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Los Angeles Biomedical Research Institute at Harbor-Ucla Medical Center v. Eli Lilly and Co.

United States Court of Appeals, Federal Circuit

February 28, 2017


         Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board, in No. IPR2014-00752.

          Ewa M. Davison, Fenwick & West LLP, Seattle, WA, argued for appellant. Also represented by David Keith Tellekson, Elizabeth B. Hagan; Virginia Kay DeMarchi, Amy Hayden, Mountain View, CA.

          Mark J. Feldstein, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, argued for appellee. Also represented by Joshua Goldberg, Yieyie Yang; Charles E. Lipsey, Reston, VA; Mark Stewart, Eli Lilly and Company, Indianapolis, IN.

          Before Newman, Bryson, and Moore, Circuit Judges.


          Bryson, 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 holding 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.



         The '903 patent claims a method of "arresting or regressing" a condition known as penile fibrosis. The method entails the long-term, daily administration of drugs known as type 5 phosphodiesterase ("PDE5") inhibitors. The drugs function by inhibiting the enzymatic action of PDE5, 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 cavernosa. Those chambers fill with blood during an erection. The corpora cavernosa are surrounded by a membrane called the tunica albuginea. Penile fibrosis 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 corporal 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.

          The two fibrotic conditions can cause erectile dysfunction, 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 tissue fibrosis, which results from the death of smooth muscle cells in the corpora cavernosa and a corresponding buildup of collagen, 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 cavernosa. The flow of blood into the corpora cavernosa in turn compresses the veins of the penis against the tunica albuginea to block the flow of blood from 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 causes of erectile dysfunction, such as those of psychological origin, are entirely unrelated to fibrosis.

         In the early 2000s, PDE5 inhibitors such as sildenafil (Viagra) and tadalafil (Cialis) were well known and commonly 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. Individuals 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 explains, 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.

         At that time, according to the patent, there was a need for adequate non-surgical treatments 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). Erectile dysfunction resulting from those conditions could be treated symptomatically 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. 44-46.

         The '903 patent, owned by LAB, claims such a treatment. Claim 1, the only independent claim, recites:

         1. A method comprising:

a) administering a cyclic guanosine 3', 5'-monophosphate (cGMP) type 5 phos-phodiesterase (PDE5) inhibitor according to a continuous long-term regimen to an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis; and
b) arresting or regressing the at least one of the penile tunical fibrosis and corporal 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. 23-32.

         The remaining four claims depend from claim 1 and concern the type of drug (claim 2), the type of fibrotic condition (claim 3), the mode of administration (claim 4), and the duration of treatment (claim 5). Id., col. 68, ll. 33-45.[1]


         In 2013, 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 infringement 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 contended 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) ("Montorsi"); International Patent Application No. WO 01/80860 (published Nov. 1, 2001) (John S. Whitaker et al., applicants) ("Whitaker"); and Hartmut Porst et al., Daily IC351 Treatment of ED, 12 Int'l J. Impotence Research (Supp. 3) S76, B13 (2000) ("Porst").[2]

          The '903 patent claims priority from Provisional Application 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 determined 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 inhibitor 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 construed the phrase "an individual with at least one of penile tunical fibrosis and corporal tissue fibrosis" to mean 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 fibrosis or corporal tissue fibrosis."

         Second, the Board construed the phrase "arresting 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 of up to 1.5 mg/kg/day for at least 45 days.

         Third, in the Decision on Institution, the Board construed 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 therapeutically effective." In its final decision, the Board concluded 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."

         The Board then addressed the three prior art references: Montorsi, Whitaker, and Porst.

         Montorsi is a review article that addresses the treatment of erectile dysfunction in the aging male population. Montorsi states that male erectile dysfunction is associated with aging; that atherosclerosis (the buildup of plaque in the arteries) is common in the elderly; and that atherosclerosis is associated with CVOD and corporal fibrosis, which can cause erectile dysfunction. Montorsi at 28, 30-31. Montorsi concludes that "it seems reasonable to hypothesise that the [erectile dysfunction] from ageing is the result of atherosclerosis-induced cavernosal ischaemia leading to cavernosal fibrosis and [CVOD]." Id. at 31.

         Montorsi discusses several relevant studies of erectile dysfunction. It begins 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 concludes that this study "opened the door to further study investigating the possible dosage of sildenafil to be administered daily at bedtime to prevent or treat [erectile dysfunction] in the elderly patient." Montorsi at 31.

         Whitaker is an abandoned patent application that claims the chronic use of low-dose PDE5 inhibitors to treat erectile dysfunction. Whitaker defines "chronic" as "the regular administration of the [PDE5 inhibitor] in intervals unrelated to the onset of sexual activity, " and states 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 dysfunction (in the absence of therapy)." Whitaker at 7. Whitaker defines "daily" as "administration of the [PDE5 inhibitor] one or more times, generally one to three times, still more preferably one time, per about 24-hour period." Id.

         Example 6 of Whitaker combines data from five clinical studies to show that chronic administration of low doses (5 mg or 10 mg) of tadalafil improved erectile function in a population of patients with male erectile dysfunction. 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 administered '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 notes "a trend toward better response with increased frequency of dose." Id. at 36 (referring to results showing better erectile 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 demonstrated by low daily dosing of a PDE5 inhibitor in treating erectile dysfunction . . . results from improved vascular responsiveness when the PDE5 inhibitor is present continuously, or essentially continuously, in plasma." Whitaker at 12. Whitaker terms that effect "vascular conditioning, " an effect that had 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 concludes 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 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 posits: "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 function.

         The Board found that Montorsi and Whitaker taught 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 taught 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 taught that long-term treatment with a PDE5 inhibitor can cause reversal of circulatory dysfunctions caused by diabetes, atherosclerosis, smoking, hypertension, or a combination of such factors.

         The Board further found that the three references together taught daily dosing 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 taught dosing of up to 100 mg of sildenafil per day. According to the '903 patent, col. 45, ll. 7-12, a dosage of 100 mg per day is roughly equivalent to 1.5 mg/kg for an average weight adult male. Although the Board acknowledged that Whitaker's Example 6 did not specifically disclose dosing every day, it noted that Whitaker taught that better results are obtained with increased frequency of dosing, that adverse effects are attenuated with daily administration, and that treatment should continue for as long as the erectile dysfunction persists. Finally, the 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 synthase ("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 of 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.

         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' provisional application, (2) in construing 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 beliefs in the field and the unexpected results achieved by the inventors.



         In order for a patent to be entitled to priority based on an earlier application or chain of applications, each previous 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 requirement, the disclosure in each application must "reasonably convey[]" to those skilled in the art that as 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-claimed invention obvious . . .; the disclosure must describe the claimed invention with all its limitations." Tronzo v. Biomet, Inc., 156 F.3d 1154, 1158 (Fed. Cir. 1998).

         In this case, the inventors filed a provisional application in October 2002 to which the '903 patent claims priority. Lilly argues on appeal that the three prior art references were published before the provisional application was filed and are thus prior art under 35 U.S.C. § 102(a) even with the priority date of October 2002. LAB 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 the question of Lilly's waiver, as we conclude 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, contends 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 in the art would be able to calculate the corresponding 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. Freireich, ...

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