{"id":89929,"date":"2017-11-10T12:45:23","date_gmt":"2017-11-10T17:45:23","guid":{"rendered":"https:\/\/ipwatchdog.com\/?p=89929"},"modified":"2017-11-10T12:45:23","modified_gmt":"2017-11-10T17:45:23","slug":"federal-circuits-doom-amgens-enbrel-monopoly","status":"publish","type":"post","link":"https:\/\/ipwatchdog.com\/2017\/11\/10\/federal-circuits-doom-amgens-enbrel-monopoly\/id=89929\/","title":{"rendered":"Did the Federal Circuit doom Amgen\u2019s Enbrel\u00ae monopoly?"},"content":{"rendered":"

\"\"<\/a>Enbrel\u00ae (entanercept) is Amgen\u2019s blockbuster, anti-inflammatory biologic drug indicated for treatment rheumatoid arthritis, psoriasis, and other inflammatory conditions.\u00a0 Enbrel\u00ae was first approved by the FDA in 1998, and yet still faces no \u201cgeneric\u201d or biosimilar competition.\u00a0 The drug has enjoyed a monopoly for close to 20 years.<\/p>\n

Amgen holds two patents purportedly covering its fusion protein, entanercept.\u00a0 Those patents are important to Enbrel\u00ae because they will not expire for another 10 years.\u00a0 The problem with those patents, however, is that they do not explicitly describe the fusion protein that they claim.\u00a0 A recent Federal Circuit decision, also involving Amgen, may exacerbate that problem because it tightened the standard for satisfying the written description requirement for antibody patents.<\/p>\n

In the case, Amgen v. Sanofi<\/em><\/a>, the Court vacated an injunction Amgen obtained against a competing drug to its new PCSK9-inhibitor.\u00a0 The Court\u2019s decision turned on a finding that the jury was improperly instructed on the criteria for invalidating a patent directed to an antibody for lack of written description.<\/p>\n

Thus, will the precedent recently established in Amgen\u2019s PCSK9 case doom the validity of its patents covering Enbrel\u00ae?\u00a0 There are likely two ways that the decision in Amgen v. Sanofi<\/em> made a validity challenge to Enbrel\u00ae\u2019s patents easier.<\/p>\n

Amgen\u2019s Entanercept Patents<\/em><\/h2>\n

In September 2015, Sandoz filed an aBLA (abbreviated Biologics License Application) with FDA for approval to sell a biosimilar version of Enbrel\u00ae.\u00a0 Under the BPCIA (Biologics Price Competition and Innovation Act), Sandoz\u2019s aBLA triggered a lawsuit commenced by Amgen in February 2016.\u00a0 In the suit, brought in the District of New Jersey, Amgen asserted five patents.\u00a0 Three of the patents (the \u2018225, \u2018605 and \u2018631) essentially cover psoriasis indications for the entanercept antibody.\u00a0 They expire in approximately 2019, and thus, are not critical to Enbrel\u00ae\u2019s continued monopoly.<\/p>\n

By contrast, two other patents cover the entanercept protein itself (U.S. Patent No. 8,063,182<\/a>) or a method of producing it (U.S. Patent No. 8,163,522<\/a>).\u00a0 These two patents are very important to Amgen\u2019s fight against Sandoz because they do not expire until 2028\/2029.\u00a0 That means that if Amgen can successfully enforce the \u2018182 and \u2018522 patents, it stands to gain another 10 years on its Enbrel\u00ae monopoly.\u00a0 That would mean a 30 year monopoly since first FDA approval.<\/p>\n

Enbrel\u00ae (entanercept) is a TNF inhibitor.\u00a0 The drug is indicated for treatment of inflammatory conditions by targeting Tumor Necrosis Factor (TNF), which is an inflammation causing substance.\u00a0 In healthy individuals, excess TNF is naturally blocked, but patients suffering from inflammatory conditions, such as rheumatoid arthritis, experience an excess of TNF.<\/p>\n

Entanercept is a fusion protein, which fuses a fragment of the TNF receptor to the human immunoglobin G antibody (IgG).\u00a0 More specifically, entanercept constitutes a soluble fragment of the 75 kilodalton human tissue TNF receptor that is fused to the hinge, CH2-CH3 region of the heavy chain of IgG.\u00a0 The purported benefits of Enbrel\u00ae\u2019s fusion protein is that fusing a receptor with IgG proteins yields increased affinity for the TNF antigen.\u00a0 The TNFr:IgG protein dimerizes, and therefore displays two copies of the receptor, thus increasing affinity.\u00a0 In addition, the half-life of the fusion protein is also purportedly much greater than the TNF receptor alone.<\/p>\n

Prosecution of Amgen\u2019s Entanercept Patents <\/em><\/h2>\n

Coherus Biosciences recently filed IPRs attacking the validity of the \u2018182 and \u2018522 patents.\u00a0 The petition states that the \u2018182 and \u2018522 patents never specifically describe a fusion protein comprising a soluble fragment of the 75 kDa TNFR and the hinge-CH2-CH3 region of a human IgG, and contains no description or examples describing etanercept.\u00a0 (IPR2017-2066, Paper 1 at 10; IPR2017-1916, Paper 1 at 10).\u00a0 The suggestion is that the patents suffer from inadequate written description.\u00a0 Coherus does not actually argue in its IPRs for invalidating the patents for lack of written description.\u00a0 Yet, that is likely because that type of argument is precluded in an IPR, and the \u2018182 and \u2018522 patents are ineligible for Post-Grant Review, where those arguments would otherwise be permitted.<\/p>\n

Written description was nonetheless challenged during prosecution of the \u2018182 and \u2018522 patents.\u00a0 Both patents were prosecuted in parallel.\u00a0 The \u2018182 patent was only allowed after an appeal to the Board, and the applicants relied upon the outcome of that appeal to gain allowance of the \u2018522 patent as well.\u00a0 Although the patents were allowed over written description rejections appealed to the Board, that Board decision was not likely decisive enough to preclude a challenge from Sandoz.<\/p>\n

The patent\u2019s specification does not actually disclose the full-length of the 75 kD TNF receptor (p75 TNF receptor.)\u00a0 Rather, it discloses a fragment of that receptor in FIG. 4 (specifically, amino acids 49-439 of the 439-amino-acid receptor.)\u00a0 During prosecution, the Examiner argued that because this was the only p75 TNF receptor fragment disclosed, the claims lacked written description for anything broader.\u00a0 That would include a fusion protein based on a p75 TNF receptor fragment including more than what is disclosed in FIG. 4.\u00a0 And since the claims can be construed to include a \u201cvast genus\u201d of fragments, ranging in size from the entire extracellular domain of p75 TNF receptor (amino acids 1-235) to a single amino acid, the Examiner asserted they lacked adequate written description.<\/p>\n

In response, the applicants argued that existing knowledge in the art would have counseled persons of skill that there were existing constraints on the size of the claimed fragment. \u00a0For instance, to successfully bind TNF, applicants pointed to references teaching that certain portions of amino acids 10-54 must be included and at least a portion of amino acids 142-162 must be included.\u00a0 Together, this indicated that at least amino acids 54-142 must be included.\u00a0 All together, applicants argued that this shows that the variations of claimed fragments are not a \u201cvast genus.\u201d<\/p>\n

In its decision, the Board essentially side-stepped the issue.\u00a0 It held that because the entire p75 TNF receptor sequence was known in the art, the claims were adequately described, even though FIG. 4 was only a portion of that receptor sequence.\u00a0 The Board did not necessarily address the issue of whether the patent disclosed sufficient examples to be representative of the genus of p75 TNF receptor fragments that are claimed. \u00a0Sandoz can thus still likely attack the validity of the entanercept patents on this ground.<\/p>\n

The Amgen v. Sanofi Decision<\/em><\/h2>\n

In Amgen\u2019s case against Sanofi and Regeneron, Amgen asserted several patents covering its PCSK9-inhibitor.\u00a0 Regeneron argued that the Amgen\u2019s patents were essentially functional claims, namely they described the claimed antibody not by what is <\/em>(its amino-acid structure,) but rather by what it does<\/em> (binds to PCSK9 at certain residues).\u00a0 The patent specifications only disclosed two example antibodies that satisfy the claims, and Regeneron argued they were not representative of the broadly claimed genus.\u00a0 Regeneron attempted to show the jury its own protein, so as to illustrate how different it was from the two disclosed examples.\u00a0 The District Court barred that evidence, and the jury found Regeneron failed to prove the patents were invalid.\u00a0 The jury instructions also suggested that characterization of the antigen itself may satisfy written description for claims directed to an antibody, known as the \u201cnewly characterized antigen\u201d test.<\/p>\n

On appeal, the parties disputed the propriety of the \u201cnewly characterized antigen\u201d test.\u00a0 PTO Guidelines first published in 2000 indicated that functional claiming of an antibody (e.g., an antibody capable of binding to antigen X) is adequately described where the specification fully characterizes the protein X, even if the patent lacks examples of any such antibodies.\u00a0 The guidelines themselves purportedly referenced a 1976 immunology text, and they appear to have presumed that production of antibodies for well-characterized antigens would be conventional or routine in light of existing antibody technology.<\/p>\n

In two subsequent cases, Enzo Biochem, Inc. v. Gen-Probe Inc.<\/em>, 323 F.3d 956, 960 (Fed. Cir. 2002) and Noelle v. Lederman<\/em>, 355 F.3d 1343, 1349 (Fed. Cir. 2004), the Federal Circuit suggested tacit endorsement, albeit in dicta, of the \u201cnewly characterized antigen\u201d test.\u00a0 The suggestion was that fully describing an antigen may be sufficient to describe and claim an antibody that binds to it.<\/p>\n

In a more recent case, Centocor Ortho Biotech, Inc. v. Abbott Labs.<\/em>, 636 F.3d 1341 (Fed. Cir. 2011), the Court finally examined the \u201cnewly characterized antigen\u201d test in more detail.\u00a0 In doing so, the Court questioned its propriety.\u00a0 The Court stated that it is routine and conventional to produce antibodies for some antigens.\u00a0 For instance, it may be routine to produce antibodies for a known protein \u201csimply by injecting that protein into a host animal that is a different species . . . [and] [t]he host generates antibodies to the foreign protein.\u201d\u00a0 636 F.3d at 1351 n.4.\u00a0 The Court noted, however, that the same may not be true for human<\/em> antibodies.\u00a0 For one thing, producing human antibodies in this way may be unethical.\u00a0 Putting that aside, the Court pointed out that some antibodies are \u201cself\u201d proteins, and a human host may not produce effective antibodies against the antigen.\u00a0 Id.<\/em>\u00a0 Indeed, in Centocor<\/em>, which also addressed the TNF protein, i.e., the antigen for Enbrel\u00ae, the Court noted that the TNF protein is such a \u201cself\u201d protein.<\/p>\n

More recently, in Amgen v. Sanofi<\/em>, the Federal Circuit once against addressed the \u201cnewly characterized antigen\u201d since the jury instruction in the underlying District Court case appeared to endorse it.\u00a0 The Court reiterated that adequate written description must \u201ccontain enough information about the actual makeup of the claimed products . . . .\u201d\u00a0 The Court simultaneously suggested that the \u201cnewly characterized antigen\u201d test \u201cflouts\u201d section 112 because it \u201callows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.\u201d\u00a0 The Court concluded that for written description of an antibody to be adequate when presented with \u201cfunctional\u201d terminology, there must be an established correlation in the art between structure and function.<\/p>\n

For instance, citing to Centocor<\/em>, the Court analogized an antigen and antibody to a lock and a key.\u00a0 For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient.\u00a0 By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.<\/p>\n

Amgen v. Sanofi\u2019s Impact on the Enbrel Patents<\/em><\/h2>\n

In Amgen v. Sanofi<\/em>, the takeaway was, for functionally claimed antibodies, the state of the art must show the correlation between the structure of the antibody and the function of binding to an antigen to satisfy \u00a7112.\u00a0 The proteins of the \u2018182 and \u2018522 patents are claimed with functional terminology, because they recite, \u201chuman tumor necrosis factor (TNF)-binding soluble fragment\u201d.\u00a0 On the other hand, they are not entirely functional.\u00a0 They do recite the specific domains of IgG, and they do recite that the claimed protein \u201ccomprises\u201d a partial <\/em>sequences for the 75-kDa TNFR.<\/p>\n

Yet, written description will still likely haunt these patents, and Sandoz is likely challenge them on that basis.\u00a0 According to the Coherus IPRs, the patents never specifically describe a fusion protein comprising a soluble fragment of the 75 kDa TNFR and the hinge-CH2-CH3 region of a human IgG.\u00a0 They also purportedly contain no description or examples describing etanercept.\u00a0 Rather, they describe how to make a fusion protein from IgG and the p55 TNF receptor, which they suggested should be sufficient to describe the claimed fusion of IgG and the p75 TNF receptor.\u00a0 Focusing on the claimed p75 fragment alone, the patent only discloses FIG. 4 (amino acids 49-249).\u00a0 Yet, during prosecution, the applicants nevertheless argued that the scope of the claims \u201ccan include additional sequences beyond Fig. 4.\u201d\u00a0 (Application No. 08\/444,790, Reply Brief, May 26, 2009 at 12).<\/p>\n

Given all this, there are two aspects of the decision in Amgen v. Sanofi<\/em> that have likely bolstered a written description challenge against the entanercept patents.<\/p>\n

First, Amgen v. Sanofi<\/em> held that for \u201cfunctional\u201d terminology in antibody patents, the state of the art must show established correlation between structure and function.\u00a0 If Sandoz can show that it was neither routine nor conventional to deduce 75p TNF receptor fragments that bind to TNF and encompassed in the claims, that could jeopardize the adequacy of the patents\u2019 written description.\u00a0 For one thing, in Centocor<\/em>, the Federal Circuit observed that it would not likely be routine to produce antibodies for TNF.\u00a0 Also, during prosecution of Amgen\u2019s entanercept patents, applicants attempted to show that, based on the state of the art, persons of skill knew which parts of the p75 TNF receptor bind to TNF.\u00a0 The relied upon two references to show that.\u00a0 In one case, they argued that the state of the art knew that certain amino acids (portions of 10-54) needed to be included in the fragment to bind to TNF.\u00a0 Applicants argued, thus, the patents did not cover a \u201cvast genus\u201d that was not adequately described.\u00a0 But the reference cited by applicants (Chan 2000) was dated 10 years after the priority date of the patent.\u00a0 Thus, it is an open question whether it actually reflected the state of the art 10 years earlier at the patents\u2019 priority date.<\/p>\n

Second, a lot will may come down to how different Sandoz\u2019s protein is compared to Amgen\u2019s protein.\u00a0 In Amgen v. Sanofi<\/em>, Regeneron tried to show the jury its own protein, so that it could illustrate how different it was from the example proteins disclosed in Amgen\u2019s patents.\u00a0 The District Court excluded that evidence on the ground that Regeneron\u2019s protein post-dated the filing date of Amgen\u2019s patents.\u00a0 On appeal, the Federal Circuit held that was error, and remanded the case for a new trial, wherein Regeneron will be permitted to show its protein to the jury.\u00a0 Likewise, in the Enbrel\u00ae case, Sandoz will likely be permitted to use its own protein to show that the examples (or lack thereof) of TNF receptor fragments disclosed in the \u2018182 and \u2018522 patents are not, in fact, representative of the claimed genus.<\/p>\n

The case between Amgen and Sandoz is scheduled to go to trial in April 2018.\u00a0 It is likely that Sandoz stakes out its stance on the written description of Amgen\u2019s Enbrel\u00ae patents before then, and the impact of Amgen v. Sanofi<\/em> may become more clear.<\/p>\n","protected":false},"excerpt":{"rendered":"

In the case, Amgen v. Sanofi, the Court vacated an injunction Amgen obtained against a competing drug to its new PCSK9-inhibitor.\u00a0 The Court\u2019s decision turned on a finding that the jury was improperly instructed on the criteria for invalidating a patent directed to an antibody for lack of written description.\u00a0 Thus, will the precedent recently established in Amgen\u2019s PCSK9 case doom the validity of its patents covering Enbrel\u00ae?\u00a0 There are likely two ways that the decision in Amgen v. Sanofi made a validity challenge to Enbrel\u00ae\u2019s patents easier.<\/p>\n","protected":false},"author":109178,"featured_media":90137,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"content-type":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[7202,82,5519,6998,228,3],"tags":[888,8586,14731,656,8285,705,553,5598,6989,14794,241,8730,357,5531,14793,14795,14733,14732],"yst_prominent_words":[],"acf":[],"_links":{"self":[{"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/posts\/89929"}],"collection":[{"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/users\/109178"}],"replies":[{"embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/comments?post=89929"}],"version-history":[{"count":0,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/posts\/89929\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/media\/90137"}],"wp:attachment":[{"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/media?parent=89929"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/categories?post=89929"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/tags?post=89929"},{"taxonomy":"yst_prominent_words","embeddable":true,"href":"https:\/\/ipwatchdog.com\/wp-json\/wp\/v2\/yst_prominent_words?post=89929"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}