” is its plain meaning:

a n individual with penile tunical fibrosis and /or corporal tissue fibrosis

. 4 The Board’s construction ( “an individual hav[ing] symptoms that may be associated with penile fibrosis, such as [ erectile dysfunction ] , but not that the patient be specifically diagnosed as having penile tunical fibros is or corporal tissue fibrosis”) reads th at limitation out of the claim . That is because erectile dysfunction can have causes other than penile fibrosis, and because penile fibrosis does not necessarily result in erectile dys function

. Because erectile dysfu nction is merely a symptom that

4 Although Lilly claims that any “plain meaning” argument was wa ived below, LAB adequately preserved that argu ment when it stated in its Response to the Petition for Institution that “a person of ordinary skill in the art would understand the claims of the ’903 patent to
concern tre atment of fibrosis, a disease.” See Phillips v. AWH Corp. , 415 F.3d 1303, 1313 (Fed. Cir. 2005) (en banc) (“[T]he ordinary and customary meaning of a claim term is the meaning that the term would have to a person of ordinary skill in the art in question at the time of the invention.”).LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 15

may be, but is not necessarily, associated with penile fibrosis, erectile dysfunction cannot be equated with tunical fibrosis and corporal tissue fibrosis

. The patent make s clear that penile fibrosis and erectile dysfuncti on are not the same thing and do not nece ssarily accompany one another

. The specification makes clear that penile fibrosis may result in erectile dysfun ction, bu t it may not. E.g.

, ’903 patent, col. 1, ll. 29

- 34, 43

- 44 (“Peyronie’s disease is a fibromatosis of the tunica albuginea” that “[c]linically

. . . quite frequently leads to erectile dysfunction” but “is not always associated with erectile dysfunction”). Conversely, the specification acknowledges that erectile dysfunction has alternative causes and may present without underlying penile fibr osis. See, e.g.

, id. , col. 2, ll. 23

- 26 (“aging associated [erectile dysfunction ] . . . is mostly related to the loss of [smooth muscle cells] in the penile corpora cavernosa by apoptosis [cell death]

, with a corresponding increase in collagen fibers”); id. , col. 2, ll. 28

- 31 (“clinical result of this aging process in the penis is defective cavernosal [smooth muscle cell] relaxation leading to [CVOD], the most

common cause of [erectile dysfunction] ” in a ging males).
The patent ed invention targets the treat ment of fibr osis, whether or not the fibrosis cause s erectile dysfunction in a particular case . For example, the invention treats Peyronie’s d isease even in a patient with no symptoms of erectile dysfunc tion

. The point is that the claimed trea tment method is intended to decrease the level of fibrotic tissue, without regard to whether the patient’s fibrosis is

accompan ied by erectile dysfunction

. The Board relied on a statement in the Background

se ction of the patent that notes that “[a] need exists for effective methods to treat and/or ameliorate the sym ptoms of a variety of fibrotic disease, such as [Peyronie’s disease]

, [erectile dysfunction] and arteriosclerosis.” ’903 patent , col. 2, ll. 42

- 44 . But that statement plainly refersLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 16

to instances of erectile dysfunction that aris e from fibrosis (a “symptom[] of . . . fibrotic disease”), not to all cases of erectile dysfunction

. The next sentence in the specific ation clarifies that the focus of the treatment method is fibrosis, not the possible symptoms of fibrosis, such as erectile dysfunction. That sentence states: “No effective method of treatment currently exists that is directed towards the molecular pathways underlying excessive collagen depo sition [fibrosis].” Id. , col. 2, ll. 44

- 46.

This c ourt’s decision in Rapoport v. Dement , 254 F.3d 1053 (Fed. Cir. 2001), is closely analogous to this case. There, the appellant argued that the claim term “trea tment of sleep apneas” encompassed treatment of the symptom s associated with sleep apnea. Id. at 1059. This

c ourt disagreed, noting that the plain meaning of the term sleep apnea and the specification made clear that the patent was directed to treatment of the underlying sleep

apnea condition, eve n though the written description noted that the claimed “treatment [also] alleviates the sleep apnea

- related symptoms of anxiety, depression, fatigue, malaise, irritability, anger and hostility.” Id. (citing patent application).
In this case, similarly, t he ’903 specification mentions various fibrotic conditions and their possible symptoms

. S ee, e.g. , ’903 patent, col. 2, ll. 13

- 22 (arteriosclerosis, or fibrosis of the media of the arterial wall, is one of the underlying cause s of hypertension) . But the claims are narrower and are clearly aimed at penile fibrosis

— not other types of fibrosis , and not at symptom s such as erectile dysfunction

. See Rap o port , 254 F.3d at 1059 (“[t]he plain language . . . unambiguously refers to ‘trea tment of sleep apneas’ narrowly defined, and does not also include by its plain terms ‘treatment of symptoms assoc ia ted with sleep apneas.’”). T he specification’s references
to erectile dysfunction as a possible symptom of penile fibrosis do not broaden the phrase “a n individual with at least one of penile tunical fibrosis and corporal tissueLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 17

fibrosis ” beyond its ordinary meaning . As in Rapoport

, the ordinary meaning “ narrowly refers to . . . the underl ying disorder itself.” Id.

T he Board’s construction would make the patent claims applicable to individuals with erectile dysfunction not caused by penile fibrosis. Yet for patients suffering from erectile dysfunction without penile fibrosis, the claimed method would have no effect on the treatment of penile fibrosis

. The Board’s construction is therefore not the broadest reasonable interpretation of the disputed claim language ; rather, it is over ly broad. G iven the relationship between erectile dysfunction and penile fibrosis

, it is unreasonable to use the symptom o f erectile dysfunction as a proxy for penile fibrosis.
On the other hand, there is no support in the patent

or the prosecution history for LAB’s contention that the phrase “a n individual with at least one of penile tunical fibrosis and corporal tissue fibrosis ” requires a n individ ual to have “clinically significant” penile tunical or corporal tissue fibrosis

. Both parties’ experts agreed that some physicians would treat fibrosis even if it was not deemed

“ clinically significant. ” We see no reason to import such a limitation here

, and we conclude that “a n individual with at least one of penile tunical fibrosis and corporal tissue fibrosis ” includes an individual with one or both of th o se conditions , even if the condition is not deemed “clinically signi ficant.”

2. The limitation “a rresting or regressing the at least one of the penile tunical fibrosis and corporal tissue fibrosis ” requires halting the progression of

, or reversing

, penile fibrosis. Lilly contends that the phrase “a rresting or regressin g the [penile fibrosis]” has no patentable weight . We conclude, however, that the phrase is more than a statement of the intended result of administering the PDE5 inhibitor within the dosage limits , with theLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 18

frequency, and for at least the minimum period prescribed in the patent.

The full text of the limitation in which the “arresting or regressing” language appears reads: “ arresting or regressing the [penile] fibrosis, wherein the PDE

- 5 inhib itor is administered at a dosage up to 1.5 mg/kg/da y for not les s than 45 days.” ’903 patent, col. 68, ll. 2 9- 32. While not dispositive, it is significant that the phrase “arresting or regressing the [penile] fibrosis” is drafted as part of a separate step of the method, not as the preamble or introduction to a process carried out by the administr ation of the drug. The structure of the ’903 patent claim 1 is therefore not comparable to the structure of patent claim s in which statements of general purpose in the preambles of method claims have been held to carry no pa tentable weight. E.g.

, Bristol

- Myers Squibb Co. v. Ben Venue Labs., Inc. , 246 F.3d 1368, 1375 (Fed. Cir. 2001) ( preamble phrase “for reducing hematologic toxicity” was “non

- limiting

, and merely expressing a purpose”); see also I

n re Montgomery , 677 F.3d 1 375, 1380 (Fed. Cir. 2012) (expressing “skeptic[ism]” that the phrase “for the trea tment or prevention of stroke” in a claim preamble was more than an expression of purpose for the claimed met hod).

Other intrinsic evidence shows that t he “arresting or regressing ” limitation does not merely duplicate th e wherein clause that fol lows. “Arresting or regressing” demands efficacy; the wherein clause does not. As e xplained in the specification, “arresting” means “halt[ing] the progression” or “prevent[ing] the further develo pment” of the fibrotic condition, and “regressing” means “reduc[ing] in size” or “reversing” the fibrotic condition. ’903 patent, col. 3, ll. 8

- 13; id. , col. 9, ll. 13

- 15 ; see also id.

, col. 2, ll. 53

- 61

. In Example 3 of the specificatio n, the inventors demonstrated the arrest or regression of fibrosis when administering a PDE5 inhibitor to rats daily for 45 days at a dosage equivalent to 1.5 mg/kg/day for an adultLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 19

human male . ’903 patent, col. 36, line 25

, through col. 37, line 5 (Examp le 3); id. , col. 45, ll. 7

- 12.

The wherein clause sets forth the minimum duration supported by the disclosure (45 days) for the arrest or regression of fibrosis at a high dosage of the PDE

- 5 inhib itor. But th e reference to a minimum duration period of 45 days says nothing about the efficacy of the method if a lower dosage of PDE5 inhibitor is administered

. As the inventor s explained during prosecution, “it is likely that if the dose [administered to the rats in Example 3] is r edu ced to 1/2 of the current dose to adapt it to the clinic and minimize side effects, the duration of the antifibrotic treatment may take 2 to 6 months or longer.” 5

Because th e ’903 patent claims specif y only a max imum dosage level and a minimum treatment period, it is different from cases in which the claims contain express dosage amounts as material claim limitations, and in which efficacy is “inherent in carrying out the claim steps.” Dawson v. Dawson , 710 F.3d 1347, 1355 (Fed. Cir. 2013) (cit ing Bristol

- Myers Squibb , 246 F.3d at 1375, and In re Montgomery , 677 F.3d at 1381). We therefore co nclude that “arresting or regressing” the fibrosis adds an efficacy requirement that is not otherwise found in the claim language.

Nor do LAB’s infringem ent contentions in the ongoing district court case render the “arresting or regressing”

5 The inventors also stated during prosecution that, “like in the aging rat model [Example 3], it takes at least 45 days of treatment with sildenafil to ameliorate the CVOD and underlying corporal fibrosis,” which “was done with daily doses equivalent to 2.5 fold the doses currently applied in the clinic to elicit an erection.”LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 20

limitation irrelevant

. 6 LAB alleged that the “[l]ong

- term administration of Cialis on a once daily basis for the treatment of [erectile dysfunction] results in the arrest or regression of penile tunical fibrosis (i.e., [ Peyronie’s d isease ]) and corporal tissue fibrosis (i.e., [CVOD]).” [LAB]’s Disclosure of Asserted Claims and Preliminary Infringement Contentions , Ex. A at 5

, Los Angeles Bi omed. Research Inst. v. Eli L illy & Co. , No. 2:13

- cv

- 08567

- JAK

- JCG (C.D. Cal. filed May 19, 2014)

. But LAB did not define “ long

- term ” in th at context. In order to prove infringement, LAB may need to show , for example, that Lilly induces the administration of 2.5 mg or 5 mg of Cialis daily by patients with penile tunical or corporal tissue fibrosis for a period of time that is long enough

, given the dosage levels

, to result in the arrest or regre ssion of fibrosis. In any event, LAB does not contend that the Cialis label in duces infringement by instructing the daily administration of 2.5 mg or 5 mg of Cialis , regar dless of the duration of the treatment.

3. Claim 1 of the ’903 patent contains a limitation providing for a “continuous long

- term regimen” in add ition to the limitation providing for administering a PDE5 inhibitor in an amount “up to 1.5 mg/kg/day for not less than 45 days

. ” The 45

- day requirement makes clear that the “continuous long

- term regimen” must be at least 45 days in length.

6 We deny LAB’s motion to strike Lilly’s references to those filings. We can properly take judicial notice of the records of related court proceedings. See Function Media, L.L.C. v. Google, Inc. , 708 F.3d 1310, 1316 n.4 (Fed. Cir. 2013). Because we take judicial notice of those records, we do not reach Lilly’s conditional objection to LAB’s reliance on the Final Written Decision in the related IPR proceeding on anticipation. See no te 2 supra

.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 21

LAB argues that the term “continuo us long

- term re gimen” add s a requirement that the drug concentration in the patient’s body attain a “constant level

, ” i.e., maintain

a “steady state ” plasma concentration . The patent , ho wever, never mentions the “steady state” of a drug or other agent

. As for “con stant level ,” LAB points to a single

se ntence buried in the middle of the 6 8- column disclosure that states :
A distinction exists between long

- term (weeks, months, years) continuous treatment with, for e xample, a PDE5 inhibitor such as sildenafi l to maintain a constant level of these agents in order to arrest or regress a fibrotic condition, versus on demand (prior to the sexual act) single pill, short

term treatment with sildenafil or other PDE5 i nhibitors to obtain smooth muscle vasodilation in the penis (male penile erection) or vagina/clitoris (female sexual arousal) upon sexual stimulation.
’903 patent, col. 10, l l. 59

- 67

. In th at passage, the term “c onstant level” is not presented as a definition of “conti nuous long

- term regimen,” or its eq uivalent. Rather, the

passage simply confirms that long

- term continu ous PDE5 inhibitor treatment excludes an “on demand . . . single pill , short

- term treat ment ” ; the passage does not exclude

any treatment that fails to maintain a n unvarying level of the drug within the patient’s body

. Nor is “a constant level” required by anything else in the specification

. If a n applicant intends to ascribe a meaning to a claim term different from its ordinary meaning, he must “set out the different meaning in the

spec ification in a manner sufficient to give one of ordinary skill in the art notice of the change from ordinary mea ning.” Innova/Pur e Water, Inc. v. Safari Water Filtration Sys., Inc. , 381 F.3d 1111, 1117 (Fed. Cir. 2004). Because the patentees in this case have not “demonstrated a clear intention to limit the claim scope ,” id.

, in a manner inco n-LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 22

sistent with the ordinary meaning of the term “contin uous,” it would be improper to construe the claim language in the manne r that LAB suggests.
Although LAB argues that the term “continuous long

term regimen” should be construed to require a “constant level of the administered PDE

- 5 inhibitor,” the position LAB took before the Board and takes in its briefs before this court make s clear that LAB is not using the word “constant” in its conventional sense. In its opening brief, LAB argues that a “constant level” of a PDE5 inhibitor refers to “the average plasma concentration of that drug upon reaching steady state,” even though the actual concentration “peaks and then declines.” LAB Opening Br. 36. In its reply brief, LAB departs even farther from the ordinary meanin g of “constant” and argues that “a meanin gf ul steady state (‘constant level’) requires a dose interval that allows drug concentration to stay within its therapeutic range.” LAB Reply Br. 16.
LAB cites its expert’s report and a pharmacology text to suppo rt its argument that frequent dosages of a drug with a short half

- life are required to maintain a high, if varying, level of plasma drug concentration . However, LAB points to nothing in the patent that supports the construction of the term “continuous lon g- term regimen” to require dosing frequency sufficient to maintain the level of drug concentration within what LAB refers to as “its therapeutic range.”

T he prosecution history also undercuts LAB ’s arg ument

. In the provisional application, claim 16 requ ired both a “c ontinuous long term regimen” and “maintaining a constant level .” It provided: “The method of claim 1, wherein said administering comprises long term contin uous treatment for weeks, months or years to maintain a constant level of the inhibit or.” But in the 2004 applic ation that matured into the ’903 patent , the claims did not include the language “maintaining a constant level

. ” TheLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 23

separate use of those terms in the provisional application gives rise to the inference that “maintaining a con stant level” is not implicit in the term “continuous long

- term regi men. ” And the omission of the reference to “maintai ning a constant level” from the non

- provision al application strongly suggests that the claim s in the patent were not
meant to require that a constant level of the PDE5 inhib itor be maintained.

LAB points out that during prosecution the inventor s distinguished “continuous long

- term” treatment from on

demand treatment

. While that is true, the inventors drew that distinction based on the duration of the treatment regimen, not on the plasma level of the drug. For exa mple, in addressing the prior art, the inventor s “predict[ed] that 21 days of even a daily or twice a day treatment with a PDE5 inhibitor would be totally insufficient

. . . to prevent or ameliorate CVOD, since in our unpublished study on the time course of CVOD in the rat after cave rnosal nerve damage,

. . . once CVOD is established,

. . . it takes at least 45 days of treatment with sildenafil to ameliorate CVOD and und erlying corporal fibrosis.” There is no suggestion in the prosecution history that a “constant level” of the drug is required for patentability or efficacy.
Finally, LAB argues that the Board’s construction i mpermissibly renders the term “continuous long

- term regimen” superfluous in light of the limitation requiring administration of the PDE5 inhibitor “at a dosage up to 1.5 mg/kg/day for not less than 45 days.” While the two limitations clearly overlap, the more general reference to a “c ontinuous long

- term regimen” limitation serves to emphasize that the treatment is continuous and not sporadic. The fact that the limitations overlap is not fatal, nor does it compel us to adopt an otherwise unsu pported construction of the claims

. See Sim pleAir, Inc. v. Sony Ericsson Mobile Commc’ns AB , 820 F.3d 419, 429 (Fed. Cir. 2016) (Although “interpretations that renderLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 24

some portion of the claim language superfluous are disfavored,” that “preference for giving meaning to all
terms

. . . is not an inf lexible rule that supersedes all other principles of claim construction.”). The overlap in the limitations that results from giving them their plain meaning does not justify importing a “constant level” or “steady state” limitation into the claims where s uch a limitation has no support in the specification or the prosecution history.

C

D etermining whether an invention would have been obvious requires consideration of the scope and content of the prior art, differences between the prior art and the patent claim s , the level of ordinary skill in the art , and any secondary considerations

. KSR Int’l Co. v. Teleflex Inc. , 550 U.S. 398, 406 (2007). In the case of a combin ation of references that together disclose all the limitations of the claimed invention

, the adjudicator must determine whether there was an “apparent reason to combine the known elements in the fashion claimed by the patent at issue,” id. at 418, and whether a person of skill in the art at the time of the invention would have had a “reasonabl e expectation of success” in pursuing that combination

, s ee Genzyme Therapeutic Prods. Ltd. P’ship v. Biomarin Pharm. Inc. , 825 F.3d 1360, 1373 (Fed. Cir. 2016)

. LAB contends that the Board’s findings are insufficient to establish obviousness under the cor rect constru ctions of “an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis” and “arresting or regressing the at least one of a penile tunical fibrosis and corporal tissue fibrosis .” We agree. The Board concluded that the references on which it relied rendered obvious the treatment of erectile dysfunction via the claimed method, but it did not determine whether th o se references showed that it w ould have been obvious to use long

- term continuous treatment with a PDE5 inh ibitor to treatLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 25

individuals with penile fibrosis and to achieve the arrest or regression of that condition

. 1. The Board found that Montorsi and Whitaker taught the treatment of erectile dysfunction, a symptom sometimes associated with penile fibrosis, and that the combination of Montorsi, Whitaker, and Porst gave rise to a reasonable expectation of success in treating erectile dysfunction. What the Board did not do, however, was to find that those references taught treating a patient with penile tunica l fibrosis or corporal tissue fibrosis

. Nor did the Board find that those references provide d the basis for a reasonable expectation of success in treating th ose condition s. See Institut Pasteur & Universite Pierre et Marie Curie v. Focarino , 738 F.3d 1337, 1346 (Fed. Cir. 2013) (“Importantly, without a sound explanation for doing otherwise, . . . the expectation -of- success analysis must match the highly desired goal, not switch to a diffe rent goal that may be a less challenging but also less worthwhile p ursuit.”). As indicated above, t h e correct construction of the pertinent claim language requires more than simply treat ing erectile dysfunction

. 7
To be sure, Montorsi t eaches that corporal fibrosis is associated with erectile dysfunction in atherosclerotic or aging patient populations

. Montorsi , however, is directed

7 The dissent states that the Board found that the method of claim 1 was used in the prior art. The Board’s findings, however, rest on its erroneous claim constru ctions, including equating erectile dysfunction with penile fibrosis. The Board found in the prior art the method of long

- term administration (i) to an individual with erectile dysfunction (ii) to symptomatically treat the erectile dysfunction. It did not find in the prior art the method of claim 1: long

- term administration (i) to a n individual with penile fibrosis (ii) in an effective amount to arrest or regress the fibrosis.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 26

to on- demand dosing of PDE5 inhibitors ; it does not teach long

- term daily treatment . The only statement in Mo ntorsi re lating in any way to long

- term treatment appears in Montor si’s discussion of a study showing that a one

time administration of sildenafil at bedtime increased nocturnal erections in men between 40 and 68 years of age with erectile dysfunction. Montorsi comments that the study “opened the door to further study in vestiga ti n g the possible dosage of sildenafil to be administered daily at bedtime.” Montorsi at 31. T he study discussed by Montorsi , however, was not limited to a population of patients suffering from erectile dysfunction caused by an underlying fibro tic condition (or even aging or atheroscl erotic patients who have a higher likelihood of an underl ying fibrosis)

. The Board found that Whitaker t aught the chronic administration of PDE5 inhibitors to individuals with erectile dysfunction and , in particular, t hat it t aught treating individuals with erectile dysfunction that is associated with atherosclerosis

. Th e first of those fin dings is supported by substantial evidence, but the second is not.

Whitaker mentions atherosclero sis only once in its 39

- page discl osure . It does so when addressing an effect that Whitaker refers to as “vascular conditioning,” which was not previously seen in patients treated with PDE5 inhib itors

. Whitaker at 12

- 13. Upon observing th at effect in the case of chronic treatment of pat ients with erectile dysfunction, Whitaker states that “[i]t is expected that vascular conditioning occurs after chronic administration of the PDE5 inhibitor, for example, after about three daily doses of up to 10 mg, preferably after five days of daily dos ing, and more preferably after seven days of daily dosing.” Id. at 13. Whitaker then states that “[ i] t is theorized, but not relied up on herein that vascular cond itioning is caused by a partial or complete reversal of circulatory dysfunctions in penile circulation arising fromLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 27

conditions such as diabetes, atherosclerosis, smoking, hypertension, or a combination of such factors ,” conditions that “ result in thickening of the arterial wall, decreased arterial compliance, and decreased responsiveness to endogenous vasodilators, such as nitric oxide.” Id.
Whitaker, however, provides no data to support this “vascular conditioning” causation theory. None of the studies reported in Examples 5, 6, and 7 of Whitaker were expressly limited to atherosclerotic, or even aging, patient populations. E.g. , Whitaker at 34 (PDE5 inhibitor in Example 6 was administered to “patients with male erectile dysfunction”). Nor can the presen ce of an unde rlying fibrotic condition be inferred, because the Board point ed to no findings regarding the rate of incidence of atherosclerosis in males with erectile dysfunction. In

sum, Whitaker provides no information about whether the vascular conditi oning effect was observed in erectile dysfunction patients with atherosclero sis and associated corporal fibrosis.
Indeed, Whitaker makes clear that the observation about “vascular conditioning” and its cause is speculative

. Whitaker states that the “vascu lar conditioning” effect

was not previously observed, and notes that its relatio nship to circulatory dysfunctions such as atherosclerosis is merely “theorized.” Whitaker at 12

- 13. As such, Whit aker’s observation cannot serve as an express or implicit
tea ching. See , e.g. , Star Scientific, Inc. v. R.J. Reynolds Tobacco Co. , 655 F.3d 1364, 1375

- 76 (Fed. Cir. 2011) (prior art’s “speculative and tentative disclosure of what ‘might’ or ‘may’ [explain the cause of a desired effect] does not sufficiently direct or instruct one of skill in this art”) ; Alza Corp. v. Mylan Labs., Inc. , 464 F.3d 1286, 1290 (Fed. Cir. 2006) (“[L]egal determinations of obviousness, as with such determinations generally, should be based on evidence rather than on mere speculation or con jecture.”).LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 28

Following its analysis of Whitaker, t he Board found that persons of skill in the art would have had a reason able expectation of success in treating erectile dysfunc tion in fibrotic patients, as in Montorsi, and doing so through long

- term treatm ent, as in Whitaker

. In so finding, however, t he Board summarily dismissed LAB’s counte rargument that those references would not have give n rise to a reasonable expectation of success in treating erectile dysfunction in th e subpopulation suffering from penile fibrosis.
According to LAB’s expert, it was widely believed at the time of the invention that the enzyme iNOS and its product nitric oxide were profibrotic , i.e., they exacerbated fibrotic conditions and the accompanying symptom of erectile dysfunct ion

. It was known that nitric oxide activates guanylate cyclase, which increases intracellular

c yclic guanosine monophosphate (“c GMP ”)

. It was also known that PDE5 inhibitors operate similarly : They inhibit the enzyme PDE5, which breaks down cGMP

, so in hibiting PDE5 also leads to an increase in intracellular cGMP. LAB contends that the prevailing view in the field at the time of the invention was that PDE5 inhibitors would also be profibrotic. Therefore , a ccording to LAB,

persons of skill in the art wo uld not have prescribed a PDE5 inhibitor on a long

- term basis to treat erectile dysfunction in patients with penile fibrosis

. The Board dismissed LAB’s argument as addressed only to the mechanism of action inherent in the claimed method, which it found was taught by the combination of Montorsi and Whitaker. That answer, however, does not address LAB’s point that even if the combination of Montorsi and Whitaker teach long

- term treatment with a PDE5 inhibitor of individual s with some forms of erectile dysfunction

, a person of skill in the art would not have been motivated to combine those references to treat individuals with fibrosis

- related erectile dysfunction because, according to LAB, the results would hav e beenLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 29

expected to be detrimental. See Institut Pasteur , 738 F.3d
at 1346 (error to disregard prior art evidence of toxicity, which was relevant to question of whether skilled artisan would have a reasonable expectation of success in achie ving the claimed invention)

. To be sure, LAB’s evidence is not undisputed. A t the time of the invention, a ccording to Lilly, th e biochemical pathway was under study by those in the field as a way of addressing CVOD. And Whitaker, in discussing the possibility of such a treatment, does not single out ather osclerotic individuals (or others with an underlying penile fibrosis) and specifically warn against the profibrotic effects of long

- term treatment with a PDE5 inhibitor.

The question remains whether a person of skill in the
art would have had a reason to combine Montorsi, Whit aker, and Porst to treat penile fibrosis with a long

- term regimen of a daily dosage of a PDE5 inhibitor, and would have had a reasonable expectation of success from doing

so. Because the Board ’s obviousness analysis was based on an erroneous construction of the claim language and an overly broad interpretation of Whitaker, and because the Board did not address th e record evidence summ arized above, we remand for the Board to make new fin dings as to wh ether there was an apparent reason to combine the prior art references and whether that comb ination would have rendered obvious the long

- term admi nistration of PDE5 inhibitors to treat penile fibrosis. 8

8 LAB contends (LAB Opening Br. 60

- 62) that the Board failed to consider the evidence of unexpected r esults as objective evidence of nonobviousness. As indi ca ted above, the issue of unexpected results (and the related question of a reasonable expectation of success) is tied to the proper construction of the claim language. We ther e-LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 30

2. T he Board also made no findings as to whether any reference or combination of references rendered obvious the claim limitation “ arrest ing or regressing the at least one of a penil e tunical fibrosis and corporal tissue fibr osis ,” because the Board erroneously concluded that arres ting or regres sing fibrosis i s an inherent effect of any regimen exceeding 45 days regardless of the dos ag e. The Board did not consider, for example, whether the chronic low dose of tadalafil (5 mg or 10 mg administered “daily” for 8 or 12 weeks ) in Whitaker’s Example 6 would arrest

or regress penile fibrosis , including the relevant inventor statements during prosecution that administration for 45 days of an extremely high dose of sildenafil was required to achieve the arrest or regression of penile fibrosis, see supra note 5

. On remand, the Board should make the findings necessary to determine whether the references render the “ arresting or regressing” limitation obvious.

3. LAB also challenges the Board’s findings regarding the limitation “ at a dosage up to 1.5 mg/kg /day for not less than 45 days .” But the Board’s findings on that issue are well founded. Porst discloses that taking up to 1.5 mg/kg/day of a PDE5 inhibitor for three weeks is safe, well- tolerated, and effective as a treatment for erectile dysfunction. Whitaker teaches chronic dosing of PDE5 inhibitor for at least 45 days

. Whitaker does not explicitly disclose that dosing must occur every day, but it suggests as much, noting that a “ better response ” was obtained

“ with increased freq uency of dose .” Whit aker at 36 (be tter results reported with closer to daily compliance

, in the context of comparing the subgroups in Example 6 ); s ee also id. at 38 (“A dverse events were . . . attenuated with continued daily treatment .” ). And those remarks are supported by Montorsi ’s observation that the study r efore leave it to the Board on remand to address that issue in the first instan ce.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 31

viewed by Montorsi “opened the door to further study investigating the possible dosage of sildenafil to be admi nistered daily at bedtime to prevent or treat [erectile dysfunction] in the elderly patient.” Montorsi a t 31.
In sum, Whitaker teaches long

- term chronic trea tment for more than 45 days, Montorsi and Whitaker suggest daily administration, and Porst and Montorsi teach a dosage of up to 1.5 mg/kg /day

. The Board’s fin dings regarding th e dosage and treatment p eriod limitation are therefore supported by substantial evidence.

4. B ecause we agree with the Board that the “conti nuous long

- term regi men” limitation is satisfied by the administration of a PDE5 inhibitor “up to 1.5 mg/kg/day for not less than 45 days,” we conclude that the same references teach “continuous long

- term regimen .” The Board’s findings regarding that limitation are therefore supported by substantial evidence as well.

III

Because the Board’s obviousness determination was predicated on an erroneous claim construction of two of the limitations of claim 1

, and because the Board did not make factual findings as to whether there was an appa rent reason to combine the prior art references to treat
pe nile fibrosis and whether a person of skill in the art would have had a reasonable expectation of success from such a combination, we remand this case to the Board. We also remand for the Board to make findings bearing on the obviousness of the “arresting or regressing” limit ation. 9 The Board’s order is vacated, and the case is r e9 Although the dissent urges that we should resolve the obviousness question without a remand, it would be improper for us to do so in the absence of the necessary factual findings by the Board. Personal Web Techs., LLC

v. Apple , Inc. , No. 2016

- 1174, at 8-9 (Fed. Cir. Feb. 14
,LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 32

manded for further proceedings consistent with this opinion.

VACATED AND REMANDED

2017) (discussing the “ basic principle[] of administrative law” that an agency must provide a full and reasoned explanation for its decision , which is necessary to both enable judicial review and “prevent judicial intrusion on agency authority” ); Ariosa Diagnostics v. Verinata Health, Inc. , 805 F.3d 1359, 1365 (Fed. Cir. 2015) (“ [W] e must not ourselves make factual and discretionary findings that are for the agency to make.”) (citing SEC v. Chener y Corp. , 332 U.S. 194, 196

- 97 (1947)); see also, e.g.

, Bilstad v. Wakalopulos , 386 F.3d 1116, 1126 (Fed. Cir. 2004) (“vacat[ing] the Board’s decision with respect to the written description requirement and remand[ing] for reconsideration under the proper t est” because the court’s “resolution of the [written description] question” previou sly decided by the Board under an incorrect legal standard would “require[] fact findings this court is not permitted to make.”).

# United States **Court of Appeals**  **for the Federal Circuit**

______________________

LOS ANGELES BIOMEDIC AL RESEARCH INSTITUTE AT HARBOR

- UCLA MEDICAL CENTER, Appellant

v.

ELI LILLY AND COMPANY, Appellee

______________________

2016

- 1518

______________________ Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board

, in No. IPR2014

- 00752.

______________________

N EWMAN , Circuit Judge

, concurring in part

, d issenting from the judgment

. I agree generally with the court’s discussion of the ’9 03 patent and the prior art. However, I conclude that
t he Patent Trial and Appeal Board correctly held the claim invalid on ground s of obviousness and inherency

. No dispositive error of law, no absence of support of dispositive findings by substantial evidence, has been shown. I would affirm the Board’s decision, and thus I respectfully dissent from the ruling of vacatur and r emand.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 2

D ISCUSSION

The subject claim of the ’903 patent is :

1. A method comprising : a) administering a cyclic guanosine 3’ ,5 ’-

mono phosphate (cGMP) type 5 phosphodiesterase (PDE 5) inhibitor according to a continuous long

term regimen to a n individual with at least one of a penile tunical fibrosis and corporal tissue fibr osis; and
b) arresting or regressing the at least one of the penile tunical fibrosis and corporal tissue fibrosis, wh erein the PDE

- 5 inhibitor is administered at a dosage up to 1.5 mg/kg/day for not less than 45 d ays.
’90 3 Patent, col. 68, lines 23

– 32. The references cited by the PTAB show the subject cGMP products for treatment of erectil e dysfunction, and discuss the mode of action in erectile dysfunction

. The cited references are in the same field of endeavor, and inc lude a review article . I outline some relevant PTAB findings :

• the prior art shows that the cGMP products of claim 1 were known PDE

- 5 inhibitors , and known to relieve erectile dysfunction ;

• the prior art shows use of these cGMP products in the claimed dosages and over extended time p eriods.

• the prior art shows that penile fibrosis was known to be a cause of erectile dysfunction

. The PTAB held trial, with evidence and expert witnesses from both sides. The Board concluded that the subject
matter of cla im 1 would have been obvious in view of the cited references. R eversible error in this conclusion has not been shown , and the Board’s findings on which itsLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 3

conclusion was based are supported by substantial ev idence.
The court’s extensive opinion sets fort h the relevant facts, which I repeat only as needed to explain why I conclude that our proper action is to affirm the decision of the PTAB.

PDE

- 5 inhibitors were known to treat erectile dysfunction, which w as known to be caused by p enile fibrosis

. That penile fibrosis is a cause of erectile dysfunction, and that erectile dysfunction is relieved by treatment with these PDE

- 5 inhibitors, was known before the filing of the ’903 application. LABio stresses that erectile dysfunction was known to have ot her causes, such as diabetes, atherosclerosis, and psychological problems. However, on the prior art and expert testimony that when penile fibrosis was present it was affected by the PDE

- 5 inhibitors , the Board found that this effect was inherent in the u se of these products to treat erectile dysfunction.

There was no claim that t he ’903 inventors discover ed that penile fibrosis is a cause of erectile dysfunction. Their work is described as relat ing to understanding the production of nitric oxide

, and other scientific aspects of the mechanism of erectile dysfunction and how PDE

- 5 inhibitors work. I do not diminish the scientific value of their investigations . Ho w ever, this does not dimin ish the evidence and the Board’s finding s that PDE

- 5 inhibit ors were known and used by others under the co nditions set forth in claim 1.

Claim 1 is directed to use of the cGMP PDE

- 5 inhib itors in dosages and for periods shown in the prior art ; and the Board found that this use existed in the prior art, with the effect on penile fibrosis inherent in this use

. This finding is supported by substantial evidence. In Atlas Powder Co. v. Ireco, Inc. , 190 F.3d 1342, 1346 (Fed.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 4

Cir. 1999)

, the court explained that “i f granting patent protection on the disputed claim would allow the patentee to exclude the public from practicing the prior art, then that claim is anticipated, regardless of whether it also covers subject matter not in the prior art. ”

We are reminded of the truism that “that which i nfringes if later anticipates if earlier .” Polaroid Corp. v. Eastman Kodak Co. , 789 F.2d 1556, 1573 (Fed. Cir. 1986) ( quoting Peters v. Active Mfg. Co. , 129 U.S. 530, 537 (1889) )

. Both parties have advise d that LABio has charged Lilly with “willfully inducing infringement of the ’90 3 patent by marketing Cialis®, whose active ingredient is the PDE

- 5 inhibitor tadalafil

, to erectile dysfunction patients for daily use, knowing and intending that it would be used to treat the penile fibrosis of those erectile dysfunction patients sufferi ng from that underling cond ition.” LABio Br. 12. 1 I agree with the court that this representation is relevant to the issues of obviousness and inherency, for the prior art shows such daily use and at the claimed dosages

. The cited references lead to the PTAB’s ruling of obviousness

T he Montorsi reference is a review article published in April 200 2, entitled “The Ageing Male and Erectile Dysfunction

. ” The Whitaker reference is a n internation al applicat i on published Nov ember 1, 2001, entitled “Daily Treatment for Erectile Dysfunction Using a PDE5 Inhib itor.” The Porst reference is an article entitled “Daily IC351 [ tadalafil ] Treatment of ED,” published in Septe mber 2000. 2

1 The district court action has been stayed pending

reso lution of the PTAB proceedings.

2 LABio appeals the PTAB’s denial of priority to LABio’s provisional application, filed on October 22, 2002.LOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 5

At the PTAB trial, witnesses discussed the mech anism whereby penile fibrosis is related to erectile dysfun ction , and the mechanism of these cGMP compounds in PDE

- 5 inhibition. The PTAB found that “treatment of ED in elderly patients or patients with atherosclerosis, as suggested by both Montorsi and Whitaker, would result in
treatme nt of patients with the fibrosis, as Montorsi teac hes that corporal fibrosis is associated with ED in those patient populations.” PTAB Op. at 22. Substantial evidence supports this finding

. The PTAB cited Montorsi , which is a review of the causes of erec tile dysfunction

, an ailment that had been extensively studied over the years. Montorsi reports on the use of cGMP compounds as P DE

- 5 inhibitors

, and compiles information from many scientific publications

. Montorsi describes studies investigating the cau ses of erectile dysfunction in aging men, summarizing that “ it seems reasonable to hypothesize that the ED from ageing is the result of atherosclerosis

- induced cavernosal i schaemia leading to cavernosal fibrosis and veno

- occlusive dysfunction.” Montorsi at 31

. Montorsi describes a study “wherein sildenafil was taken as required, but no more than once daily, over a 12 week to 6 month period

, ” relied on by the PTAB to show

“ that sildenafil is an effective treatment of ED in elderly men.” PTAB Op. at 20. The court observes that “Monto rsi teaches that corporal fibrosis is associated with erectile dysfunction in atheroscleros is of aging patient popul ations, ” Maj. Op. at 25 , and finds that substantial evidence

Lilly po ints out, without apparent dispute, that the rel evant prior art would not be eliminated by LABio’s prov isional applicat i on’s filing date of October 22, 2002

, because all the references are prior art within the mea ning of 35 U.S.C. § 102(a), even if they do not qualify under § 102(b)

. Lilly Br. at 18.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 6

supports “the Board[s] f[inding] that Whitaker ta ught the chronic administration of PDE5 inhibitors to individuals with erectile dysfunction.” Id. at 26. I agree. Whitaker states th at “[t]o receive the full benefit of the present invention, chronic administration generally refers to regular administra tion for an extended period , preferably daily for three or more days, and still more preferably daily as long as the patient suffers from erectile dysfun ction (in the absence of therapy) .” Whitaker at 7. Lilly’s expert testified that “it would take ‘ months ’ to resolve ED based on circulatory dysfunction due to diabetes, ather osclerosis, smoking hypertension or a com b ination of those factors (i.e., Whitaker’s patient population).” Goldstein Decl. at 73

. The court cites Whitaker’s statement that “ [i] t is e xpected that vascular conditioning occurs after c h ronic administrati on of the PDE5 inhibitor, . . . ” Maj. Op. at 26, citing W hitaker at 13. M y colleagues criticize Whitaker’s lack of data on vascular conditioning

. Id. at 27. However, that does not eras e Whitaker’s teaching of chronic admi nistration ; and I point out that claim 1 does not mention or require vascular conditioning. The PTAB found that “Whitaker expressly teaches once daily dosing, teaches that treatment should last as long as the erectil e dysfun ction continues, and expressly teaches time periods of eight to twelve weeks.” PTAB O p. at 21

. Th ese finding s are sup ported by substantial evidence.
On this appeal LABio argues, as it did during pros ecution, that “ [t] he pending claims are directed to a ‘cur ative’ effect as opposed to a ‘palliative’ effect . . . for a long

term result (e.g., years), not a pathophysiology (function) for a very short

- term result of a vasodilation (e.g., hours, maximum 2

- 3 days.” LABio Br. 10. However, the refe rences show use longer than hours or 2

- 3 days. The Porst reference shows clinical trials in which tadalafil was administered for three weeks to “men with mild t o mo derate erectile dysfunction.” The dosages were in theLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 7

range shown in claim 1. The P TAB considered this refe rence in combination with the references to Montorsi and Whitaker ; no error has been shown in this combination for the treatment of erectile dysfunction

. The PTAB’s decision accords with precedent

P recedent has dealt with a varie ty of f actual situ ations in which a purported new use or property has been discovered for a known product , and patentability is sought o n various premises

. In Bristol

- Myers Squibb Co. v. Ben Venue Lab oriatories , Inc. , 246 F.3d 1368 (Fed. Cir. 2001 )

, the court held that “[n] ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent ,” having observed that the claimed term “for reducing hematologic activity” “merely express [ed] a purpose” and is “no nlimiting.” Id. at 137 5 , 137 6.
Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 (Fed. Cir. 2012)

, involved a claim to a method comprising “stabilizing conjunctival mast cells by topically admini stering” olopatadine in a known composition

. Id. at 1364. The prior art described the known composition u sed as an antihistamine. Id. Th is court reversed the district court’s finding that a person would not have used the compos ition to stabilize mast cells because “a person of ordinary skill in the art at the time of the invention would have been motivated to use olopatadine to treat human eye allergies as claimed for its established antihistaminic efficacy.” Id. at 1369. A contrary result was r e ached in Allergan, Inc. v. Sandoz Inc. , 726 F.3d 1286 (Fed. Cir. 2013) , where the proposed claim was for “reducing the number of daily topical ophthalmic doses.” Id. at 1289. T he court held that the enhanced efficacy was not taught in or suggested in the prior art or inher ent in the prior dosage regimen, Id. at 1294, and allowed claims to the multiple daily do ses. In Alcon Research

, the court allo wed claims to aLOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 8

specific high concentration of a known product for trea tment of allergic eye disease, finding that the prior art only taught lower concentration s , and that the higher conce ntrat i on would not be obvious to try. Id. at 1370. And in Rapoport v. Dement , 254 F.3d 1053 (Fed. Cir. 2001) , the court upheld claims to t he use of a known product to treat sleep apnea, holding that the prior use to treat anxiety “did not address treatment of the underlying sleep apnea disorder” because the sleep apnea treatment was not inherent in the prior art’s anxiety treatment. Id. at 106 0

, 1062

– 63

. While LABio states that Allergan and Rapoport support its position, each of those cases relies on facts missing here

. Precedent thus illustrates that the later discovery of a new and unobvious use of a known product may be p atentable when the standards of unobviousness are met. Here, however, penile fibrosis was known in the prior art to be a mechanism of causing erectile dysfunction. A person of ordinary skill would, as the PTAB found, use the claimed compounds at the claim ed doses for the claimed duration, for the purpose of treating erectile dysfunction in patients with penile fibrosis

. The PTAB’s findings are supported by substantial evidence, and its conclusions based thereon are in accordance with law. See Alcon Resea rch , 687 F.3d at 1369 (“ Given that the patent defines, and expressly claims, olopatadine conce ntrations that are ‘ therapeutically effective ’ to stabilize conjunctival mast cells, Kamei ’ s disclosure of overlapping concentrations, even if for a different pur pose, meets these claim limitations. ”). The PTAB’s decision should be affirmed.
Finality and the America Invents Act
I respectfully dissent from my colleagues’ judgment of vacatur and remand, for such further proceedings fail the policy and purpose of the America Invents Act, and should be invoked only when there are major defects in the PTABLOS ANGELES BIOMEDICAL v. ELI LILLY AND COMPAN Y 9

proceeding, requiring activi ty and redetermination that is not avai lable on the appellate record.
The court at its footnote 9 takes issue with my pos ition that our appellate obligation is to decide the appeal on the record on which the appeal reaches us. The court states that if an aspect is insufficiently established in the PTAB proceeding, our appellate role is to remand, despite the usual protocol that when sufficient basis has not been provided to support a necessary ruling, the side with the burden of establishing that position, loses. When, as here, the dispositive facts are not in dispute, it is not customary to authorize the deficient party to return to the trial tribunal to try again.
The America Invents Act adds rigor to this protocol, for the AIA created an expedited administrative proc edure with strict time limits. Within these time limits, the parties must present their case and the PTAB must make its decision. It negates a foundation of the AIA for the appellate tribunal simply to remand for further procee dings after t he statutory deadline. Our obligation is to decide the appeal as it reaches us.
According to the majority, the Board did not find that the prior art taught “long

- term administration (i) to an individual with penile fibrosis (ii) in an effective amount
to arrest or regress the fibrosis.” Maj. Op. at 25 n.7

, 31. Respectfully, the majority is incorrect, because the Board expressly found that the Whitaker reference taught long

term administration to patients with erectile dysfunction, and the Board expressly found that in some of those patients erectile dysfunction is caused by penile fibrosis. It is not necessary to return to the Board to find whether the prior art administered “an effective amount to arrest or regress the fibrosis,” id

. at 25 n.7 , because LABiomed has conceded that it does; that is the basis for its litig ation position.LOS ANGELES BIOMEDIC AL v. ELI LILLY AND COMPAN Y 10

Our obligation is to review the rulings of law and fact on the record presented. On this record, preponderant evidence is on the side of obviousness. Thus the decision in this IPR proceeding should be affirmed, not vacated and remanded.

The America Invents Act was enacted to remedy the lack of expedition and to add predictability in infring ement disputes, by assigning to an expert administrative tribunal and presumed expert federal court the resolution of some major patentability issues , with tight procedural rules and deadlines

. It was expected that in the normal course questions of patentability under Section 102 and 103 would be reliably and speedily resolved. Implemen ting this policy

, when we find analytic lapses by the PTAB

, it appears that the statu t e contemplates that we will make the determination

, on the record that was made at the Board. Indeed, the depth of briefing by the parties suggests that this was their understanding, too.

I don’t say that remands are never appropriate, but remand s should be rare . Here the issues w ere fully developed, wit h eloquent argu m ent all around, and a n extensive Board opinion in which my colleagues find only slight gaps . F inality is available ; it is our ob ligation to decide the merits.