A tale of two tribunals. Four Acorda multiple sclerosis patents go from --not invalid-- to invalid in less than one month!
On March 10, 2017, FiercePharma had a post about Acorda's victory over Kyle Bass, et al., at PTAB, which included the text:
Acorda Therapeutics can chalk up another win over patent challenger Kyle Bass and his Coalition for Affordable Drugs.
Thursday, the U.S. Patent and Trademark Office’s Patent Trial and Appeal Board upheld all four patents on multiple sclerosis med Ampyra, thwarting Bass’ attempt to get the Ardsley, New York-based drugmaker’s IP tossed out.
It’s a “great victory” for Acorda and “certainly the drug industry” as it handles challenges from Hayman Capital Management founder Bass and others who follow his lead, Paul Hastings LLP’s Naveen Modi, who co-led Acorda’s legal effort, said in an interview. Bass has been using the inter partes review system, initially set up to weed out low-quality patents involved in litigation, to attack the IP shields of drugmakers he’s shorted, profiting from the process when his activities spook investors and send shares south.
[link: http://www.fiercepharma.com/pharma/acorda-wins-big-over-thwarted-patent-challenger-bass-as-pto-upholds-ampyra-s-ip ]
The four U.S. patents upheld include 8,663,685 (the '685 patent), 8,440,703 (the '703 patent), 8,354,437 (the '437 patent) and 8,007,826 (the '826 patent), which are set to expire in 2025, 2025, 2026 and 2027, respectively.
BUT HOLD ON!
On March 31, 2017, Acorda had a press release which noted:
Acorda Therapeutics, Inc. (Nasdaq: ACOR ) today [March 31] announced that the United States District Court for the District of Delaware upheld U.S. Patent No. 5,540,938 (the ‘938 patent), which pertains to the formulation of AMPYRA® (dalfampridine) Extended Release Tablets, 10 mg and is set to expire in July 2018. The Court invalidated U.S. Patent Nos. 8,663,685 (the ‘685 patent), 8,007,826 (the ‘826 patent), 8,440,703 (the ‘703 patent), and 8,354,437 (the ‘437 patent) which pertain to AMPYRA. The Company will appeal the ruling on these patents.
YES, the very four patents that PTAB held not invalid are the same four that the district court of Delaware found INVALID!
The invalidity, if sustained, would adversely impact Acorda. TheStreet observed:
A District Court judge found four Acorda patents on Ampyra were invalid due to obviousness. The ruling clears the way for an earlier-than-expected competition from generic versions of Acorda's drug, which is prescribed to multiple sclerosis patients to improve their walking ability.
Ampyra sales were $493 million in 2016, or 95% of the Acorda's total revenue. The first generic version of the drug could launch in 2018, said Leerink analyst Paul Matteis.
In a matter related to a different MS drug (Tecfidera), IPBiz has questioned some reasoning of PTAB.
Two different PTAB IPR requests on US 8,399,514 (Tecfidera/multiple sclerosis) yield different reasoning by PTAB
**In passing, from the opinion by Judge Stark, available at 2017 U.S. Dist. LEXIS 48479 (Acorda, P v. Roxane, D) :
As to PHOSITA:
166. The parties have offered different definitions of a person of ordinary skill in the art ("POSA"). Plaintiffs define POSA as having "the knowledge of someone with an M.D. with experience treating MS patients and [*55] a Ph.D. in pharmaceutics, or pharmacology, and at least five years of experience in clinical research and drug development, including researching, designing, and testing drug formulations, particularly for the treatment of multiple sclerosis." (D.I. 262 ¶ 68) Defendants' definition differs from Plaintiffs' only in that Defendants do not believe that a POSA must have experience treating MS patients. (See D.I. 252-1 Ex. 3 ¶¶ 22-24) All of the testifying experts agreed, however, that their opinions regarding obviousness would be the same regardless of which definition the Court adopts. (Peroutka Tr. at 72; Kibbe Tr. at 184; Fassihi Tr. at 323; Lublin Tr. at 406; Goodman Tr. at 430) Therefore, the Court need not make an express finding as to which party's definition of a POSA it will use.13
Because this was a proceeding in district court (rather than an IPR before PTAB), the patent challenger had a high burden:
An issued patent is presumed to be valid. See 35 U.S.C. § 282. Therefore, to invalidate a patent, a party must carry its burden of proof by "clear and convincing evidence." See Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009). Clear and convincing evidence is evidence that "proves in the mind of the trier of fact an abiding conviction that the truth of [the] factual contentions [is] highly probable." Intel Corp. v. ITC, 946 F.2d 821, 830 (Fed. Cir. 1991) (internal quotation marks omitted; first alteration in original). A defendant's burden to prove obviousness is "especially difficult when the prior art [on which the party relies] was before the PTO examiner during prosecution of the application." Hewlett-Packard Co. v. Bausch & Lamb Inc., 909 F.2d 1464, 1467 (Fed. Cir. 1990).
--->Concerning the "Elan patent" [ The Elan Patent is a divisional of U.S. Application No. 73,651 ("Application No. 73,651"), filed June 7, 1993, which issued as U.S. Patent No. 5,370,879 on December 6, 1994. ]
Of some prior art:
The Court is persuaded that the Rush Studies establish that a POSA would have had a reasonable expectation of success of administering 4-AP to achieve a therapeutic effect in MS patients. In the first study, reported in Stefoski, 12 patients with MS and five men without MS received intravenous doses of between seven and 35 mg of 4-AP. (Findings of Fact ("FF") ¶ 45) As Plaintiffs acknowledge, most of the MS patients demonstrated some improvement in symptoms, including vision, ocular motor function, and motor function (defined as power, coordination, and gait). (Id.) Stefoski concluded that "4-AP lessens multiple neurological deficits in multiple sclerosis" and "suggests a clinical usefulness for [4-AP]." (JTX-0112 at 71, 76) Similarly, the second study, reported in Davis, found that orally administered 4-AP produces clinically important improvements in multiple, chronic deficits resulting from MS. (JTX-0043 at 186) Davis was a placebo-controlled study of the effect of 10-25 mg immediate-release doses of 4-AP in 20 MS patients (15 patients received 4-AP and five patients received placebo). (FF ¶ 48) Davis reported mild to marked improvement in all patients, including improvements in motor coordination in nine out of 13 subjects tested. (Id.)
In addition to suggesting that 4-AP could improve symptoms of MS, the Rush Studies' findings about 4-AP's safety suggested that there would be a viable therapeutic window for the drug (i.e., a range of doses at which the drug was both non-toxic and had therapeutic effects). Davis, for example, reported no serious adverse events in patients taking 10-25 mg oral doses. Davis concluded that, even in light of prior research indicating that 4-AP could cause seizures, the results of the reported study suggested that 10-25 mg per day could be a "safe and effective therapeutic window for orally administered 4-AP for visual and motor deficits in . . . MS patients."17 (JTX-0043 at 191)
Still, as even Plaintiffs acknowledge, the prior art need not contain "[c]onclusive proof of efficacy" in order to support a finding that a POSA would have been motivated to develop, and would have had a reasonable expectation of success in developing, a medical treatment. See Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014). Rather, a POSA need only have a "reasonable expectation [*64] of success in developing [the claimed invention]." Allergan, Inc. v. Sandoz, Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013).
Here, the patentee broadly claimed the use of 4-AP to achieve blood levels having any "therapeutic effect." (D.I. 195 at 6) The prior art would have given a POSA a reasonable expectation of success in using 4-AP to achieve a therapeutic effect in MS patients. Although the Rush Studies each involved a limited number of patients and did not include statistical analysis (see D.I. 272 at 15), a vast majority of patients involved in these studies reported some improvement in symptoms.
Taken as a whole,19 the evidence would have strongly suggested to a POSA at the pertinent time that 4-AP could be used to improve symptoms of MS. Thus, the Court concludes that a POSA would have had a reasonable expectation that 4-AP would be "therapeutically effective" in treating MS.20 (JTX-0001 at 22:23)
Having found that a POSA would have had a reasonable expectation of success in using 4-AP to treat MS, the Court must next determine whether a POSA would also have had a reasonable expectation of success in developing a sustained-release formulation of 4-AP to treat MS. It is undisputed that the asserted claims of the Elan Patent are directed [*66] to sustained-release formulations of 4-AP. (Kibbe Tr. at 219; Fassihi Tr. at 374) Thus, the parties' dispute centers on whether development of a sustained-release dosage form would have been obvious to a POSA.
Defendants argue that a POSA would have had a reasonable expectation of success in developing such a formulation because a POSA would have recognized the advantages of such a dosage form for 4-AP and would have found the development process to be routine. (See D.I. 265 at 30-31) Plaintiffs respond that there was insufficient information in the prior art to provide a POSA with a reasonable expectation of success in developing such a formulation. (See D.I. 272 at 20-25)
The parties do not genuinely dispute that a POSA would have understood the hypothetical advantages of a sustained-release formulation of 4-AP as compared to an immediate release formulation. (See Fassihi Tr. at 325; Kibbe Tr. at 207-08) Dr. Peroutka testified that a POSA would have concluded that 4-AP's short half-life (reported in Stefoski and Uges) and narrow therapeutic window (reported in Davis) would make a sustained-release formulation of the drug particularly advantageous, because a sustained-release formulation [*67] could overcome the need for dosing at inconvenient three- or four-hour intervals. (Peroutka Tr. at 77-78, 81) Indeed, Dr. Blight, one of the two named inventors on the Acorda Patents, testified that it was "not unusual" or "particularly mysterious" to pursue development of a sustained-release formulation for a drug with a short half-life. (Blight Tr. at 164)
Based on this testimony, it is evident that the prior art would have provided a clear motivation for a POSA to prepare a sustained-release formulation of 4-AP. The Elan Patent itself, in discussing the prior art, expressly states that "it can be appreciated . . . that there is a need for an improved dosage form" of 4-AP, as a POSA would have known based on the prior art that "it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid patient compliance." (JTX-0001 at 2:8-12) Thus, the key factual dispute for the Court to resolve is whether a POSA would have had a "reasonable expectation of success" in developing a sustained-release formulation that could realize those hypothetical and strongly-desired, benefits.
The topic or "routine experimentation" arose:
In Defendants' view, a POSA could have overcome the challenges Dr. Fassihi highlighted by engaging in "routine experimentation." (D.I. 273 at 18) Dr. Kibbe testified that resolving concerns unique to sustained-release formulations, such as avoiding "dose dumping," was a common consideration for formulators and part of the routine optimization process to formulate a sustained-release drug. (Kibbe Tr. at 194-98) Similarly, Dr. Kibbe pointed out that at least one polymer suitable for developing sustained-release formulations of soluble products already existed in the prior art. (See id. at 209-10) Additionally, Dr. Kibbe disagreed with Dr. Fassihi's views about the impact of a lack of pharmacokinetic information, noting that all of the available information about 4-AP's pharmacokinetics tended to suggest that the drug would be a good candidate for sustained release. Dr. Kibbe noted that Uges reported that 4-AP had a short (four-hour) half-life, high bioavailability, low risk of biotransformation, and a low risk of first pass effect — all characteristics that made 4-AP a favorable candidate for the development of a sustained-release formulation. (See id. at 201-02)21 In Dr. Kibbe's view, this information would have given a POSA a reasonable expectation of success in developing a sustained-release 4-AP formulation to treat MS. Based on this testimony, Defendants argue that, despite some uncertainty about exactly which formulations would work, a POSA would have had a reasonable expectation of success in developing a sustained-release formulation of 4-AP. The need to engage in routine testing or optimization efforts — even if expensive and technically challenging — does not render an invention non-obvious, if a POSA would reasonably expect the testing or optimization efforts to succeed. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367-68 (Fed. Cir. 2007). Thus, a POSA may have a reasonable expectation of success despite "a showing of some degree of unpredictability in the art." Id. at 1364; see also Allergan, 726 F.3d at 1292.
Absent prior art showing the 4-AP blood levels that would be therapeutically effective, a POSA might nevertheless have formed a reasonable expectation of success in developing a sustained-release formulation had the prior art "taught or suggested" that a particular formulation could be effective. Id. at 1070. Here, however, the record lacks such evidence as well. Although Dr. Kibbe testified that a POSA would be able to identify prior art sustained-release platforms and excipients that would be particularly likely to complement 4-AP, given the drug's characteristics (see, e.g., Kibbe Tr. at 208-10) (explaining that POSA would understand that encapsulated dissolution, and particular known polymers, would be appropriate for 4-AP), he did not testify as to why a "skilled artisan would have had a reasonable expectation [that these platforms and excipients] would succeed in being therapeutically effective." Cyclobenzaprine, 676 F.3d at 1070 (emphasis added). Thus, while the record indicates that it may have been obvious to experiment with certain approaches to developing a sustained-release formulation, nothing in the record demonstrates that a POSA would have had a "reasonable expectation" that at least one of those approaches [*77] would have resulted in a therapeutically effective sustained-release formulation of 4-AP. Id.
Defendants urge the Court overlook these evidentiary shortcomings, arguing that there is no "credible evidence" to support a finding that a POSA would not have had "a reasonable expectation of successfully formulating 4-AP into any of multiple available sustained-release dosage forms." (D.I. 273 at 18) (emphasis in original) But the burden in this case does not reside with Plaintiffs. Rather, it is Defendants' burden to present clear and convincing evidence that a POSA would have had a reasonable expectation that one of the multiple available sustained-release dosage forms could be combined with 4-AP to create a therapeutically effective formulation when administered as claimed. Defendants have shown that the prior art included many sustained-release platforms, that many drugs had been formulated using these sustained-release platforms, and that no affirmative evidence existed that would have dissuaded a POSA from pursuing a sustained-release dosage form of 4-AP. Defendants have not shown, however, that a POSA would have inferred from this evidence that success would reasonably be expected [*78] from an attempt to develop a therapeutically-effective, sustained-release formulation for any drug, and most particularly for 4-AP.
The Court is mindful that the evidence regarding the inventors' actual experience in developing the invention of the Elan Patent is not inconsistent with Dr. Kibbe's testimony. Dr. Myers, one of the inventors, stated that it took him only three or four weeks to put three or four formulations of 4-AP on paper and then about a day actually to prepare a sustained-release formulation of 4-AP. (See Myers Tr. at 154-55) Dr. Myers further explained that this process essentially involved substituting 4-AP for the active ingredients he had previously used in sustained-release platforms, and "adjust[ing] the platform[s] with routine testing" until he obtained the desired dissolution pattern. (Kibbe Tr. at 211) Among the disclosed sustained-release formulations in the Elan Patent is one platform that had been disclosed in the 1990 edition of Remington's. (See JTX-0001 at 4:41-46; Kibbe Tr. at 219-20)
While this evidence does nothing to discredit Dr. Kibbe's testimony that developing a sustained-release formulation of 4-AP was straightforward, it also does not help Defendants to meet their burden of showing that a POSA would reasonably have expected it to be so. "[I]n addressing the question of obviousness a judge must not pick and choose isolated elements from the prior art and combine them so as to yield the invention in question if such a combination would not have been obvious at the time of the invention." Abbott Labs. v. Sandoz, 544 F.3d 1341, 1348 (Fed Cir. 2008) (internal quotation marks omitted). Without the benefit of hindsight, the record here does not support a finding that the approach taken by the Elan Patent represented an "identified, predictable solution" that produced an "anticipated success." KSR, 550 U.S. at 421. As such, the Court finds that Defendants have not met their burden to establish, by clear and convincing evidence, that the Elan Patent is invalid as obvious.
---Concerning the Acorda patents
The asserted claims of the Acorda Patents are directed to a method of improving walking in a human with multiple sclerosis by administering a 10 milligram dose of 4-AP twice per day, for either two weeks or twelve weeks.25 Certain claims also require that this dosage regimen produce particular pharmacokinetic results.26 (See, e.g., JTX-0002 at 27:55-57; JTX-0003 at 28:55-57; JTX-0004 at 31:28-31) Certain claims further mandate that there be no titration before or after administration of the 10 mg/twice-daily dose. (JTX-0002 at 27:48-49) Defendants argue that all of these claims are obvious because the prior art would have given a POSA a reasonable expectation of success in combining these limitations. (See D.I. 265 at 38-43) Plaintiffs disagree and further argue that secondary indicia of non-obviousness preclude a finding that the invention of the Acorda Patents was obvious. (See D.I. 272 at 31)
The Acorda patents meet a different fate from the Elan patent
As explained below, the Court concludes that Defendants have shown that the prior art taught the four disputed limitations: the use of 4-AP to improve walking; the use of a 10 mg/twice-daily dosage; the use of stable dosing; and the inherent pharmacokinetic limitations. The Court finds that a POSA would have been motivated to combine these limitations with a reasonable expectation of success. The Court also agrees with Defendants that the secondary indicia do not support a finding of non-obviousness with respect to any claim. As such, the asserted claims of the Acorda Patents are invalid.27
Footnote 27 states: Defendants contend that the Acorda Patents "are presumed obvious as a matter of law, because they simply claim an optimized dose selected from a discrete, narrow range of doses disclosed in the prior art," including the Elan Patent. (D.I. 265 at 5) (emphasis in original) (citing Tyco Healthcare Grp., LP v. Mut. Pharm. Co., 642 F.3d 1370, 1372-73 (Fed. Cir. 2011); Galderma Labs., L.P. v. Tolmar, 737 F.3d 731, 738 (Fed. Cir. 2013)) Plaintiffs disagree, arguing that "unlike in Galderma and Tyco, there was no prior art teaching that any dose of 4-AP — any single dose or any range of doses — was safe and effective to improve walking or increase walking speed in MS patients. The Acorda inventors were not seeking to improve upon what was already a known process, and their invention was not the mere optimization of a known dose range." (D.I. 272 at 54) (emphasis in original) Given the Court's conclusion that Defendants have proven, by clear and convincing evidence, that the asserted claims of the Acorda Patents are obvious, it is unnecessary for the Court to also determine whether these claims should be presumed obvious.
Nevertheless, the Acorda claims were deemed obvious:
Taking all of this into account, the Court concludes that a POSA would have examined and interpreted the prior art holistically and cautiously. Despite all of Plaintiffs' valid concerns, the Court finds that Defendants have proven, by clear and convincing evidence, that a POSA would have formed a reasonable expectation of success based on [*89] Schwid and Goodman, in light of the totality of the prior art. That neither Schwid nor the Goodman references report on the results of a randomized, placebo-controlled study that was "properly designed to assess efficacy" would be taken into account by a POSA, but would not have led a POSA to conclude that there was not a reasonable expectation of success in using 4-AP to improve walking speed. (D.I. 272 at 38)
Several aspects of the record support the Court's conclusion on this issue. First, both the Schwid and MS-F201 studies have two of the three characteristics Plaintiffs deem essential to a persuasive efficacy study: each is randomized and placebo-controlled. (See id.) The studies' key shortcomings are their relatively small size and multi-endpoint, exploratory design. (See id.) While these features increase the probability of obtaining a false positive result (see Goodman Tr. at 472; PTX-0416 at 5), the combined message a POSA would have discerned from Schwid together with the Goodman references was a reasonable expectation of success in treating walking with 4-AP. Just as conducting a study with multiple endpoints increases the overall likelihood of uncovering at least one false-positive, obtaining the same result in a second study decreases the likelihood that the first result was a fluke. (See D.I. 273 at 31-33)
Considering the prior art as a whole would not have tempered a POSA's expectations. The results Schwid and Goodman present are consistent with the results of earlier studies such as Polman, in which patients subjectively reported improvements in ambulation (see JTX-0095 at 295), and Davis, in which patients demonstrated improvements in motor function (see JTX-0043 at 186). These results are also consistent with Solari, which reported that a meta-analysis of past studies of aminopyridines (including 4-AP) suggested that such drugs improved ambulation in MS patients (p < 0.001). (See PTX-0416 at 1) Considering these results in light of the VEP results reported in the Rush Studies, which demonstrated that 4-AP had real physiological effects in MS patients at doses falling within a viable therapeutic window,32 the prior art would not have undermined the conclusion that a POSA would have drawn from the combination of Stefoski and Goodman: that 4-AP could reasonably be expected to be successful in improving walking in patients with multiple sclerosis.33
Of "unexpected results," the district court noted:
Evidence that a "claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected" may suggest that the invention is non-obvious. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Plaintiffs argue that the efficacy of a 10 mg/twice-daily dose of 4-AP would have been surprising to a POSA, as would have been the fact that a 10 mg dose was as effective in treating walking as higher doses. In Plaintiffs' view, these results are unexpected because "[n]one of the [prior] art, viewed alone or in combination, supported an expectation that the 10 mg[/twice-daily] dosing regimen of the Acorda [P]atent claims would improve walking or increase walking speed." (D.I. 274 at 6) Specifically, Plaintiffs argue that the limited and varied data in the prior art would have prevented a POSA from developing such an expectation. (See id. at 6-9)
A showing that a drug was slightly more or less effective than the prior art would suggest does not constitute an "unexpected result" for purposes of assessing obviousness. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 739 (Fed. Cir. 2013); In re Merck, 800 F.2d at 1098-99. As discussed above with respect to the obviousness of the 10 mg dose, the prior art, while perhaps insufficient to prove the effectiveness of that dosage, did not render its effectiveness unexpected. Further, although the prior art in this case suggested that larger doses of 4-AP might be more effective than smaller doses, there was not sufficient evidence of dose-response to render a 10 mg/twice-daily dose non-obvious under an obvious-to-try-standard.
For these reasons, the Court finds that Plaintiffs have not presented evidence of unexpected results that militates in favor of finding that the claims of the Acorda Patents are non-obvious.
UPDATE on April 5, 2017:
Genetic Engineering and Biotechnology News (GEN) reported on April 5:
Acorda Therapeutics said today [April 5] it will eliminate 20% of its workforce in a restructuring that comes five days after a federal judge invalidated four of the five patents protecting the company’s top-selling drug, the multiple sclerosis treatment Ampyra (dalfampridine).
The layoffs are expected to total about 120 jobs, based on the 597 employees the company reported as constituting its workforce as of February 20, according to its Form 10-K annual report for 2016, filed February 27.
Acorda said the restructuring will enable it to focus on two late-stage programs to develop new treatments for Parkinson’s disease. One is CVT-301, a self-administered inhaled formulation of levodopa (L-dopa) indicated for treatment of Off periods (periods of worsening symptoms during therapy) in people with Parkinson’s that is now in Phase III trial, and the company’s most advanced pipeline program.
CVT-301—which applies Acorda’s ArCUS drug delivery technology—generated positive data in February, showing a statistically significant improvement in motor function. The company today restated earlier plans for filing an NDA for CVT-301 during the second quarter.
The other priority program for Acorda is tozadenant, an oral adenosine A2a-receptor antagonist also in Phase III development as an adjunctive treatment to levodopa in Parkinson’s disease patients to reduce Off periods. Acorda acquired worldwide rights tozadenant when it bought Biotie Therapies in a deal completed September 30, 2016, for $376 million.
Tozadenant, envisioned as a chronic therapy for reducing overall Off time, is expected to generate Phase III data this year.