Maker of Cialis Accused of Patent Infringement

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U.S. Patent No. 8,133,903 (“the ’903 patent”) was granted to Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (“LAB”) on March 13, 2012. That patent, directed to methods of using of phosphodiesterase (“PDE5”) inhibitors in the treatment of fibrotic diseases, has been the subject of drawn out litigation since the year after.

In 2013, LAB filed a complaint in the U.S. District Court for the Central District of California against Eli Lilly & Co. (“Lilly”), alleging that Lilly’s marketing of the drug Cialis induced infringement of the ’903 patent. Lilly then filed multiple petitions asking that the Patent Trial and Appeal Board (“PTAB”), the administrative appeals arm at the U.S. Patent & Trademark Office, conduct a review of the ’903 patent. In order for an invention to be patentable, it must be “novel” and “non-obvious” in light of what came before it (“prior art”). Lilly’s contention was that all the claims of the ’903 patent were obvious in light of three prior art references, and therefore, invalid. The PTAB has the authority to review a U.S. patent, and invalidate it if it is found that the patent was erroneously issued. In the present case, the PTAB reviewed the ‘903 patent, and issued an order in favor of Lilly, invalidating all the claims of LAB’s patent.

In response, LAB appealed to the United States Court of Appeals for the Federal Circuit (the “Court”) for a review of the order. The Court issued two decisions on February 28, 2017, vacating (i.e. lifting) the PTAB’s order and remanding for further proceedings (sent back to the PTAB for a new trial). The decisions are discussed together here in combination for ease of description.

To understand this case, it is helpful to have some background on penile fibrosis. Since I am not a doctor, I will rely on the Court’s description in its decisions for the information, which reads as follows:

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 build up 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 caver-nosa. 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.

According to the Court, in the early 2000s, PDE5 inhibitors, such as Viagra and Cialis, were commonly used for the on-demand treatment of erectile dysfunction (“ED”). Patients with ED of varying causes were instructed to take PDE5 inhibitors before sexual activity in order to obtain an erection at the desired time. The use of such drugs for that purpose was not restricted to cases of erectile dysfunction resulting from penile fibrosis. The Court cited to a passage in the ’903 patent, which recites that use of “PDE5 inhibitors” was “not addressed to the long-term cure of underlying tissue fibrosis.” The ’903 patent, owned by LAB, is directed to such a treatment. Claim 1 of the patent recites:

A method comprising:

a) administering a cyclic guanosine 3’, 5’-monophosphate (cGMP) type 5 phosphodiesterase (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 PDE5 inhibitor is administered at a dosage up to 1.5 mg/kg/day for not less than 45 days.

The infringement trial appears to basically be on hold, while the PTAB reviews are completed. It is the job of the PTAB to determine whether the ‘903 patent is valid or invalid. In order to do so, the scope of the claims must be determined.  Once the proper scope is known, the claims must be compared to prior art to determine whether such prior art would render them non-novel or obvious. Here, the Court reviewed whether the PTAB made the proper decisions in holding:

(i) The patent claims to be novel (i.e. not anticipated by the Whitaker reference), and

(ii) The patent claims to be obvious in view of Whitaker and two other references, thereby invalidating the ‘903 patent.

Below highlights some of the points made in the Court’s decisions, but is not meant to be a full synopsis or complete summary.  A link to each decision is provided in the text for your convenience if you’d like to explore further.

A. Anticipation

A claim is not patentable if a prior art reference “anticipates” the claim. Anticipation requires a showing that each and every element of the claim is described in the reference.  The Court stated the standard for anticipation:

“To anticipate a claim, a prior art reference must disclose every limitation of the claimed invention, either expressly or inherently.” Rapoport v. Dement, 254 F.3d 1053, 1057 (Fed. Cir. 2001). “In the context of anticipation, the question is not whether a prior art reference ‘suggests’ the claimed subject matter[;] … [r]ather, the dispositive question regarding anticipation is whether one skilled in the art would reasonably understand or infer from a prior art reference that every claim element is disclosed in that reference.” AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1055 (Fed. Cir. 2010) (internal brackets and quotation marks omitted).

Lilly argued that the ‘903 patent is invalid because International Patent Application No. WO 01/80860 (published Nov. 1, 2001) (John S. Whitaker et al., applicants) (“Whitaker”) anticipates the claims of the patent. The Court states that Lilly’s argument boils down to saying that Whitaker’s definition of “chronic administration” anticipates the ‘903 patent’s daily administration for 45 days or more [look above at (b) in the claim] because a person of skill would understand that ED (in the absence of therapy) can last longer than 45 days. The Court, in its decisions, agreed with the PTAB quoting, that, “at best, is an obviousness argument.” Whitaker’s definition of “chronic administration,” which is “regular administration for an extended period, preferably daily for three or more days, and still more preferably daily as long as the patient suffers from erectile dysfunction (in the absence of therapy),” does not expressly teach daily treatment for at least 45 days. Accordingly, the Court affirmed (upheld) the PTAB’s decision that Whitaker does not anticipate the claims of the ‘903 patent.  To review the Court’s anticipation decision, click here.

B. Obviousness

A claim is obvious if a combination of references discloses each and every element of a claim, and there is shown a motivation to combine those references.  To make this determination, the scope of the claims must be decided, and then compared to the content of the references.

  1. Establishing Claim Scope

The first step that the Court took in the obviousness examination was to establish proper claim scope – proper construction/interpretation of the language of the claims. This is important because the language of the claim defines what a patent owner actually owns. There are three disputed interpretations in this case, which we’ll go through one by one.

The first issue relates to the following language from the claim:

…an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis… [see (b) in the claim above]

The issue is whether this language requires the treated individual have symptoms of such fibrosis or actually have been diagnosed with such fibrosis. The PTAB interpreted the phrase as requiring only symptoms. The Court however disagreed “…because erectile dysfunction can have causes other than penile fibrosis, and because penile fibrosis does not necessarily result in erectile dysfunction.” In other words, as the Court further explains in its decisions, “[t]he patent makes clear that penile fibrosis and erectile dysfunction are not the same thing and do not necessarily accompany one another.” The Court goes on to say that the patented invention targets the treatment of fibrosis, regardless of whether the fibrosis causes ED in a particular case. Accordingly, the Court found that a diagnosis is required, rather than just associated symptoms.

The second issue relates to the following language of the claim:

…arresting or regressing the at least one of the penile tunical fibrosis and corporal tissue fibrosis… [see (b) in the claim above]

The issue is whether such language is a limiting element of the claim or, instead, only an “intended result.” Intended result language carries no weight when interpreting a claim – it is essentially ignored. The Court went through some claim construction rules (which is beyond the scope of our discussion here), and held that the element was in fact limiting, and should be included when interpreting the claims. Therefore, the Court held that the language should not be ignored when reading the claim.

The third issue relates to the following language of the claim:

…administering a cyclic guanosine 3’, 5’-monophosphate (cGMP) type 5 phosphodiesterase (PDE5) inhibitor according to a continuous long-term regimen… [see (a) in the claim above]

The PTAB interpreted 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.” The PTAB 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.” LAB argued that the term “continuous long-term regimen” adds a requirement that the drug concentration in the patient’s body attain a “constant level,” i.e., maintain a “steady state” plasma concentration. The Court, however, explains that the ‘903 patent never mentions the “steady state” of a drug or other agent. As for “constant level,” LAB points to a single sentence in the ‘903 patent (col. 10, ll. 59-67) that states:

A distinction exists between long-term (weeks, months, years) continuous treatment with, for example, a PDE5 inhibitor such as sildenafil 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, shortterm treatment with sildenafil or other PDE5 inhibitors to obtain smooth muscle vasodilation in the penis (male penile erection) or vagina/clitoris (female sexual arousal) upon sexual stimulation.

The Court explains that in that passage, the term “constant level” is not presented as a definition of “continuous long-term regimen,” or its equivalent. Further, the Court explains that the passage simply confirms that long-term continuous PDE5 inhibitor treatment excludes an “on demand . . . single pill, short-term treatment”; the passage does not exclude any treatment that fails to maintain an unvarying level of the drug within the patient’s body.

LAB argued that the Board’s construction impermissibly 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.” The Court held that “[w]hile the two limitations clearly overlap, the more general reference to a ‘continuous 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 unsupported construction of the claims.”

  1. Compare the Claim Scope to the Prior Art

The Court reversed the PTAB’s decision holding that the claims of the ‘903 patent were obvious, and therefore, invalid in view of three prior art references. The Court’s decision stated the standard for an obviousness analysis:

Determining 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 claims, 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 combination 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 “reasonable expectation of success” in pursuing that combination, see Genzyme Therapeutic Prods. Ltd. P’ship v. Biomarin Pharm. Inc., 825 F.3d 1360, 1373 (Fed. Cir. 2016).

The cited prior art references were:

(i) Francesco Montorsi et al., The Ageing Male and Erectile Dysfunction, 20 World J. Urology 28-53 (2002) (“Montorsi”);

(ii) International Patent Application No. WO 01/80860 (published Nov. 1, 2001) (John S. Whitaker et al., applicants) (“Whitaker”); and

(iii) Hartmut Porst et al., Daily IC351 Treatment of ED, 12 Int’l J. Impotence Research (Supp. 3) S76, B13 (2000) (“Porst”).

The PTAB had found the claims, as constructed, to be obvious in light of Montori, Whitaker, and Porst. The PTAB found that Montorsi and Whitaker taught the treatment of ED, 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. The Court disagreed with the PTAB on both of these conclusions.

The Court held that the PTAB’s obviousness determination was predicated on an erroneous claim construction of two of the limitations of claim 1, as discussed here above. The Court also held that the PTAB did not make factual findings as to whether there was an apparent reason to combine the prior art references to treat penile fibrosis and whether a person of skill in the art would have had a reasonable expectation of success from such a combination. The Court remanded to the PTAB for a new trial on those issues, as well as to make findings bearing on the obviousness of the “arresting or regressing” limitation. To read the full text of the Court’s obviousness decision, click here.

The PTAB will have to review the ‘903 patent again relating to the obviousness question in light of the claim construction set forth by the Court.  In the meantime, the infringement litigation at the California District Court will likely remain on hold.  Patent infringement battles can be long and costly – An instance where big isn’t always better.  This case is most certainly no exception.

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