Abstract
In a 2023 Holman Report, I reviewed case law supporting the proposition that it is not necessary for a patentee to disclose proof of safety and/or efficacy in order to satisfy the requirements of patentability (and in particular the enablement requirement) for claims directed toward drugs or methods of using drugs, at least when the claim does not recite safety and/or efficacy as a limitation. 1 That article was prompted by the Federal Circuit’s 2023 decision in United Therapeutics v. Liquidia, which reaffirmed the court’s long-standing position that proof of safety and efficacy is a matter for the Food and Drug Administration (FDA), not the Patent and Trademark Office (PTO). 2
This installment of the Holman Report focuses a somewhat related topic, i.e., the question of whether a recitation of safety and/or efficacy in a patent claim directed toward a method of using a drug can serve as a limitation that distinguishes the claimed method over prior art that otherwise discloses the method, e.g., the design of a clinical trial, but that does not disclose that the method was shown to be safe and/or effective. In a recent Federal Circuit decision, Bayer Pharma Aktiengesellschaft v. Mylan Pharms. Inc., the court affirmed a decision by the Patent Trial and Appeal Board, which answered the above question in the negative. 3 The claims at issue recited not only specific drugs, dosages, and methods of administration but also recited that the drugs and dosages had been “clinically proven effective.” The prior art described a clinical trial that embodied the claimed method, but did not report the results of the clinical trial, and thus did not explicitly disclose that the claimed dosages of drugs had been “clinically proven effective.” In an inter partes review (IPR) of the claims, the Board found that the term “clinically proven effective” was not limiting because it was redundant with the explicit recitation of drugs and dosages, and thus did not serve to distinguish over the prior art. In the alternative, the Board held that if “clinically proven effective” was treated as a limitation, it was inherent in the prior-art disclosure of the clinical trial. 4 On appeal, the Federal Circuit affirmed, but on a somewhat different basis, holding that the term “clinically proven effective” was non-limiting because it lacked a functional relationship with the rest of the claimed method. In basing its decision on a lack of “functional relationship,” the court implicitly invokes case law arising out of the “printed matter doctrine,” which was itself the subject of a 2018 Holman Report. 5
In Bayer, the Federal Circuit sought to distinguish its holding from the court’s 2019 decision in Allergan Sales, LLC v. Sandoz, Inc. 6 In that case, the court held that recitations of safety and efficacy in a method-of-treatment claim were limiting, and thus material to patentability, rendering the claim not anticipated by prior art that did not disclose the recited safety and efficacy, but otherwise disclosed the claimed method. Although the Bayer court distinguished the facts of that case over those in Allergan, it is notable that the court did not overrule or even question the holding in that earlier decision. As discussed later in this article, the Bayer court’s explanation for the distinction between the claims at issue in Bayer and Allergan seems to be based more on the manner in which the claims were drafted, as opposed to the substance of the claimed methods.
The question of whether a recitation of clinical proof of safety and/or efficacy in a patent claim is limiting, and thus material to patentability, is of substantial practical significance. Pharmaceutical innovators generally try to file patent applications directed toward FDA-approved methods of treatment prior to the publication of the parameters of a clinical trial that will be used to establish the required proof of safety and efficacy. If a description of the parameters of a clinical trial is published prior to the filing of a patent application claiming a method of treatment that was the subject of that clinical trial, then that publication can serve as anticipatory prior art that renders the claims invalid. As the court ultimately held in Bayer, this prior art can anticipate the claims even if the prior art does not disclose the clinical results, which establish the safety and/or efficacy of the method. If a recitation of clinical proof of safety and/or effectiveness in a patent claim directed toward a method is given patentable weight, this can serve to distinguish the claimed method over the prior art that discloses the parameters of the method, but not the proof of safety/efficacy. This is what Bayer attempted to do, and it succeeded in getting the patent issued, but ultimately succumbed to the IPR. Although Bayer failed, the question remains whether the approach might succeed with different facts, or a different claim drafting strategy. As discussed in this article, Allergan suggests that even after Bayer it might still be possible, at least under some circumstances, for a pharmaceutical innovator to succeed in overcoming a prior art-based rejection based on a recitation of proven clinical safety and/or efficacy that is not disclosed in the prior art.
The article begins by reviewing some Federal Circuit case law of particular relevance to Bayer, including Allergan. It then takes a deep dive into Bayer, looking at Bayer’s patent, the Board’s IPR decision, the parties’ briefs filed with the Federal Circuit, and the Federal Circuit’s decision. The article concludes with a discussion of the implications of Bayer, and some thoughts on where things currently stand.
SOME RELEVANT FEDERAL CIRCUIT CASE LAW
Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc.
In Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc. (BMS), the patents at issue were directed toward methods of administering the antitumor drug paclitaxel. 7 A representative claim from one of the patents recited:
A method for reducing hematologic toxicity in a cancer patient undergoing [t]axol treatment comprising parenterally administering to said patient an antineoplastically effective amount of about 135–175 mg/m2 taxol over a period of about three hours. 8
In construing the claims, the district court held that the phrase “antineoplastically effective amount” was inseparable from the specific concentrations described in the claims and only stated the purpose of the invention comprising the stated method steps. 9 The court then granted summary judgment that the claims were invalid as anticipated by a prior art article (“Kris”), which described the treatment of patients with three-hour infusions of paclitaxel within the claimed dosage ranges, but observed no antitumor response.
On appeal, the patent owner (BMS) argued that “antineoplastically effective amount” is limiting because it was added to the claims by amendment to distinguish over the prior art, and that the phrase distinguishes the claimed process over Kris, which did not show usefulness for treating cancer in three-hour paclitaxel infusions. The defendants responded that “antineoplastically effective amount” merely states the intended result of the claim and is non-limiting, pointing out that the phrase “antineoplastically effective amount” was not required by the Examiner to distinguish over the prior art, and that, in fact, BMS had voluntarily added the phrase to the claims after the Examiner had already found them to be allowable. They further argued that the claimed method and the prior art method were both directed to that same use—treating cancer—and that BMS’s sole contribution was recognizing a new result of that same use, i.e., that it worked to treat cancer.
The Federal Circuit affirmed the district court’s interpretation of “antineoplastically effective amount,” holding that it was nothing more than a non-limiting expression of intended result that essentially duplicates the dosage amounts recited in the claims, particularly given that the patent described these amounts as being “antineoplastically effective.” In particular, the specification states that “[it has] been surprisingly discovered that lower taxol dosages, such as about 135 mg/m2 can be administered via infusions lasting about 3 hours to about 28 hours, and still be antineoplastically effective.” The court found that while the express dosage amounts recited in the claims are material claim limitations, the statement of the intended result of administering those amounts did not change those amounts or otherwise limit the claim.
The court also agreed with the defendants that it was significant that the amendment adding “antineoplastically effective amount” was voluntarily made after the Examiner had already indicated to BMS that the claims were allowable and held that such “unsolicited assertions of patentability made during prosecution do not create a material claim limitation where we have determined that the language does not create one.”
As to BMS’s argument that new uses of old processes are patentable, and that expressions of efficacy should be treated as limitations because they distinguish the new use of the process over the prior art, the court acknowledged that new uses of known processes may be patentable but found the processes recited in the claims at issue were not directed to a new use, but rather to the same use as described by Kris, consisting of the same steps. The court observed that “[n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” 10
In re Montgomery
In In re Montgomery, the claims at issue were directed toward the administration of a renin-angiotensin system (“RAS”) inhibitor, e.g., ramipril, to patients diagnosed as in need of stroke treatment or prevention. 11 The three claims at issue recited:
42. A method for the treatment or prevention of stroke or its recurrence, wherein said method comprises administering, to a patient diagnosed as in need of such treatment or prevention, an inhibitor of the rennin-angiotensin system, said inhibitor having a Clog P of greater than about 1.
43. The method as claimed in claim 42, wherein the inhibitor of the rennin-angiotensin system comprises at least one inhibitor of angiotensin-converting enzyme.
45. The method as claimed in claim 43, wherein the inhibitor of angiotensin-converting enzyme comprises ramipril.
During the examination of Montgomery’s patent application, the Examiner rejected the claims as anticipated by each of four prior art references, all of which describe the administration of ramipril to subjects at risk of stroke. One of those references, referred to as Heart Outcomes Prevention Evaluation (HOPE), describes the design of “a large, simple randomized trial of … ramipril … and vitamin E … in the prevention of myocardial infarction, stroke, or cardiovascular death,” which recruited “[o]ver 9000 [patients] at high risk for cardiovascular events such as myocardial infarction and stroke.” HOPE discloses that at the time of its publication, all 9,541 patients had been randomized and had been receiving ramipril or a placebo for at least one month. The HOPE study ultimately found that patients receiving ramipril had a statistically significant reduction in the risk of stroke, but these results were not published until after Montgomery’s priority date.
On appeal, the Board affirmed the Examiner’s rejection of all three claims as anticipated by each of the asserted prior art references. The Board found that claim 42 recited two elements: (1) “to administer an inhibitor of the rennin-angiotensin system” and (2) “the patient population receiving the inhibitor … encompasses patients diagnosed as required stroke treatment or prevention.” The Board explained that each reference teaches administration of ramipril to stroke-prone patients, and that “the HOPE study was clearly enabled to treat patients, including patients with previous stroke, with ramipril.”
While the Board did not rule directly on whether the claims required that the administration be effective at treating or preventing stroke, it appeared to assume that they did include such a requirement. In particular, the Board rejected Montgomery’s argument that none of the references demonstrated that ramipril actually treats or prevents stroke, noting that ramipril inherently treats or prevents stroke, and “it matters not that those of ordinary skill heretofore may not have recognized these inherent characteristics.”
On appeal, the Federal Circuit concluded that HOPE discloses both of the contested elements of the claims, i.e., the administration of ramipril (1) “to a patient diagnosed as in need of [stroke] treatment or prevention,” (2) where such administration is “for the treatment or prevention of stroke or its recurrence,” and that it was thus unnecessary to address the other prior art. The court found that the Board had implicitly assumed that the “for the treatment or prevention of stroke or its recurrence” language in the claim preamble was limiting and that this limitation created an efficacy requirement. Although the court expressed skepticism as to whether a proper interpretation of the claims would include any requirement of efficacy, particularly given that in the context of patent examination claims are given their broadest reasonable interpretation, 12 the court found that it need not resolve this question because even if one were to assume that the claims include an efficacy requirement, efficacy is inherent in carrying out the steps of the claims. The court found that there was no question that treating stroke-prone patients with ramipril does in fact inevitably treat or prevent stroke and that it was well established that “[n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” 13 In particular, HOPE discloses a protocol for the administration of ramipril to stroke-prone patients, and administering ramipril to stroke-prone patients inevitably treats or prevents stroke. Thus, HOPE inherently anticipates the claims at issue, even if the claims are interpreted as including an efficacy limitation.
In Re Copaxone
In In Re Copaxone Consol. Cases, 14 the patents at issue were directed to methods of using COPAXONE® 40 mg/mL to treat relapsing-remitting multiple sclerosis (“RRMS”). The active ingredient in COPAXONE® 40 mg/mL is glatiramer acetate (“GA”), a synthetic mixture of polypeptides. Some of the patent claims at issue recited the following terms: (1) “the regimen being sufficient to alleviate the symptom of the patient,” i.e., the “sufficiency” term; (2) “which reduces brain atrophy and for reducing the frequency of relapses by 30% or more as compared to placebo in a human population,” i.e., the “reducing the frequency of relapses” term; and (3) “which is as effective as administration of 20 mg of glatiramer acetate s.c. daily,” i.e., the “effectiveness terms.” The district court found these terms to be “strikingly similar” to those appearing in the patents at issue in BMS and construed all three of the terms to be non-limiting statements of intended effect. The district court then concluded that all of the claims at issue were invalid for obviousness in view of prior art disclosing clinical trials involving the use of glatiramer acetate.
On appeal, the Federal Circuit agreed that there was no meaningful difference between the BMS claims and those at issue in In re Copoxane, explaining:
The phrase “the regimen being sufficient to reduce the frequency of relapses in the patient” does not change the express dosing amount or method already disclosed in the claims, or otherwise result in a manipulative difference in the steps of the claims. The claims are clear that the dosing has to be “therapeutically effective regimen”; the addition of “the regimen being sufficient to” be therapeutically effective is superfluous, does not change the claimed method or require any additional required structure or condition for the claims, and is therefore non-limiting. 15
Teva argued that the “sufficiency” terms were limiting because they were added during prosecution to overcome rejections. However, the Federal Circuit found that in fact the addition by amendment of the “regimen being sufficient …” term to the claims was neither necessary nor relevant to the Examiner’s allowance of the claims. The court went on to conclude that the district court had not erred in invalidating all asserted claims of the Copaxone patents as obvious.
Allergan Sales, LLC v. Sandoz, Inc.
In Allergan Sales, LLC v. Sandoz, Inc., the claims at issue recite a method of treatment comprising administering specific doses of two ophthalmic drugs “wherein the method is as effective as” a prior-art method and “wherein the method reduces the incidence of one o[r] more adverse events” as compared to that prior-art method.6 The district court granted Allergan’s motion for preliminary injunction, finding that Allergan was likely to succeed on the merits in its patent infringement lawsuit filed against abbreviated new drug application (ANDA) applicant Sandoz. The court’s determination that Allergan was likely to succeed on the merits was based in part on its construction of the “wherein” clauses as limiting, from which the court concluded that the claims are not invalid in view of the prior art based on the holding of earlier decisions by the Federal Circuit involving patents in the same patent family. 16 In those decisions, the Federal Circuit held that analogous efficacy limitations recited in claims appearing in those closely related patents were limiting and neither suggested nor inherent in any prior art in the record.
In particular, in a 2013 decision involving related patents reciting a dose reduction “from 3 to 2 times a day without loss of efficacy” limitation. The court found that while it might be true that the mere administration of the recited dosages (i.e., 0.2% brimonidine and 0.5% timolol) twice daily in any fixed-combination formulation inherently produces the claimed result, it might be the case that only certain fixed-combination formulations produce this result. The evidence of record was insufficient to allow the court to draw a conclusion in favor of either proposition and as such failed to establish that the dose reduction “from 3 to 2 times a day without loss of efficacy” limitation is an inherent property or a necessary result of the administration of 0.2% brimonidine and 0.5% timolol in a single composition. 17
Subsequently, in an unpublished 2017 decision involving related patent claims, the court held that not only were the efficacy limitations not disclosed by any prior art reference in the record but, to the contrary, the prior art showed that the combination dosed twice daily produces a loss of efficacy in the afternoon. The court found that the record supported the district court’s finding that the efficacy limitations are not inherent in the administration of the recited ophthalmic composition. Accordingly, the scope of the claims at issue was limited to those administrations of the composition that satisfy the efficacy limitations. The efficacy limitation served to exclude from the scope of the claims methods of administering the recited composition that end up in, e.g., a loss of efficacy, examples of which, according to the court, “abound in the prior art.” 18
In its 2019 decision, the Federal Circuit again affirmed the district court’s finding of non-obviousness, holding that the wherein clauses of the claims at issue in those cases were likewise limiting and material to patentability. The court found that the patent specification demonstrated that the claimed invention “is ultimately a formulation (and methods of using that formulation) that allows for increased efficacy and safety, i.e., a decreased risk of adverse events,” and that the specification demonstrated that Allergan believed the increased efficacy and safety of the claimed methods to be material to patentability. Furthermore, the court found it significant that Allergan had relied on the efficacy and safety of the claimed methods during prosecution of the patents at issue when responding to the Examiner’s rejections. For example, in distinguishing the claimed methods over the prior art, Allergan explained that the prior art:
does nothing to teach or suggest that the claimed fixed combination of brimonidine tartrate and timolol maleate administered twice daily would be as effective as the administration of 0.2% w/v brimonidine tartrate monotherapy three times per day, nor that administration of the claimed fixed combination would cause an unexpected reduction in adverse events.
The court also found that the Examiner had explicitly relied on the “wherein” clauses in explaining why the claims at issue were novel and non-obvious over the prior art. The Examiner explained that the prior art was insufficient to teach the recited efficacy limitations and credited Allergan with having shown that the prior art “fail[ed] to teach the reduction in adverse events as compared to the administration of 0.2% w/v brimonidine tartrate monotherapy three times a day as claimed.” The prosecution history thus demonstrated that the formulation’s efficacy and safety—as reflected in the disputed “wherein” clauses—were expressly relied on to define the claimed methods and distinguish them from the prior art.
In distinguishing over BMS and Copoxane, the court pointed out that in BMS the court expressly noted that the disputed claim terms “w[ere] voluntarily made after the Examiner had already indicated … the claims were allowable” and such “unsolicited assertions of patentability made during prosecution do not create a material claim limitation.” As to Copaxone, the court held in that case that the disputed claim terms were not “necessary or relevant to the Examiner’s approval.” In contrast, in the present case, both Allergan and the Examiner explicitly relied on the “wherein” clauses to distinguish the claimed methods over the prior art during prosecution. The “wherein” clauses were neither unnecessary nor irrelevant but were instead material to the Examiner’s patentability determination.
BAYER v. MYLAN
U.S. Patent No. 10,828,310
The patent at issue in Bayer v. Mylan, U.S. Patent No. 10,828,310 (the ‘310 Patent) was granted on November 10, 2020, with a priority date of February 2, 2018. Representative claim 1 recites:
1. A method of reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral artery disease, comprising administering to the human patient rivaroxaban and aspirin in
The specification does not explicitly define “clinically proven effective,” but defines “effective” and “efficacy” as preferably referring to “a dosage determined by the U.S. FDA as acceptable for administration to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in [coronary artery disease (‘CAD’)] and/or [peripheral artery disease (‘PAD’)] patients.” The specification states that the findings presented in the ‘310 Patent were obtained from a phase III clinical trial [“the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial”] evaluating the efficacy and safety of rivaroxaban (Xarelto®) for the prevention of major adverse cardiac events including cardiovascular death, myocardial infarction, and stroke in patients with CAD or PAD. The specification further states the results are also reported in the New England Journal of Medicine in an article entitled, “Rivaroxaban with or without aspirin in stable cardiovascular disease.” FDA did not approve the regimen embodied by the claims until after the February 2018 priority date.
The Board’s decision
Several generic drug companies, including Mylan, filed petitions requesting IPR of claims 1–8 of the ‘310 Patent, and the cases were instituted and joined by the Board. 19 In its Institution Decision, the Board preliminarily construed the term “clinically proven effective” to mean “the amounts of aspirin and rivaroxaban in combination that have been clinically shown to reduce the risk of myocardial infarction, stroke, or cardiovascular death in patients with CAD and/or PAD.” However, in its Final Written Decision, dated July 28, 2023, the Board revised its preliminary construction and agreed with the Petitioner that the term “clinically proven effective” is in fact non-limiting. The Board concluded that a person of skill in the art (“POSA”) would have understood from a plain reading of the claims that the “amounts” of rivaroxaban and aspirin specifically recited in the claims are “clinically proven effective,” and that further identifying these amounts as “clinically proven effective” is redundant and unnecessary, in no way altering the method steps of administering the pharmaceutical as otherwise recited by these claims. 20
Turning to the specification, the Board noted that although it does not expressly define “clinically proven effective,” it repeatedly describes administering rivaroxaban and aspirin “in amounts that are clinically proven effective,” “wherein rivaroxaban is administered in an amount of 2.5 mg twice daily and aspirin is administered in an amount of 75–100 mg daily.” The Board also pointed out that the specification described the COMPASS study and its results, and that the results of this clinical trial were characterized as establishing the clinical efficacy of the recited combination of dosages.
In further support of its conclusion that the phrase “clinically proven effective” is non-limiting, the Board pointed to BMS as precedent on point. As described above, in BMS, the Federal Circuit held that the term “antineoplastically effective amount” was non-limiting because it did no more than express an intended result that “essentially duplicates the dosage amounts recited in the claims that are also described in the specification as ‘antineoplastically effective.’” The Board noted that in BMS, the court found that while the express dosage amounts are material claim limitations, the statement of the intended result of administering those amounts does not change those amounts or otherwise limit the claims.
The Board found that the claims of the ’310 Patent similarly recite the specific amounts of rivaroxaban and aspirin that are “clinically proven effective,” i.e., 2.5 mg rivaroxaban twice daily and 75–100 mg aspirin once daily.” But just as the patent specification in BMS taught that the claimed dosage amount was “antineoplastically effective,” the Board concluded that the ’310 Patent specification teaches that the claimed dosage amounts of rivaroxaban and aspirin are “clinically proven effective.” As such, like the term “antineoplastically effective” in BMS, the term “clinically proven effective” does not change those amounts or otherwise limit the claim. The Board agreed with Petitioner that “being subsequently proven clinically effective in COMPASS is at most simply a latent property of the prior-art method; nothing in the claimed method changes—no steps are added, subtracted, or modified for the prior-art patient—as a result of this knowledge.”
Bayer argued that it was significant that in a supplemental examination of the ’310 Patent, conducted at the behest of the patent owner, the Examiner gave patentable weight to the “clinically proven effective” limitation in maintaining the validity of the claims at issue. However, the Board gave that construction no weight, finding that the Examiner’s construction of the claims was inconsistent with Federal Circuit precedent, which the Examiner did not consider in his analysis.
Turning to the patentability challenges, the Board began by finding that claims 1 and 2 of the ’310 Patent were anticipated by a journal article (“Foley”) that discloses the COMPASS trial and describes it as studying the effects of rivaroxaban in patients with CAD or PAD. Foley states the COMPASS patients are randomized into one of three arms: (1) 2.5 mg rivaroxaban twice daily and aspirin (100 mg once daily); (2) 5 mg rivaroxaban twice daily and aspirin (same dosage); and (3) placebo twice daily and aspirin (same dosage). Foley notes that the COMPASS trial was ongoing and estimated to be completed in February 2018.
The Board found that Foley’s disclosure of the COMPASS clinical trial and its protocol of administering 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily to patients with CAD or PAD discloses each limitation of claims 1 and 2. It was presumed that a POSA would have understood that COMPASS’s study of preventing major cardiovascular events such as myocardial infarction, stroke, or cardiovascular death in CAD or PAD constitutes a method of reducing the risk of those events in human patients with CAD and/or PAD, as required by the claims’ preamble. The Board also found that Foley’s disclosure of administering 2.5 mg of rivaroxaban twice daily and 100 mg aspirin once daily discloses the step of “administering to the human patient rivaroxaban and aspirin in amounts that are clinically proven effective in reducing the risk of myocardial infarction, stroke, or cardiovascular death in a human patient with [CAD and/or PAD], wherein the rivaroxaban is administered in an amount of 2.5 mg twice daily and aspirin is administered in an amount of 75–100 mg daily.”
The Board explained that although it had determined that the term “clinically proven effective” was non-limiting, it would have found the claims anticipated even if it had given the term patentable weight. That is, even if the claims were construed in the manner that the patent owner advocated for, i.e., “clinically proven with data demonstrating a statistically significant difference in the efficacy observed between the regimen at issue compared to the standard of care,” the Board would have found that Foley inherently discloses the limitation. The Board held that the fact that the COMPASS study results may not yet have been published was irrelevant, as “[n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” 21 Foley clearly discloses the claimed dosage amounts, which read on the material claim limitations requiring 2.5 mg rivaroxaban twice daily and 75–100 mg aspirin daily. The fact that those amounts were not yet identified as “clinically proven effective” did not change the required dosage amounts or otherwise limit the claimed method.
The patent owner argued that a POSA would not have considered the results of a clinical trial to be inherent. Specifically, the patent owner asserted that “[n]umerous factors can impact whether a dosing regimen will be ‘clinically proven effective,’ including the inclusion and exclusion criteria for the patients to be studied, and the design and conduct of the study itself.” In other words, because the design of clinical trials can vary, the dosing regimen of rivaroxaban and aspirin disclosed in Foley would not necessarily be found to be “clinically proven effective.” The patent owner further argued that “there is nothing about the COMPASS protocol that makes clinical proof of efficacy ‘necessarily present’ and ‘recognized’ by the POSA.”
But the Board disagreed, stating that the question was not whether clinical trials may exist where the disclosed dosing regimen may not be clinically proven effective or whether a POSA would necessarily recognize clinical proof of efficacy from the COMPASS protocol taught by Foley. To the contrary, the question was whether “the [prior art] disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function.” 22 If so, Federal Circuit precedent dictates that the disclosure should be regarded as sufficient. 23
The Board found the disclosure in Foley to be sufficient to show that the natural result of the disclosed dosing regimen would be “clinically proven effective” by the COMPASS study disclosed by Foley, as confirmed by the results of the COMPASS study. 24 Accordingly, the Board found that even if the claim term were limiting, Foley inherently discloses “clinically proven effective” amounts of rivaroxaban and aspirin.
The Board went on to find that all of the claims at issue, i.e., claims 1–8, were obvious in view of Foley alone or the combination of Foley with another prior art reference, i.e., Plosker. In arriving at this conclusion, the Board found the Federal Circuit’s decision in Persion Pharmaceuticals LLC v. Alvogen Malta Operations Ltd. to be instructive. 25 In that case, the claims recited a method of treating pain in a patient having mild or moderate hepatic impairment, comprising administering an oral dosage unit comprising an extended-release formulation of hydrocodone bitartrate, wherein the dosage unit provides a specific pharmacokinetic release profile of hydrocodone. The district court determined the claims were invalid as obvious because a POSA would have been motivated to administer the extended-release hydrocodone formulation disclosed in an asserted Devane reference to patients with mild or moderate hepatic impairment, as taught by the other asserted prior art references. The district court held that “the pharmacokinetic limitations … are ‘inherent in any obviousness combination that contains the Devane formulation’ because the recited pharmacokinetic parameters were ‘necessarily present’ in the Zohydro ER [i.e., extended release hydrocodone] formulation described in both Devane and the asserted patents.”
On appeal, the Federal Circuit affirmed, noting that “[i]nherency may supply a missing claim limitation in an obviousness analysis.” The court also noted that “[i]t is long settled that in the context of obviousness, the ‘mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art.’” The patentee argued that the district court erred in applying inherency to its obviousness analysis because the “natural result flowing from the operation as taught” by Devane cannot be the claimed pharmacokinetic values for hepatically impaired patients because Devane does not teach administering its hydrocodone to hepatically impaired patients. The Federal Circuit rejected this argument, because “[t]here was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents-in-suit, necessarily exhibited the claimed parameters under these conditions.” Accordingly, the Federal Circuit held the district court did not err in finding the pharmacokinetic limitations of the asserted claims to be “inherent and added no patentable weight to the pharmacokinetic claims.”
The Board found the case for inherency in the case of the ‘310 Patent was even stronger than it was in Persion, because there was no need to combine multiple references to determine “the natural result flowing from the operation as taught” by Foley. Rather, Foley discloses a method including the exact dosing regimen, drugs, and patients described and claimed in the ’310 Patent. Thus, like the Zohydro ER formulation of Devane and the patents-in-suit in Persion, the Board found that the “natural result flowing from the operation as taught” in Foley is necessarily a finding of “clinically proven effective” amounts of rivaroxaban and aspirin. Thus, the court found that Foley alone or in combination with Plosker teaches or suggests each limitation of the claims at issue and a POSA would have had a reasonable expectation of success in reaching the claimed invention.
The parties’ appeal briefs
Bayer’s brief
In its Petitioner’s Brief to the Federal Circuit, Bayer argued that the Board’s conclusion that “clinically proven effective” was non-limiting was based on a misinterpretation of BMS. Bayer argued that while BMS found “antineoplastically effective amount” to be an “expression of intended result,” the term “clinically proven effective” cannot be an expression of intended result because administering the recited amounts of rivaroxaban and aspirin a single time could not provide clinical proof of efficacy, given that the amounts could not be “clinically proven effective” until an appropriately designed clinical trial has been performed in the relevant patient population and deemed to be successful. Bayer went on to argue that “clinically proven effective” requires that the clinical proof of efficacy has preceded administration of the rivaroxaban and aspirin, whereas an “intended result” is that which would follow the administration of rivaroxaban and aspirin.
Bayer argued further that a particularly relevant distinction between the two cases was that in BMS, the claims were amended to recite “antineoplastically effective amount” after the Examiner had already indicated they were allowable, whereas its claims recited “clinically proven effective” from the outset. Bayer argued that the court in BMS regarded “antineoplastically effective amount” to be mere “surplusage” because they were added after the claims were already deemed allowable. In contrast, according to Bayer, the PTO treated “clinically proven effective” to be a distinction over the COMPASS-related prior art presented during supplemental examination. 26
Finally, Bayer argued that it was significant that BMS found that the process claimed in that patent consisted of the same steps as described by the prior art and thus was not directed to a new use, while in the present case, the administration of the recited doses of rivaroxaban prior to the results from COMPASS was not administering doses that are “clinically proven effective,” even if they are numerically the same amounts.
Bayer characterized BMS as an outlier, a narrow exception to the ordinary rule of claim construction that “[i]t is highly disfavored to construe terms in a way that renders them void, meaningless, or superfluous.” 27 It identified in particular two Federal Circuit decisions that it considered to be more on point and representative of applicable precedent, Allergan Sales, LLC v. Sandoz, Inc. and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center v. Eli Lilly & Co. (“Eli Lilly”).
Of the two, Allergan was the most on point. As described above, the claims at issue in that case recited a method of treatment comprising administering specific doses of two ophthalmic drugs “wherein the method is as effective as” a prior-art method and “wherein the method reduces the incidence of one o[r] more adverse events” as compared to that prior method. The Federal Circuit held that these wherein clauses were limiting and “material to patentability.” In distinguishing BMS, the Allergan court found that the wherein clauses did more than “merely state the intended results of administering” the drug. Rather, the court concluded that the benefits recited in the wherein clauses, i.e., improved efficacy and safety relative to prior art ophthalmic treatments) were “described throughout the specification … as recited in the claims,” and that both the patentee and the Examiner had “expressly relied on” the wherein clauses “to define the claimed methods and distinguish them from the prior art.”
Bayer argued that, similarly, the ’310 patent specification repeatedly relies on the “clinically proven effective” language to describe the invention and made clear that the invention is premised on the results of COMPASS, which provided the clinical proof of efficacy of the rivaroxaban-plus-aspirin regimen. Furthermore, Bayer argued that it had expressly relied on the “clinically proven effective” term to define the claimed methods and distinguish them from the prior art,” particularly during supplemental examination. Bayer pointed to In re Copaxone Consolidated Cases as another example where the Federal Circuit held that the disputed claim terms were not “necessary or relevant to the Examiner’s approval” in finding certain claim language in that case to be non-limiting. 28
In Eli Lilly, the other decision that Bayer argued was applicable to the present case, the Federal Circuit found that the term “arresting or regressing” was limiting in the context of the claim phrase “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.” 29 The court found that “arresting or regressing” was a limitation because it “demands efficacy,” whereas the amounts recited in the claim on their face did not require efficacy. In addition, the court stated that it was “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 administration of the drug.” It held that the structure of the claim was “therefore not comparable to the structure of patent claims [such as BMS] in which statements of general purpose in the preambles of method claims have been held to carry no patentable weight.”
Bayer argued that the phrase “clinically proven effective” likewise “demands efficacy,” whereas the individual amounts of rivaroxaban and aspirin recited in the claims do not by themselves demand efficacy. Not only that, “clinically proven effective” requires more than just efficacy, but rather clinical proof of efficacy. Bayer further argued that, like the claims in Eli Lilly, the structure of its claim reflects that “clinically proven effective” is a limitation rather than a general statement of purpose. In particular, the phrase “clinically proven effective in reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral arterial disease” is part of a clause separate from the numerical amounts of rivaroxaban and aspirin recited in the claim.
In its petition, Bayer further argued that the Board’s alternate holding that “clinically proven effective” is inherent was legally flawed and unsupported by substantial evidence. In particular, Bayer argued that the Board had misapplied the legal standard for inherency when it held that the results of COMPASS demonstrating clinical proof of efficacy served as evidence that clinical proof of efficacy was the “natural result” of prior art disclosing the rivaroxaban-plus-aspirin dosing regimen used in the clinical study, but not the results of the study. Bayer argued that the fact that COMPASS turned out to provide clinical proof of efficacy did not mean that the “natural result” of the clinical trial for purposes of inherent anticipation was clinical proof of efficacy. Bayer pointed to King Pharms., Inc. v. Eon Labs, Inc. for the proposition that inherency requires that the prior art “must necessarily include the unstated limitation,” and that a prior art disclosure must “show that the natural result flowing from the operation as taught would result” in the missing limitation.
While Foley disclosed that COMPASS aimed to enroll 21,400 patients, the ’310 patent explains that COMPASS ultimately enrolled 27,395 patients—a 28% increase. Bayer argued that the Board erred by offering no analysis as to whether COMPASS would still have provided clinical proof of efficacy without the enrollment of such additional patients.
Bayer further argued that “there was no dispute between the experts” that the results of a clinical trial such as COMPASS are not inherent. For example, Bayer’s expert testified that numerous factors beyond a particular dosing regimen itself impact whether the dosing regimen will end up being clinically proven effective, ranging from the design and conduct of the study, including which patients are enrolled and how they are monitored throughout the trial, to the treatment regimens that are evaluated and the selection of the efficacy and safety outcomes. Mylan’s expert, according to Bayer, also admitted that the design of a clinical trial can affect whether a study will achieve its primary endpoint, “which is inconsistent with the idea that clinical proof of efficacy is the ‘natural result’ of the method of treatment being evaluated in a clinical trial such as COMPASS.”
Bayer also pointed to Sanofi v. Watson Laboratories Inc. as Federal Circuit precedent supporting the proposition that the results of a clinical trial are not inherent. 30 In that case, the rationale and design of a phase III clinical trial (ATHENA) were disclosed in the prior art, but the prior art did not disclose the results of the trial. 31 The question presented was whether (1) a method of decreasing the risk of cardiovascular hospitalization derived from the results of the ATHENA clinical trial by administering an “effective amount” of the study drug was patentable in light of (ii) the prior art disclosure of the ATHENA design and a prediction of success in the trial. The court concluded that the claimed method was non-obvious because there was no reasonable expectation of success or efficacy. Bayer argued that in Sanofi, not only were the claims held to be patentable but the notion that efficacy from a clinical trial was inherently disclosed by the prior art disclosure of the study design was not even raised. Nor was there any finding that the efficacy language was non-limiting.
Bayer also identified as relevant the Federal Circuit’s decision in Endo Pharms. Sols., Inc. v. Custopharm Inc., which disagreed with an assertion that a particular vehicle formulation was “necessarily present” in prior art references, even though it was later revealed to be the actual formulation the authors of those references used in their reported clinical studies. 32
Mylan’s brief
In its Response Brief, Mylan argued that the Board was correct in determining that “clinically proven effective” was non-limiting, asserting that Bayer had failed to identify any way in which the term affects the manner in which the claimed method is performed. Mylan cited Federal Circuit precedent for the proposition that additional knowledge of a user of a method does not change the patentability status of the method. 33 Mylan also argued that it was significant that the specification repeatedly identified the claimed dosage amounts of rivaroxaban and aspirin—2.5 mg twice daily and 75–100 mg daily, respectively—as amounts that are “clinically proven effective.” Furthermore, Mylan noted that that even if the Examiner gave patentable weight to “clinically proven effective” during the supplement examination, the Board had ultimately concluded that the Examiner’s findings had been “inconsistent with Federal Circuit precedent, which the Examiner did not consider in his analysis.”
In its brief, Mylan sought to rebut Bayer’s assertion that the facts of the present case can be distinguished over BMS. It pointed out that the prior art in BMS involved a Phase I trial that administered “three-hour infusions of 135 mg/m2 paclitaxel to three patients and 160 mg/m2 to four patients,” thereby “perform[ing] all of the claimed steps at dosage levels that anticipate those in the claims.” The prior art reference, however, “did not observe any anticancer effects” (i.e., did not achieve the intended result of antineoplastic effectiveness); nevertheless, the court found this omission to be immaterial for purposes of anticipation. Mylan also argued that Bayer had put undue weight on the fact that in BMS, the claims were amended to recite “antineoplastically effective amount” after the Examiner had already indicated they were allowable, arguing that the court’s non-limiting construction did not turn on the fact that the limitation was added after allowance. 34
Mylan also sought to distinguish over the facts of Allergan, Eli Lilly, and In re Copaxone. With respect to Allergan, Mylan pointed to some observations made in a concurring opinion filed by Judge Prost in that case. For example, the judge observed that the claim language at issue in that case “on its face confirm[ed] that [the “wherein”] clauses give meaning and purpose to the other manipulative steps of claim 1.” 35 In particular, she pointed out that the claims were written in open format, and as such, while the claimed treatment must include the two recited compositions (0.2% w/v brimonidine tartrate and 0.68% w/v timolol maleate), other compositions can be present in the formulation, such as solvents, buffers, and preservatives typical for ophthalmic solutions. But, she pointed out, there was nothing in the claims—or the rest of the intrinsic record for that matter—stating that any and all combinations of these two compositions will necessarily satisfy the ‘wherein’ clauses.” Thus, the “wherein” clauses served to further define the scope of formulations containing the two recited compositions by specifying safety and efficacy benchmarks the formulation must meet. In contrast to the claims in Allergan, Mylan argued that Bayer’s claims specify the exact dosages of rivaroxaban and aspirin to be administered to a patient (in a wherein clause), and that the term “clinically proven effective” provides no work to further define the dosages that are administered.
Turning to Eli Lilly, Mylan argued that the court in that case expressly distinguished cases like BMS, stating that “[b]ecause the [] patent claims specify only a maximum 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.’” 36
Mylan also argued that In re Copaxone actually confirms the applicability of BMS to the present case. There, the claims required the administration of “three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regimen being sufficient to alleviate the symptom of the patient.” The Federal Circuit affirmed the district court’s conclusion that the phrase “the regimen being sufficient to alleviate the symptom of the patient” was not limiting. In doing so, the court saw “no meaningful difference between the claims in [BMS] and those at issue here.” The phrase did “not change the express dosing amount or method already disclosed in the claims, or otherwise result in a manipulative difference in the steps of the claims.”
Mylan also argued that the Board was correct in its alternative holding of inherent anticipation and, in particular, its conclusion that the term “clinically proven effective” was inherent in Foley’s disclosure of the COMPASS trial. Mylan argued that although the COMPASS study confirmed the clinical efficacy of the claimed dosage regimen, it did not create the expected property of the regimen, which Mylan argued is necessarily present in the specific amounts tested—otherwise, the trial would have failed. Moreover, Mylan pointed to In re Montgomery as Federal Circuit precedent illustrating that a clinical trial can support a finding of inherency. 37
Mylan also disputed Bayer’s reliance on Endo and Sanofi in its attack on the Board’s inherency analysis. It argued that in Endo, while the prior art reference had disclosed using a composition comprising the claimed active ingredient, the actual formulation of the composition was not reported until after the patent’s priority date. In light of this fact, the Endo court found that the POSA did not “hav[e] access to that composition, thereby precluding use of the inherency doctrine to fill in disclosure about the product missing from” the reference. As to Sanofi, Mylan argued that the issue of inherency (or even whether efficacy language was non-limiting) was not addressed by the court in Sanofi.
Mylan further argued that Bayer was essentially seeking a per se rule whereby the results of a clinical trial automatically transform a prior art regimen studied in that trial into something novel and non-obvious later, after the results are published, and that such rule would be inappropriate:
Whether analyzing a claim term as non-limiting or inherent, the analysis involves consideration of numerous factors, including the claims’ language as a whole, the patent’s specification, and the prior art. To hold otherwise would permit patentees to do what Bayer tried to do here: dedicate a dosage regimen to the public and claw back that same regimen on the basis that statistically significant clinical results were obtained and disclosed to the public later. Patentability does not, and cannot, turn on clinical results alone. Compare Montgomery, 677 F.3d at 1382 (“It is well established that a patent may be secured, and typically is secured, before the conclusion of clinical trials.”), with Blue Br., 33-34 (asserting recited amounts “cannot be ‘clinically proven effective’ until an appropriately designed clinical trial has been performed in the relevant patient population and deemed to be successful”). Here, for whatever reason, Bayer chose to forgo patent coverage until long after the method was in the public domain. 38
The Federal Circuit’s decision
A unanimous panel of the Federal Circuit agreed with Mylan and the Board that the phrase “clinically proven effective” did not render the claims patentable over the prior art. However, the court based its decision on a somewhat different rationale than the Board.3 The court held that it did not need to decide whether “clinically proven effective” is limiting in view of its conclusion that, even if the phrase were limiting, “clinically proven effective” would still be a functionally unrelated limitation that fails to make the challenged claims patentable. The court cited King Pharmaceuticals, Inc. v. Eon Labs, Inc. for the proposition that a claim limitation must have a functional relationship with the claim in order to bear patentable weight. 39
In King, the Federal Circuit held that an otherwise anticipated method of treatment was not made patentable simply by adding a limitation of “informing the patient” about the benefits of the anticipated method. “[T]he relevant inquiry … [was] whether the additional instructional limitation … [had] a ‘new and unobvious functional relationship’ with the known method of [treatment].” 40 King explained that the rationale underlying this inquiry is “preventing the indefinite patenting of known products [and methods] by the simple inclusion of novel, yet functionally unrelated limitations.” 41
The court held that the rationale underlying King applies to the challenged claims of the ‘310 patent, explaining that:
Just as it would be troubling if one could patent a long-practiced method of treatment simply by adding an instructional limitation or a limitation referencing a subsequent accolade (e.g., “Best Drug of 2026”), see Oral Arg. at 5:47–6:55, we find it equally troubling that one could claw back from the public domain an anticipated method of treatment merely by adding a limitation that the method subsequently performed well in a clinical trial. Like the instructional limitation in King, “clinically proven effective” has no “functional relationship” with the claimed method. Even if the term required clinical proof of efficacy, such proof in no way transforms the process of taking the drugs at the amounts and frequencies expressly recited in the claims. Irrespective of whether the anticipated treatment regime is proven to be clinically effective, the actual method … is the same. In other words, even if the phrase were limiting, “clinically proven effective” cannot make the challenged claims patentable because it would still lack a new and unobvious functional relationship with the remainder of the claimed methods, which the Board determined to be unpatentable. 42
The court held that Allergan is distinguishable from the present case because the claims at issue in Allergan were written in open format with the “wherein” clauses modifying the overall composition rather than any specifically recited ingredients within the composition. As such, the “wherein” clauses were functional limitations that limited the open-ended universe of potential compositions that included 0.2% w/v brimonidine and 0.68% w/v timolol maleate by specifying safety and efficacy benchmarks that the overall composition must meet. 43 The court found that, in contrast, the phrase “clinically proven effective” serves no analogous function. Because the claims of the ’310 patent already specify the exact dosages of rivaroxaban and aspirin to be administered to a patient, the additional recitation that the amounts be “clinically proven effective” does not further define the dosages that are administered.
In view of its determination that “clinically proven effective”—even if limiting—cannot breathe patentability into the challenged claims as a functionally unrelated limitation, the court found it unnecessary to decide the question of whether “clinically proven effective” was inherently anticipated. 44
IMPLICATIONS
One notable aspect of Bayer is that although the court affirmed the Board’s decision finding the challenged claims to be invalid, it arrived at that conclusion by a different route. That is, while the Board based its finding of unpatentability on its conclusion that the term “clinically proven effective” is non-limiting and, in the alternative, inherently anticipated, the court held that even if the phrase were limiting, it failed to render the challenged claims patentable because it lacks the necessary “functional relationship” with the remainder of the claimed method. As such, the court found it unnecessary to decide whether or not “clinically proven effective” was limiting nor did it reach the question of whether “clinically proven effective” was inherently anticipated, given its determination that “clinically proven effective”—even if limiting—could not “breathe patentability into the challenged claims as a functionally unrelated limitation.”
The court cited a single Federal Circuit decision, King, as the precedent supporting this requirement that a claim limitation bear a “functional relationship” to other elements of a method claim in order for the limitation to “breathe patentability” into the claim. In doing so, the court is implicitly invoking the printed matter doctrine and, in particular, a notable expansion of that doctrine that occurred in a number of fairly recent Federal Circuit decisions, including King. As explained in a 2018 Holman Report, the printed matter doctrine originated as a means to prevent the patenting of a product in situations where the sole purported basis for patentability resides in novel and non-obvious information appended to a product that is otherwise unpatentable. For example, in In re Ngai, decided in 2004, a patent applicant attempted to claim a ‘‘kit’’ comprising conventional molecular biology reagents along with instructions for performing a novel method of normalizing and amplifying a population of RNA that would involve the use of the recited reagents. 45 The PTO rejected the claims for lack of novelty, invoking the printed matter doctrine and refusing to give the instructions any patentable weight, and on appeal, the Federal Circuit affirmed.
Although the printed matter doctrine originated in the context of physical products paired with literally printed material, i.e., printed information on a physical substrate such as paper or a computer-readable medium, post-Ngai, the Federal Circuit has overseen a significant expansion of the doctrine to encompass method claims, as well as information that is not embodied in any physical medium, such as advice orally provided by a physician to a patient, and even just thinking about information, i.e., a mental step. Although the Bayer court does not explicitly mention the printed matter doctrine, it is clearly invoking the doctrine when it cites King for the requirement of a “functional relationship” between a claim limitation and the remainder of the claim in order for that limitation to bear patentable weight.5
One possible explanation for the Federal Circuit’s decision to invoke the printed matter doctrine and its requirement of a functional relationship in Bayer was a recognition that BMS and the other precedent cited by the Board and by Mylan involved “efficacy” limitations, while the Bayer claims recited “clinically proven efficacy.” Arguably, a prior art reference might be deemed to disclose, explicitly or inherently, an effective pharmaceutical composition without disclosing that the effective pharmaceutical composition has been “clinically proven” effective. The “clinically proven” element of “clinically proven effective” is informational in nature, and for that reason, I suspect the court might have found the printed matter doctrine and the policy rationale behind that doctrine a more appropriate means for addressing the claims. As to that policy rationale, Professor Kevin Collins has opined that the “contemporary core” of the printed matter doctrine is intended to address:
claims with limitations that recite information with content that is meaningful to the human mind. More specifically, [the doctrine] employ[s] a point-of-novelty analysis to invalidate claims for a lack of novelty under § 102 or nonobviousness under § 103 when the only difference between a claimed invention and the prior art resides in the content of the claimed information. 46
In distinguishing the Bayer claims from the claims at issue in Allergan, the court seemed to leave open the possibility that a “clinically proven effective” claim limitation would be given patentable weight if the limitation pertained to the “overall” pharmaceutical composition as opposed to “specifically recited ingredients within the composition.” This was the only distinction between the two cases that the Bayer court was able to identify. The court pointed out that because the Allergan claims were “written an open format,” with the “wherein” clauses modifying the overall composition rather than any specifically recited ingredients within the composition, the “wherein” clauses were functional limitations that “limited the open-ended universe of potential compositions that included 0.2% w/v brimonidine and 0.68% w/v timolol maleate by specifying safety and efficacy benchmarks the overall composition must meet.” In contrast, the court found that since the claims of the Bayer patent already specified the exact dosages of rivaroxaban and aspirin to be administered to a patient, the additional limitation that the amounts be “clinically proven effective” did not further define the dosages.
It seems to me that Bayer’s claims could have been drafted differently such that they would be indistinguishable from the Allergan claims, at least with respect to the controlling distinction identified by the Federal Circuit, but still retain essentially the same substance as the original claims. For example, consider the following three claims. The first is a representative Allergan claim, the second is claim 1 of Bayer’s ‘310 patent, and the third is my revision of Bayer’s claim 1 that seems to satisfy the criteria that the Bayer court identified as accounting for the divergent treatment of the claims at the Federal Circuit.
A representative Allergan claim:
A method of treating a patient with glaucoma or ocular hypertension comprising
topically administering twice daily to an affected eye a single composition comprising 0.2% w/v brimonidine tartrate and 0.68% w/v timolol maleate,
wherein the method is as effective as the administration of 0.2% w/v brimonidine tartrate monotherapy three times per day and
wherein the method reduces the incidence of one o[r] more adverse events selected from the group consisting of conjunctival hyperemia, oral dryness, eye pruritus, allergic conjunctivitis, foreign body sensation, conjunctival folliculosis, and somnolence when compared to the administration of 0.2% w/v brimonidine tartrate monotherapy three times daily. 47
Bayer’s invalidated claim 1:
A method of reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral artery disease, comprising
administering to the human patient rivaroxaban and aspirin in amounts that are clinically proven effective in reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral arterial disease,
wherein rivaroxaban is administered in an amount of 2.5 mg twice daily and aspirin is administered in an amount of 75–100 mg daily.
My redrafting of Bayer’s invalidated claim in the format of the Allergan claim:
A method of reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral artery disease, comprising
administering rivaroxaban in an amount of 2.5 mg twice daily and aspirin in an amount of 75–100 mg daily to the human patient,
wherein the method is clinically proven effective in reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral arterial disease.