This article was published in Law360 on November 21, 2018. © Copyright 2018, Portfolio Media, Inc., publisher of Law360. It is republished here with permission.
When the America Invents Act of 2011 ushered in a number of new administrative procedures for challenging issued patents, the biotechnology and pharmaceutical industries at first seemed largely unconcerned. The new procedures, after all, were primarily intended to weed out those so-called “business method” patents that trolls liked to litigate — or so they thought.
However, when Kyle Bass, a hedge fund manager, formed the Coalition for Affordable Drugs in 2012 and began suing to invalidate key drug company patents and open the way to generic competition to branded blockbuster drugs, the biotech and pharmaceutical companies belatedly took notice of the new administrative procedures, most notably the inter partes review procedure, which allows petitioners to challenge a patent anytime during its lifetime.
The Biotechnology Innovation Organization and the Pharmaceutical Research and Manufacturers of America even lobbied Congress in 2015 for a blanket exemption from IPR challenges for biotech and pharma patents. The lobbyists were unsuccessful, and the challenges to bio/pharma patents continued to grow. Despite Kyle Bass’ limited success, generic drug manufacturers themselves began to see IPR proceedings as a way to short-circuit the lengthy delays inherent in abbreviated new drug application litigation under the Hatch-Waxman Act.
The number of biotech and pharma patents that have been challenged over the past five years has indeed been surprising. But, perhaps more surprising has been the success rate of biotech and pharmaceutical companies in defending their patents while other patent owners have failed before the Patent Trial and Appeal Board, dubbed by some as the “patent death squad” at the U.S. Patent and Trademark Office.
A study by BiologicsHQ in June 2017 found that only 44 percent of IPR petitions against Orange Book drug patents over the first five years of IPR proceedings resulted in trial institution decisions, as compared to 53 percent for all other petitions. The same study found that even when a trial was instituted, 50 percent of the Orange Book patents in instituted trials survived with no claims invalidated — as compared to a less than 20 percent all-claims survival rate for other patents subject to IPR trials. (A similar analysis by the USPTO in November 2017 produced somewhat different numbers but likewise concluded that bio/pharma patents were still faring better than others. For example, according to the USPTO statistics, Orange Book patents had an 83 percent chance of surviving an IPR challenge unscathed during the first five years of IPR proceedings.)
Why has this one industry sector fared so much better than others? Several factors appear to contribute to the relatively low success rate when it comes to challenging biotech and pharma patents.
Bio and Pharma Patent Claims Are Often More Narrowly Drawn
Unlike many litigated patents that are drawn very broadly and find themselves subject to inter partes review, where the breadth of the claim language can be a vulnerability, bio/pharma patent claims are often rather specific. Typically, a bio/pharma patent need only cover the precise biologic or drug composition approved by the U.S. Food and Drug Administration. So long as the claim covers the FDA-approved product (e.g., a new composition of matter or formulation) or a method of treatment with the product, it is eligible for listing in the Orange Book (drugs) or Purple Book (biologics). Under the Hatch-Waxman and Biosimilars Acts, a patent listed in the Orange or Purple Book precludes generic manufacturers from getting marketing approval unless they can overcome each of the listed patents owned by the innovator. Therefore, a patent claim to specific salt of an active ingredient at a precise concentration and dosage may be enough to block generic approvals — unless the would-be competitor can show that this precise composition is anticipated or obvious.
For example, in a 2014 IPR proceeding, the petitioner challenged a patent for drug delivery formulations that incorporate a drug within a polymeric matrix.1 The matrix was designed to swell upon immersion in water to promote gastric retention of the drug. Preferred polymeric matrices included water-swellable polymers, such as hydroxypropylmethylcellulose and poly(ethylene) oxide.
The principal claim of the patent recited, in part, a controlled release dosage form of a “drug whose solubility in water is greater than one part by weight of said drug in ten parts by weight of water,” and further recited that the dosage form included a polymeric matrix that “when swollen in a dimensionally unrestricted manner as a result of imbibition of water is of a size exceeding the pyloric diameter ... to promote retention in the stomach ... [and] upon immersion in gastric fluid retains at least about 40% of said drug one hour after such immersion.”
Although the petitioner cited numerous prior art references to controlled release formulations involving drugs incorporated into polymeric matrices — and some even using the same preferred HPMC and PEO polymers, the PTAB concluded that the petitioner failed to show that any of the references explicitly or inherently met the solubility, dimensionally unrestricted swelling, and 40 percent after one-hour retention limitations.
Another example of specific limitations saving a patent can be found in a 2018 IPR proceeding,2 where the petitioner challenged a patent directed to methods of treating cancer with paclitaxel in an albumin carrier, “wherein the albumin and the paclitaxel in the composition are formulated as particles, wherein the particles in the composition have a particle size of less than about 200 nm, and wherein the weight ratio of albumin to paclitaxel in the composition is about 1:1 to about 9:1.”
The petitioner cited a reference disclosing a cancer drug formulation of albumin-coated paclitaxel particles that met the particle size limitation. The reference further included at least one example in which albumin and paclitaxel were initially mixed together in a 9:1 ratio. However, the PTAB panel construed the claimed ratio as pertaining to the final product and held that the petitioner had failed to show that there would be no loss of the paclitaxel component during manufacturing and, hence, no anticipation. The petitioner also argued that even if the reference did not necessarily teach a final product falling within the recited paclitaxel-to-albumin ratio, it would have been obvious to a person having ordinary skill in the art to increase the paclitaxel concentration and would have been motivated to do so to provide a higher response rate. The patent owner argued to the contrary that the skilled artisan would have no reason to change the ratio taught by the reference and even if they did, the hypothetical skilled artisan would have been motivated to increase the albumin concentration rather than decrease it to promote uptake into the blood stream. The PTAB agreed with the patent owner and found the reference did not render the claim obvious either.
Chemistry Is an Unpredictable Art
To be valid under the U.S. patent laws, a patent claim must be nonobvious to a person having ordinary skill in the art. Usually, a patent challenger can prove obviousness by arguing that the purported invention merely combines prior art elements using known methods to achieve predictable results. This is especially true for the substitution of one known element for another. Moreover, it is considered “obvious to try” such combinations and substitutions when there are a finite number of identified, predictable solutions, with a reasonable expectation of success.3
However, the key words here are “predictable,” and “reasonable expectation of success” — and this is where bio/pharma patents typically have a leg up on almost all other fields of invention. The field of chemistry has long been acknowledged to be unpredictable.4 Chemistry is an experimental science, meaning that one often cannot predict the outcome of an experiment without actually carrying out the experiment in the laboratory. (“Although there is a vast amount of knowledge about general relationships in the chemical arts, chemistry is still largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave.”)5
For example, in a 2015 IPR proceeding, the petitioner challenged a patent directed to a cyclopropyl-fused pyrrolidine-based peptidase inhibitor (a “DP 4 inhibitor” sold by AstraZeneca as Onglysa) and method of treating diabetes with this compound.6 In this case, the PTAB final written decision began with a detailed recitation of the law of obviousness as it relates to new chemical compounds:
A determination of whether a new chemical compound would have been obvious over the prior art typically follows a two prong inquiry considering first, whether one of ordinary skill would have selected one or more lead compounds for further development and, second, whether the prior art would have supplied sufficient motivation to modify a lead compound to arrive at the compound claimed with a reasonable expectation of success.
In this case, the PTAB rejected the petitioner’s argument that the skilled artisan would have selected a certain pyrrolidine as a “lead compound” and then be motivated to modify it to arrive at the claimed compound. The PTAB panel found that the petitioner’s evidence was insufficient to conclude that the skilled artisan would have even selected the hypothetic lead compound since there were many other compounds that were equal or better choices as the petitioner’s purported “lead compound.” The PTAB also criticized the data that supported the petitioner’s argument because it was obtained from in vitro tests at room temperature rather than in vivo testing.
The PTAB also rejected the petitioner’s arguments as to motivation to further modify its lead compound to arrive at the claimed invention, adopting the reasoning of the patent owner’s expert that there was no reasonable expectation of increased stability or increased potency.
Prior Art Raised by Petitioners Is Sometimes Suspect
Although the AIA permits IPR proceedings to adjudicate patent validity based on patents and other “printed publications,” PTAB judges appear to be most receptive to conventional reference sources, e.g., patents, textbooks and journal articles as prior art. More often than in other fields, challengers to bio/pharma patents have tried to bring less conventional prior art sources, such as product inserts, website pages, clinical trial reports or FDA documents into their proceedings. These less conventional source documents raise problems both in terms of authentication and proof of public dissemination.
An example of authentication problems can be found in a 2017 IPR proceeding, in which the petitioner challenged a patent covering Rituxan — Biogen’s blockbuster drug for treatment of non-Hodgkin’s lymphoma.7 As one ground for invalidity, the petitioner relied upon a product label purportedly distributed with the Rituxan product in 1998. The patent owner asserted that the petitioner had failed to authenticate the proffered label as a publicly accessible document at the relevant time. The petitioner had submitted a copy of the label from the FDA website on an unspecified but relatively recent date, a printout of the Rituxan page from the patent owner’s website as it existed on Jan. 23, 1998, and an entry for Rituxan from the 1999 edition of "Physicians' Desk Reference."
The PTAB panel agreed with the patent owner and found that the petitioner had failed to authenticate the label. They held that the FDA website’s present identification of the document as the original approved label is insufficient to establish that it was publicly accessible prior to the critical date. As to the webpage obtained via the WayBack Machine, the PTAB concluded it was a materially different document. Even if the webpage was available in 1998, it does not establish that the label was as well. (The label being the actual evidence relied upon.) Likewise, the entry in the 1999 PDR — even if it contained the same information — was not the same document as the label.
The petitioner ultimately overcame these authentication problems in a subsequent IPR petition8 by showing via declaration that the label was indeed the label approved by the FDA in 1997 — and by also introducing the archived webpage and the 1999 PDR as separate exhibits.
Several other challenges to bio/pharma patents have been derailed by failures to authenticate.9
Even when a petitioner can overcome authentication issues with nonpatent references, the challenger must also show that the document was “publicly accessible.” To satisfy this requirement the party proffering the evidence must make a satisfactory showing that the document has been “disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art exercising reasonable diligence can locate it.”10
In another 2018 IPR proceeding challenging a patent on Abbvie’s blockbuster drug Humira, a PTAB panel found that the petitioner had failed to prove that two Humira labels bearing 2002 and 2003 dates were publicly accessible in 2002 or 2003.11 The PTAB decision denying trial institution noted:
Petitioner also does not direct us to any source-identifying information from the FDA (e.g., a copy of the labels on the FDA’s website), a publication date, or other indicia indicating when Humira 2002 Label or Humira 2003 Label became publicly available. Nor does the Petition include or cite to information related to how one might have obtained a copy of Humira 2002 Label or Humira 2003 Label.
The PTAB panel hinted at what was missing: “Such evidence could include in this case, for example, testimony from a person interested in the art explaining how one could have located the labels by searching the FDA ’s website; or evidence of indexing on the internet such that a search using any combination of search words, would have led to the [labels] appearing in the search results.”
Objective Evidence Can Weigh in Favor of Successful Therapeutics
Finally, even if a patent challenger presents a prima facie case for invalidity based on obviousness, the law has long recognized that a patent owner can sometimes overcome such evidence by showing “objective indicia of non-obviousness.”12 Such objective indicia can include evidence of criticality or unexpected results, commercial success, long-felt but unsolved needs, failure of others, or skepticism of experts. Thus, factual evidence that a therapy has proven effective and become a blockbuster product can turn out to be the ace-in-the-hole for bio/pharma patent owners.
The Onglysa case, discussed above, also provides an example of objective indicia helping a bio/pharma patent owner. In that case, the PTAB held that even if the petitioner had established obviousness by a preponderance of evidence, “secondary considerations also weigh in favor of a finding of nonobviousness.” Specifically, the PTAB panel found that the patent owner’s objective evidence was persuasive on (1) failure of others, (2) unpredictable and unexpected properties of the claimed compound and (3) satisfaction of a long-felt need.
Endnotes
1 IPR2014-00655, Endo Pharm., Inc v. Depomed, Inc. (USP 6,635,280).
2 IPR2018-00163, Cipla v. Abraxis Bioscience, Inc. (USP 7,923,536).
3 KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
4 See Boston Scientific Corp. v. Johnson & Johnson, Inc., 679 F. Supp. 2d 539, 557 (D. Del. 2010).
5 In re Carleton, 599 F.2d 1021, 1026 (C.C.P.A. 1979).
6 IPR2015-01340, Mylan Pharm. v. Astrazeneca (USP RE44,186).
7 IPR2017-01166, Pfizer v. Biogen (USP 8329172).
8 IPR2018-00086, Pfizer v. Biogen (USP 8329172).
9 See, e.g., IPR2016-01566, Mylan v. Boehringer Ingelheim (finding that a purported “printed package insert” was not a printed publication); IPR2016-00649, Frontier Therapeutics, LLC v. Medac (dates alone on a package insert are inadequate to show the document was a printed publication).
10 Kyocera Wireless Corp. v. ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008).
11 IPR2018-00002, Sandoz v. Abbvie (USP 9,512,216).
12 Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966).
