Abiraterone - USA

On Oct 26, 2018, Judge Kevin Mcnulty of District of New Jersey found method of use patent of Zytiga® invalid under obviousness.

This is Hatch-Waxman actions for infringement of US 8,822,438 brought by Janssen and BTG International Ltd. The ‘438 patent contains twenty claims covering - methods for the treatment of prostate cancer by administering various dosages of abiraterone acetate and prednisone in combination. Plaintiffs alleged infringement of claims 4, 8, 11, 19 and 20, all of which dependent on claim 1 of the 438 patent, based on the defendants’ filing of ANDAs. The Court conducted a bench trial beginning on July 23, 2018 and concluding on August 2, 2018. As a defense to infringement, defendants asserted that the ‘438 patent is invalid for lack of a written description and for obviousness.

Written Description:

Defendants alleged that the asserted claims in the ‘438 patent do not meet the written-description requirement of 35 U.S.C. § 112. Specifically, defendants argued that the specification is inadequate because it fails to disclose test results showing that prednisone itself provides an anti-cancer benefit. Also, it does not provide sufficient information to permit a POSA to understand that both agents, abiraterone and prednisone, “treat” prostate cancer. Court disagreed & said that the specification in the ‘438 patent sufficiently identifies prednisone as an anti-cancer agent for purposes of written-description requirement. The specification is directed to the administration of abiraterone acetate with “at least one additional therapeutic agent, such as an anti-cancer agent or a steroid.” Prednisone is explicitly identified as an antibiotic agent under broad category of anti-cancer agent. Second, the specification provides a list of steroids, including hydrocortisone, prednisone, and dexamethasone. The specification also provides the “amount of the steroid administered to a mammal having cancer is an amount that is sufficient to treat the cancer whether administered alone or in combination with a 170-hydroxylase/C17,2o-lyase inhibitor.” Thus, whether identified as either an “anti-cancer agent” or a “steroid,” prednisone is sufficiently identified in the specification as an agent that “treats” cancer. Therefore, claims have written description support.

Obviousness:

Defendants alleged that the combination therapy claimed in the ‘438 patent would already have been obvious to a person of ordinary skill in the art (“POSA”) under 35 U.S.C. § 103. Defendants asserted that, as of that date, a POSA familiar with the prior art would have been motivated to combine abiraterone acetate with prednisone for three reasons: (1) for its anti-cancer effects; (2) to mitigate abiraterone’s side effects; or (3) for prednisone’s palliative properties. The crux of defendants’ argument is that the prior art would have motivated a POSA to combine abiraterone with prednisone with a reasonable expectation of success.

Court in its analysis said that by the priority date of Aug. 25, 2006, it was understood that both ketoconazole and abiraterone were steroid inhibitors, and both inhibited the CYP17 enzyme. Barrie 1994 and O’Donnell 2004 both used ketoconazole as a starting point for their discussions regarding abiraterone and its potential to be a more selective inhibitor. Barrie 1994, comparing the inhibition levels of hormone production by abiraterone with ketoconazole, concludes that abiraterone was more effective than ketoconazole in decreasing testosterone levels. O’Donnell 2004 specifically notes that abiraterone’s ability to sustain testosterone suppression in castrate males, when given in 500 to 800 milligram doses, suggested that it could be used as a second-line treatment. From all of this, it can be concluded that abiraterone had been identified in the prior art as a second-line prostate cancer treatment. It can also be concluded that it was regarded as a superior swap for ketoconazole, in that it performed a parallel function in a more targeted manner. As for prednisone itself, Tannock 1996 suggested that corticosteroids provide some level of palliation to cancer patients. Sartor 1998 goes farther, and suggests that prednisone can cause reduced PSA levels, a marker of anticancer effect. That conclusion is supported by three other prior art references: Fossa 2001, Fakih 2002, and Harris 2002. Thus, there was more than sufficient motivation for a POSA to combine abiraterone with prednisone.

Moreover, Gerber 1990 suggests that a patient whose PSA levels are increasing can be treated with a combination of ketoconazole and a glucocorticoid, which can result in a decrease in PSA levels. Gerber 1990 also teaches that the combination of ketoconazole and 5mg a day of prednisone, twice daily, is safe and effective for treating hormone-refractory advance prostate cancer. O’Donnell 2004 corroborates that in the clinical use of ketoconazole, it was “common practice” to administer supplementary hvdrocortisone. It states cautiously that “further studies with abiraterone acetate will be required to ascertain if concomitant therapy with glucocorticoid is required on a continuous basis, at times of physiological stress, if patients become symptomatic or indeed at all.” Thus, A POSA would have interpreted ketoconazole’s clinical use as a basis to take the next investigative steps with abiraterone. It made sense to replace ketoconazole with abiraterone, as it became clear that abiraterone was a superior, more selective inhibitor. Co-administration of 10mg per day of prednisone would naturally carry over from the ketoconazole combination therapy to the abiraterone combination therapy. There would have been concerned about the potential reduction in cortisol as a side effect of abiraterone’s inhibition of CYP17. Specifically, a POSA would have seen the potential for resulting excess mineralocorticoid (aldosterone) and adrenal insufficiency. They do not, however, outweigh the clear teaching in prior arts & court did not agree, as plaintiffs suggest, that prior art “taught away” from the combination therapy. In short, to the POSA, the prior art would have suggested that abiraterone could be combined with prednisone with a reasonable probability of success.

With respect to secondary considerations court held that these factors do not overcome convincing evidence of obviousness.  As to the commercial success factor, there can be no dispute that ZYTIGA® has yielded billions of dollars in sales. “Evidence of commercial success . . . is only significant if there is a nexus between the claimed invention and the commercial success.” Moreover, “if the feature that creates the commercial success was known in the prior art, the success is not pertinent.” Onnco, 463 F.3d at 1311-12; see also fT. Eaton, 106 F.3d at 1571. Also, “where ‘market entry by others was precluded [due to blocking patents], the inference of non-obviousness of [the asserted claims, from evidence of commercial success, is weak.’” Galdenna Labs., L.P. v. Tolmar, Mc, 737 F.3d 731, 740 (Fed. Cir. 2013) (quoting Merck, 395 F.3d at 1377). Defendants argued that Abiraterone was previously known in the art & there is earlier blocking patent, US 5,604,213. From 1997 through 2016, that patent granted its holder the exclusive right to market abiraterone. Also the sales of ZYTIGA may not be wholly attributable to the patented combination therapy. These are powerful offsetting factors. With respect to long-felt need and unexpected results, Plaintiffs stated that the claimed invention was an advance on the prior art in that it had less toxicity, was better tolerated, and improved overall survival. Defendants pointed to existing contemporaneous alternatives: Jevtana was approved by the FDA in 2010, a year before ZYTIGA® was approved; Xtandi was approved in 2012. Therefore, court held that it does not suggest that all other efforts had failed, or that the abiraterone/prednisone combination therapy was unexpected “ in kind and not merely in degree.” Thus, balancing the entire prior art and the other indicia, court found that the evidence favors a conclusion of obviousness.

Judge also ruled on infringement issue & found patent infringed by Defendants if it would have been held valid.

Dimethyl fumarate – USA

On Oct 24, 2018, Federal Circuit affirmed Patent Trial and Appeal Board’s decision that Forward pharma’s MS treatment claim is not supported by adequate written description. 

This appeal arises from an interference proceeding at Patent Trial and Appeal Board and involves a treatment method for multiple sclerosis with a particular daily dosage—480 mg—of fumaric acid esters. Appellee Biogen MA, Inc. (Biogen) owns U.S. Patent No. 8,399,514, which describes and claims this method of treatment. The US’514 claims priority to a provisional application filed on February 8, 2007. Appellant FWP IP ApS (Forward) is the assignee of U.S. Patent Application No. 11/576,871, which discloses controlled release compositions of fumarates. The US’871 claims priority to a Danish patent application filed on October 8, 2004. Forward argues that its patent application describes the specific treatment method in dispute. While the Board found that Forward’s ’871 application had an earlier priority date than Biogen’s ’514 patent, it granted Biogen’s motion for judgment that the MS treatment claims of US’871 application are not supported by adequate written description under 35 U.S.C. § 112.

The Board found that the ’871 application’s focus on “controlled release fumarate compositions” and “general teaching of applicability of the fumarates to the treatment of a variety of possible disease or conditions and the teaching of a broad range of possible dosages would not have conveyed possession of the specific treatment of MS that Forward now claims.” Reviewing the ’871 application’s specification, the Board found that the principal focus of the disclosure is the minimization of gastro-intestinal side-effects through the use of controlled release of fumarates. As to the treatment of specific diseases and conditions, the Board found that Forward’s specification lists over twenty diseases and conditions, and MS is not identified as of any particular interest. The only diseases that the ’871 application discusses in any detail, however, are psoriasis and conditions associated with psoriasis. The two commercial compositions of fumarates the specification identifies are Biogen’s Fumaderm® and TioFarma’s Fumaraat 120®, both of which can be used for treating psoriasis. With respect to the fumarate content, the Board found that, while the ’871 application’s specification teaches the active ingredient can be any fumarate, it does separately identify DMF, MMF, and their combination for use in treatment formulations such that a skilled artisan would have recognized that the inventors had considered those fumarates to be significant. The daily dosage paragraph teaches that the dosage can be from 240 to 360 mg, 360 to 480 mg, 480 to 600 mg, 600 to 720 mg, 720 to 840 mg, 840 to 960 mg, or 960 to 1080 mg, given in one to three administrations. The 480 mg/day dose thus is identified as both the low and high end of ranges within a broader, overall disclosed dosage range of 240 to 1080 mg/day. While 480 mg/day dosage is expressly mentioned three times in the specification, the Board found that there “is no discussion that would guide one skilled in the art to treat MS with a therapeutically effective dose of 480 mg/day, or any other therapeutically effective dose within the ranges disclosed. Thus, the Board concluded that Forward’s claims 55– 70 failed to meet the written description requirement. The Board found that, even though each required claim element is mentioned separately in Forward’s specification, the specification did not disclose the claimed invention in a manner that adequately describes the now claimed MS treatment to a skilled artisan. Forward appealed.

On appeal, Forward argued that the upscale table (1) discloses a 480 mg/day dosage, (2) is reasonably directed at using DMF to treat the listed conditions, and (3) is linked to the treatment of MS. And at oral argument, Forward again asserted that the kits for administration of fumarates over the up-titration schedule (up-scale table) tie together the dose, drug, and disease. Forward contends that the up-scale table in the ’871 application expressly discloses this 480 mg/day dosage during the seventh week of a contemplated nine-week scale-up period. Forward argued, POSA would have recognized that all of the listed dosages in that nine-week up-scale table are therapeutically effective dosages for all of the conditions and diseases listed elsewhere in the specification. Federal Circuit, however not persuaded & agreed with Board that the up-scale table does not discuss therapeutically effective dosages at all, much less the specific dosage of 480 mg of fumarates per day as being therapeutically effective for treating MS. Rather, the up-scale table as simply providing guidance on gradual dosing over a period of several weeks to help patients’ gastro-intestinal systems acclimate to the side-effects of fumarates. The 480 mg/day disclosure in week seven is an interim dosage, and Forward has not presented persuasive evidence why a skilled artisan would have understood the week seven interim dosage to be therapeutically effective. On the other hand, Biogen’s expert testified that, because MS is a chronic disease, a skilled artisan would not have viewed a one week, interim dosage in the middle of a nine week up-scale schedule as an adequate treatment dosage, let alone one for a particular disease, such as MS. Substantial evidence supports the Board’s finding that Forward’s ’871 application lacks adequate written description support for the claimed treatment method. Moreover, a person of ordinary skill in the art reading [the ’871 application] would not have expected that a dose of an agent for potentially treating one of the many listed non-neurological diseases would also treat a neurological disease such as MS.”

Forward next tried to rely on the prior art for establishing a prior, known link between MS and fumarates. But Federal Circuit held that the prior art does not teach the key limitation of the count: the 480 mg daily dosage. Biogen counter argued that it was only during its phase 3 clinical trials when it confirmed that 480 mg/day of DMF is effective for treating MS. Lastly, Forward argued that the ’871 application’s original claims—which it canceled and replaced with new claims to provoke the interference proceeding— adequately describe the MS treatment it now seeks to claim. Federal Circuit sided with Board & held that Board correctly observed that a skilled artisan would need to pick and choose from Forward’s claims without any guidance from the written description. Forward provides no explanation as to why a skilled artisan would be able to cobble together selected elements from several different claims and thus recognize the now-claimed 480 mg/day of DMF and/or MMF for the treatment of MS from these 45 claims covering a broad scope of subject matter.

Thus, Federal Circuit affirmed Board’s finding that the MS treatment Forward now claims is not supported by adequate written description under 35 U.S.C. § 112.

Glycerol Phenylbutyrate - USA

Decision on IPR: Oct 24, 2018

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Status
IPR2018-01550	08/21/2018	--	Par Pharmaceutical, Inc.	9,561,197	Horizon Therapeutics	Terminated-Settled

On’197 patent, Lupin field IPR (IPR2018-00459) on 01/12/2018 which was terminated due to settlement on July 25, 2018.

US 9,561,197 (Horizon Therapeutics, LLC; Exp: 09/22/2030) – OB listed

1. A method of treating a urea cycle disorder in a subject comprising administering to a subject having a plasma PAA to PAGN ratio outside the target range of 1 to 2, a dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) effective to achieve a plasma PAA to PAGN ratio within the target range of 1 to 2.

2. A method of treating a urea cycle disorder in a subject comprising administering to a subject having a plasma PAA to PAGN ratio outside the target range of 1 to 2.5, a dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) effective to achieve a plasma PAA to PAGN ratio within the target range of 1 to 2.5.

Linagliptin / Linagliptin & Metformin – USA

On Oct 15, 2018, New Jersey district court found two patents of Boehringer Ingelheim related to antidiabetic drug(s) invalid.

According to news, Court found in favor of Defendants (Mylan & Aurobindo) which were seeking to market generic versions of Tradjenta® (linagliptin) and Jentadueto® (linagliptin/metformin), for treatments of controlling blood sugar levels in patients with type 2 diabetes. In 2015, Boehringer Ingelheim Corporation brought a Hatch–Waxman suit & trial was held in Aug 2018. Court ruled that the two patents-in-suit (US 8,673,927 & US 9,173,859 expiring in May 2027) were invalid on grounds of both non-statutory double patenting and obviousness. Specifically order states that the Claims 7, 9, 15, 17, 19, 25, 26 of '927 Patent and Claims 1, 14, 15, 20, and 21 of '859 Patent are invalid on the grounds of non-statutory double patenting; The Claims 7, 9, 15, 17, 19, 25, 26 of '927 Patent and Claims 1, 14, 15, 20, and 21 of '859 Patent are invalid due as obvious in view of the prior art under 35 U.S.C § 103.

The case is Boehringer Ingelheim Pharms., Inc. v. HEC Pharm Co., No. 3:15-cv-05982. The Memorandum is sealed for a period of sixty days within which the parties shall confer and redact the Memorandum.

Ezetimibe & Simvastatin - Germany

On Oct 01, 2018 Düsseldorf court revoked preliminary injunction granted previously against ratiopharm based on combination SPC.

Plaintiff (Merck) sued Defendant (Ratiopharm) for an injunction due to alleged infringement of the supplementary protection certificate DE 12 2004 000 026. This SPC protects the product "ezetimibe or pharmaceutically acceptable salt thereof in combination with Simvastatin (INEGY®). Plaintiff was the holder of the European Patent EP 0720599 B1 ("Basic Patent"), which expired on 14 September 2014. The SPC has been effective in the Federal Republic of Germany since 15 September 2014 and will presumably expire on 2 April 2019. The Basic Patent concerns the hydroxy-substituted azetidinone compound ezetimibe, or pharmaceutically acceptable salts thereof, and the combination of ezetimibe with a cholesterol synthesis inhibitor. Previously, Plaintiff obtained first SPC on same basic patent for single ezetimibe product (EZETROL®) which expired on 17 April 2018.

At Plaintiff's request, the chamber granted a preliminary injunction on 16 May 2018, which prohibited Defendant from offering drugs containing ezetimibe/simvastatin combination in Germany. With a pleading dated 2 July 2018, Defendant objected to the preliminary injunction.

With respect to Art. 3 a) of SPC Regulation, Court held that the active ingredient simvastatin can be understood not only as included in the umbrella term cholesterol biosynthesis inhibitor in claim 9, but beyond that is specifically named in claim 17. Moreover, the Basic Patent addresses the specific combination of active ingredients both in the claims and in the description. Therefore, the contested combination constitutes a specific part of the technical teaching of the Basic Patent, and therefore is a protected product for the purposes of Art. 3 a) SPC Regulation.

With respect to Art. 3 c) of SPC Regulation, Court held that conditions were not met because ezetimibe represents the sole subject matter of the protected invention & it had already got SPC for that. The combination of the active ingredients ezetimibe and simvastatin does not constitute the core of the Basic Patent's technical teaching. The extension should be made only once, since a certificate may not have been granted for one and the same product (cf. Art. 3 c) SPC Regulation). So only one SPC should be granted per product, which is understood in a more narrow sense as an active ingredient (of combination of active ingredients). A purely additive effect from two combined active ingredients, in which the combination of active ingredients achieves the same therapeutic effect as the separate administering of both active ingredients, doesn't satisfy the CJEU as the sole subject matter of the invention (cf. CJEU, GRUR 2014, 157 - Actavls/Sanofi). And the Federal Patent Court also seems to view delineation between additive and synergistic effects as a useful distinction criterion, even if it doesn't focus on the core of the invention.

According to these principles, the combination of ezetimibe and simvastatin does not constitute a product as such which embodies the central advance protected by this Basic Patent. The invention's core is only to provide the new active ingredient ezetimibe. But Certificate has already been granted for that single product. Thus, the prerequisite in accordance with Art. 3 c) SPC Regulation for granting second Certificate for combination product has not been met.

Glatiramer acetate - USA

On Oct 12, 2018 Federal Circuit  affirmed decisions of Delaware court and the Patent Trial and Appeal Board that patents on Teva's blockbuster multiple sclerosis drug Copaxone are invalid.

Yeda Research & Development Co., Ltd. is the assignee of U.S. Patent Nos. 8,232,250, 8,399,413, 8,969,302, and 9,155,776; all entitled “Low Frequency Glatiramer Acetate Therapy.” The patents, collectively referred to as the “Copaxone patents,” share a common specification and claim priority to the same two provisional applications. The earliest priority date of the Copaxone patents is August 20, 2009. The Copaxone patents describe and claim COPAXONE® 40mg/mL, a treatment for relapsing remitting multiple sclerosis (“RRMS”). RRMS is a form of multiple sclerosis, an autoimmune disorder that causes the body’s immune system to attack the central nervous system. The active ingredient in COPAXONE® 40mg/mL is glatiramer acetate (“GA”), a synthetic mixture of polypeptides. GA is also known as “copolymer 1” or “Cop. 1.” COPAXONE® 40mg/mL is supplied as a single-dose prefilled syringe. For analyzing the obviousness of the Copaxone patents in this case, a key limitation of the asserted claims is the administration of a 40mg GA dose in three subcutaneous injections over seven days. All asserted independent claims require at least one day between doses.

The district court held a seven-day bench trial during which it considered the invalidity of the asserted claims of the Copaxone patents by defendants (Sandoz, Momenta, Dr Reddy’s, Mylan, Synthon, Amneal & Pfizer). The district court found that a 40mg GA dose was explicitly disclosed in references that predate the Copaxone patents, specifically Cohen, Pinchasi, and FORTE. The court rejected Teva’s arguments that Cohen and FORTE taught away from a 40mg dose, and that a person of ordinary skill in the art (“POSITA”) would have thought that 20mg was the optimal dose. The district court also found that, as of the priority date, POSITAs knew that daily injections of 20mg were difficult to tolerate based on the 1996 FDA SBOA, Flechter, and Khan 2008. Relying in part on trial testimony, the district court found that POSITAs were familiar with the adverse reactions, pain, and treatment adherence problems associated with daily injections, and would have been motivated to pursue less frequent dosing with a reasonable probability of success. In light of these factual findings, the district court concluded that a 40mg GA 3x/week dosage would be obvious to try, noting that there were only two tested dosage amounts in the prior art—20mg and 40mg—and that researchers were pursuing less frequent dosing regimens while recognizing there are a limited number of days in a week on which to test frequency. The court recognized that obvious-to-try logic is not always appropriate, but found that “[h]ere, there was market pressure to solve a known problem—the fact that many MS patients could not tolerate daily injections—and there were a finite number of predictable solutions that a person of ordinary skill in the art would have good reason to pursue.”

Teva appealed. On appeal, Teva disputed that the 40mg GA 3x/week dosing regimen disclosed in the Copaxone patents would have been obvious to a person of skill in the art. Teva also appealed the invalidation of claim limitations in the ’250 and ’413 patents relating to improved tolerability and reduced frequency of adverse effects, and the invalidation of the ’776 patent’s claims relating to reduced severity of injection site reactions. Teva contended that the district court erred in finding the claimed 40mg GA 3x/week dosing regimen obvious. Specifically, Teva argued that the district court impermissibly relied on hindsight and an improper “obvious to try” analysis, and analyzed the obviousness of individual claim elements, rather than the invention as a whole. Federal circuit, however, disagreed & said that here the prior art focused on two critical variables, dose size and injection frequency, and provided clear direction as to choices likely to be successful in reducing adverse side effects and increasing patient adherence. As of the priority date, only two GA dose sizes had been shown to be effective, safe, and well-tolerated: 20mg and 40mg. Concerning frequency, the 1996 FDA SBOA, Flechter, and Khan 2008 all encouraged POSITAs to pursue a less frequent than daily dosing regimen; these references indicated that less frequent injections of GA were just as effective as daily injections, and less frequent injections improved patient adherence and reduced adverse reactions. Given this motivation, a POSITA had only a limited number of permutations of dose and frequency to explore that were not already disclosed in the prior art. The district court also gave appropriate weight to the testimony of Dr. Green regarding patient compliance with thrice-weekly administrations and the Rebif® regimen, noting that “even though Rebif® is a different MS drug with a different mechanism of action, those in the art would still be motivated to try dosing GA three times a week based on the higher rates of patient adherence to the Rebif® therapy. Teva made numerous challenges to factual findings by the district court, none of which court found persuasive. Federal circuit finally held that the 40mg GA 3x/week regimen is obvious in light of the prior art, and found no clear error in district court’s analysis.

Next, Teva argued that the prior art did not lead POSITAs to expect improved tolerability and reduced frequency of injection reactions from the claimed regimen compared to 20mg GA daily. Claims 14, 16, and 17 of the ’250 patent and claim 7 of the ’413 patent require that the 40mg GA 3x/week regimen reduce the frequency of injection reactions relative to the daily 20mg GA regimen. Claim 15 of the ’250 patent, on which claims 16 and 17 depend, requires that the claimed regimen improve tolerability as compared to the daily 20mg regimen. Federal circuit disagreed, and found no clear error in the district court’s findings regarding Khan 2008, Caon, and Flechter, all of which demonstrate that improved tolerability and less frequent injection reactions were expected from the claimed less frequent regimen, as compared to 20mg daily. Thus finally federal circuit concluded that the district court did not err in invalidating all asserted claims of the Copaxone patents as obvious.

PTAB proceedings:

Alternatively in PTAB, Mylan filed petitions for inter partes review (IPR2015-00643, IPR2015-00644, and IPR2015-00830), challenging all claims of the ’250, ’413, and ’302 patents, respectively, on grounds pursuant to 35 U.S.C. §§ 102 and 103. Subsequently, Amneal later filed the petitions & joined IPR. The Board concluded that, in light of the evidence presented, a POSITA would have had a reason to modify Pinchasi’s dosing regimen of 40mg GA every other day to 40mg GA 3x/week, thus rendering the claimed 40mg 3x/week limitation obvious. Federal circuit here also found no error in the Board’s finding of obviousness & affirmed the decision.              

Tadalafil - USA

On Oct 10, 2018, Federal Circuit upheld (Rule 36 Judgment) a $20 million verdict against Eli Lilly & Co. for marketing erectile dysfunction drug Cialis.

Previously, plaintiff Erfindergemeinschaft UroPep GbR sued Eli Lilly and Company for infringement of U.S. Patent No. 8,791,124. Claim 1 of the ’124 patent is to a method of administering an effective amount of a compound known as an inhibitor of the enzyme phosphodiesterase (“PDE”) V, in order to treat the condition of benign prostatic hyperplasia (“BPH”). UroPep alleged that Lilly induced infringement of claim 1 by marketing and selling the drug Cialis for the treatment of BPH. Lilly denied infringement and asserted various invalidity defenses. After a trial, a jury found the ’124 patent infringed and not invalid. The jury awarded damages in the amount of $20 million. The evidence at trial showed that Lilly made approximately $704.3 million in sales of Cialis attributable to the BPH indication between October 9, 2014 (the date on which Lilly was notified of UroPep’s patent), and April 16, 2017 (the day before the beginning of the trial). Then pursuant to Rules 50(b) and 59, Fed. R. Civ. P., Lilly moved for judgment as a matter of law or, in the alternative, a new trial. Court denied the motion in Aug 2017.

Pregabalin - Netherlands

On Oct 04, 2018, Advocate General Kokott at the Court of Justice of the European Union issued opinion on label carve-out issue filed by Warner-Lambert Company.

Background: Warner-Lambert markets worldwide the medicinal product Lyrica®, with the active substance pregabalin, for the indications epilepsy, generalised anxiety disorder and neuropathic pain. Warner-Lambert is the holder of the European Patent EP 0 934 061 (expired in 2017) which claims neuropathic pain. After the data exclusivity period for the medicine Lyrica had expired in 2015, several manufacturers of generic medicinal products, including Aurobindo, applied to the Medicine Evaluation Board (CBG) under the decentralised procedure for a marketing authorisation for a generic medicinal product. The original application by Aurobindo in the decentralised authorisation procedure did not contain a carve-out for the indication neuropathic pain, but a full label version of the summary of product characteristics, which also included the still patented indication. After the marketing authorisation had been granted, but before its generic pregabalin-based medicinal product had been placed on the market, Aurobindo notified the CBG that it would subsequently introduce a carve-out, that is, in the case at hand, delete from the summary of product characteristics the still patented indication neuropathic pain. Aurobindo requested the CBG to publish the summary in accordance with the subsequent carve-out. The CBG did not comply with that request, however, but published the full label version of the summary. Thereupon, Warner-Lambert made an application for interim measures at the Hague District Court, claiming that the Netherlands State should be ordered to instruct the CBG to replace the published full label version of the summary of product characteristics with the carve-out version. The court hearing the application for interim measures allowed Warner-Lambert’s claims in part. In the appeal proceedings before the Court of Appeal, the Netherlands State is now requesting that the judgment of the Hague District Court be set aside. By order of 4 July 2017 the Court of Appeal made a reference to the CJEU.

Questions: The question was basically, whether carved out summary of product characteristics of generic referring to indications or dosage forms covered by the patent of a third party should be considered as a request to limit the marketing authorisation for that generic medicinal product & whether it must be interpreted as precluding the competent authority from making public the whole summary of characteristics and the package leaflet of a medicinal product, in a situation where the marketing authorisation applicant or holder has sought approval for non-patented indication only.   

Opinion: Advocate General Kokott in her opinion stated that the marketed version of a medicinal product must be the same as the authorised version. This is not only essential in order to guarantee legal certainty and transparency, but it is also consistent with the spirit and purpose of the carve-out arrangement in the second sentence of Article 11 of Directive 2001/83. Not only the initial introduction of a carve-out at the time of submitting marketing authorization application but also the subsequent introduction of a carve-out must therefore result in the limitation of the marketing authorisation for a medicinal product. The carve-out arrangement in the second sentence of Article 11 of Directive 2001/83, whereby still patented indications or dosage forms of the reference medicinal product need not be included in the summary of characteristics of a generic medicinal product, permits an exception to the principle of the uniformity of the reference medicinal product and the generic medicinal product. This is necessary so that generic medicinal products can be placed on the market after the data exclusivity period for reference medicinal products has expired, even if individual indications or dosage forms of the reference medicinal product are still patented. The wording of the second sentence of Article 11 of Directive 2001/83 is unclear in respect of whether a carve-out can also be introduced after the marketing authorisation has been granted for a medicinal product. However, the subsequent carve-out proves to be essential in any case in the complex system of authorisation of medicinal products under Directive 2001/83. Even though patent protection differs in the various Member States, the directive nevertheless provides for parallel application for a marketing authorisation for a medicinal product in all or several Member States or application for recognition of a marketing authorisation granted in one Member State in other Member States. Against this background, it seems logical to interpret the second sentence of Article 11 of Directive 2001/83 to the effect that it is also possible to introduce a carve-out after the marketing authorisation has been granted for a medicinal product. In order to ensure that the authorised version of a medicinal product corresponds to the version placed on the market, a subsequent carve-out of this nature must be regarded as an application to limit the marketing authorisation.

With respect to second question, the referring court wants to know whether the competent authorities may publish a full label version of the summary of product characteristics even though a carve-out has been notified. The third question seeks to ascertain whether it makes any difference that the authority requires the authorisation holder to refer in the package leaflet for the medicinal product, which does not contain the indication affected by the carve-out, to the authority’s website, on which the full label version of the summary of product characteristics can be found. The answer to the second and third questions follows from the proposed answer to the first question since, under Article 21(3) of Directive 2001/83, the competent authorities must make publicly available the summary of the product characteristics for each medicinal product which they have authorised. Accordingly, Article 11 and Article 21(3) of Directive 2001/83 must be interpreted as precluding the competent authority from making public the summary of characteristics and the package leaflet of a medicinal product, including those parts referring to indications or dosage forms which are covered by patent law, in a situation where the marketing authorisation applicant or holder has notified the authority that, in accordance with the second sentence of Article 11 of the directive, he is not including such indications or dosage forms in the summary of characteristics and the package leaflet.  

In light of the foregoing, Advocate General Kokott proposed that the Court answer the request for a preliminary ruling from the Gerechtshof the Haag (Court of Appeal, The Hague, Netherlands) as follows:

1.      Articles 10 and 11 of Directive 2001/83/EC on the Community code relating to medicinal products for human use, as amended by Directive 2012/26/EU, must be interpreted as meaning that a communication whereby the marketing authorisation applicant or holder for a generic medicine, within the meaning of Article 10, notifies the authority that he is not including in the summary of product characteristics and the package leaflet, pursuant to the second sentence of Article 11, those parts of the summary of product characteristics for the reference medicine referring to indications or dosage forms covered by the patent right of a third party should be considered as a request to limit the marketing authorisation for that generic medicinal product to the remaining indications or dosage forms.

2.      Article 11 and Article 21(3) of Directive 2001/83 must be interpreted as precluding the competent authority from making public the summary of characteristics and the package leaflet of a medicinal product, including those parts referring to indications or dosage forms which are covered by patent law, in a situation where the marketing authorisation applicant or holder has notified the authority that, in accordance with the second sentence of Article 11 of the directive, he is not including such indications or dosage forms in the summary of characteristics and the package leaflet.

Glyceryl phenylbutyrate - USA

IPR decision (Oct 05, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01767	07/13/2017	01/30/2018	Par Pharma	9,254,278	Terminated-Settled
IPR2017-01768	07/13/2017	01/30/2018	Par Pharma	9,095,559	Terminated-Settled
IPR2017-01769	07/13/2017	01/30/2018	Par Pharma	9,326,966	Terminated-Settled

On US’278 patent, Lupin filed IPR (IPR2017-01159) on 03/27/2017 which was terminated because of settlement on 07/26/2018.

On US’559 patent, Lupin filed IPR (IPR2016-00829) on 04/01/2016 & final written decision (unpatentable) issued by PTAB on 09/26/2017.

On US’966 patent, Lupin filed IPR (IPR2017-01160) on 03/27/2017 which was terminated because of settlement on 07/26/2018.

On US 9,254,278 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method of treating a subject with a urea cycle disorder, the method comprising: administering to the subject in need thereof glyceryl tri-[4-phenylbutyrate] in an amount sufficient to produce a fasting plasma ammonia level that is less than half the upper limit of normal for plasma ammonia level.

4. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, and wherein the method further comprises restricting the subject's dietary protein intake.

8. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, and wherein the method further comprises monitoring the subject's ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not being adequately digested by the subject's pancreatic lipases.

12. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of sodium phenylbutyrate and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; (c) administering an initial dosage of glyceryl tri-[4-phenylbutyrate], wherein the initial dosage is determined by the amount of the initial dosage of sodium phenylbutyrate, and (d) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage of glyceryl tri-[4-phenylbutyrate] if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

US 9,095,559 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in a subject being treated for a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

2. A method of treating a subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

3. A method of administering glyceryl tri-[4-phenylbutyrate] to a subject having a urea cycle disorder, the method comprising: (a) measuring a first fasting plasma ammonia level for the subject; (b) comparing the first fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an initial dosage of glyceryl tri-[4-phenylbutyrate] to the subject if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level and less than the upper limit of normal for plasma ammonia level.

US 9,326,966 (Horizon Therapeutics, Inc.; Exp: Mar 9, 2032)

1. A method of treating a subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level, wherein the upper limit of normal for plasma ammonia level is in the range of 26-64 .mu.mol/L.

6. A method of treating a pediatric subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the pediatric subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

9. A method of treating an adult subject with a urea cycle disorder who has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma ammonia level less than the upper limit of normal for plasma ammonia level, the method comprising: (a) measuring a fasting plasma ammonia level for the adult subject; (b) comparing the fasting plasma ammonia level to the upper limit of normal for plasma ammonia level; and (c) administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater than the initial dosage if the fasting plasma ammonia level is greater than half the upper limit of normal for plasma ammonia level.

12. A method of treating a patient having a urea cycle disorder comprising: (a) administering an initial effective dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) to the patient, wherein the initial effective dosage is calculated based on body surface area of the patient; (b) measuring the patient's urinary PAGN and/or fasting plasma ammonia level to determine whether to change the dosage of the glyceryl tri-[4-phenylbutyrate] (HPN-100); and (c) administering a subsequent effective dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100) to the patient that is either the same as the initial effective dosage or is an increased dosage, wherein said increased dosage, if any, is calculated based on the patient's urinary PAGN and/or fasting plasma ammonia level.

Rituximab - USA

IPR decision (Oct 04, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01095	03/15/2017	10/06/2017	Celltrion Inc.	9,296,821	Claims 1–6 are unpatentable

On US’821 patent, Pfizer previously filed IPR (IPR2018-00186) which was instituted on 06/14/2018.

US 9,296,821 (Biogen Inc; Exp: Jun 11, 2019)

1. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method comprises administering 375 mg/m.sup.2 of rituximab, and wherein the method provides a beneficial synergistic effect in the patient.

2. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient 375 mg/m.sup.2 of C2B8 during a chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and prednisone (CVP therapy).

3. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient 375 mg/m.sup.2 of a chimeric anti-CD20 antibody during a chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the chimeric anti-CD20 antibody is produced from nucleic acid encoding a light chain variable region comprising the amino acid sequence in SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence in SEQ ID NO: 2, and comprises human gamma 1 heavy-chain and kappa light-chain constant region sequences.

4. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method comprises administering 375 mg/m.sup.2 of rituximab once every 3 weeks for 8 doses, and wherein the method provides a beneficial synergistic effect in the patient.

5. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient 375 mg/m.sup.2 of C2B8 once every 3 weeks for 8 doses during a chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and prednisone (CVP therapy).

6. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient 375 mg/m.sup.2 of a chimeric anti-CD20 antibody once every 3 weeks for 8 doses during a chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the chimeric anti-CD20 antibody is produced from nucleic acid encoding a light chain variable region comprising the amino acid sequence in SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence in SEQ ID NO: 2, and comprises human gamma 1 heavy-chain and kappa light-chain constant region sequences.

Trastuzumab - USA

IPR decision (Oct 03, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-00804	01/30/2017	07/27/2017	Hospira, Inc.	6,627,196	Claims 1–3, 5, 7, 9–11, and 17–33 are patentable
IPR2017-01139	03/24/2017	10/04/2017	Celltrion, Inc.		Claims 1–3, 5, 7, 9–11, 13–15, and 17–33 are patentable
IPR2017-00805	01/30/2017	07/27/2017	Hospira, Inc.	7,371,379	Claims 1–3, 5, 7, 9–11, 16–28, and 30–40  are patentable
IPR2017-01140	03/24/2017	10/04/2017	Celltrion, Inc.		Claims 1–3, 5, 7, 9–11, 13–28, and 30–40 are patentable
IPR2017-00737	01/20/2017	07/27/2017	Hospira, Inc.	7,892,549	Claims 1–17 are Unpatentable
IPR2017-01122	03/21/2017	10/04/2017	Celltrion, Inc.		Claims 1–11 and 14–17 are Unpatentable

On US’196 patent, Samsung Bioepis filed IPR (IPR2017-01958) on 08/25/2017 which was terminated.

On US’379 patent, Samsung Bioepis filed IPR (IPR2017-01959) on 08/25/2017 which was terminated.

On US’549 patent, Samsung Bioepis filed IPR (IPR2017-01960) on 08/25/2017 which was terminated & institution was denied on another Hospira’s petition (IPR2017-00739).

US 6,627,196 (Genentech, Inc.; Exp: Aug 25, 2020)

1. A method for the treatment of a human patient diagnosed with cancer characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of an anti-ErbB2 antibody to the human patient, the method comprising: administering to the patient an initial dose of at least approximately 5 mg/kg of the anti-ErbB2 antibody; and administering to the patient a plurality of subsequent doses of the antibody in an amount that is approximately the same or less than the initial dose, wherein the subsequent doses are separated in time from each other by at least two weeks.

16. A method for the treatment of a human patient diagnosed with cancer characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of an anti-ErbB2 antibody to the human patient, the method comprising: administering to the patient an initial dose of the antibody, wherein the initial dose is a plurality of doses, wherein each of the plurality of initial doses is at least approximately 1 mg/kg and is administered on at least 3 consecutive days, and administering to the patient at least 1 subsequent dose of the antibody, wherein at least one subsequent dose is at least approximately 6 mg/kg, and wherein administration of the last initial dose and the first subsequent and additional subsequent doses are separated in time by at least 3 weeks.

24. A method for the treatment of cancer in a human patient comprising administering to the patient a first dose of an anti-ErbB2 antibody followed by two or more subsequent doses of the antibody, wherein the subsequent doses are separated in time from each other by at least two weeks.

US 7,371,379 (Genentech, Inc.; Exp: Feb 16, 2022)

1. A method for the treatment of a human patient diagnosed with cancer characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of an anti-ErbB2 antibody to the human patient, the method comprising: administering to the patient an initial dose of at least approximately 5 mg/kg of the anti-ErbB2 antibody; and administering to the patient a plurality of subsequent doses of the antibody in an amount that is approximately the same or less than the initial dose, wherein the subsequent doses are separated in time from each other by at least two weeks; and further comprising administering an effective amount of a chemotherapeutic agent to the patient.

29. A method for the treatment of a human patient diagnosed with cancer characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of an anti-ErbB2 antibody to the human patient, the method comprising: administering to the patient an initial dose of the antibody, wherein the initial dose is a plurality of doses, wherein each of the plurality of initial doses is at least approximately 1 mg/kg and is administered on at least 3 consecutive days, and administering to the patient at least one subsequent dose of the antibody, wherein at least one subsequent dose is at least approximately 6 mg/kg, and wherein administration of the last initial dose and the first subsequent and additional subsequent doses are separated in time by at least 3 weeks, and further comprising administering an effective amount of a chemotherapeutic agent to the patient.

US 7,892,549 (Genentech, Inc.; Exp: Dec 10, 2018)

1. A method for the treatment of a human patient with breast cancer that overexpresses ErbB2 receptor, comprising administering a combination of an antibody that binds ErbB2, a taxoid, and a further growth inhibitory agent to the human patient in an amount effective to extend the time to disease progression in the human patient, wherein the antibody binds to epitope 4D5 within the ErbB2 extracellular domain sequence.

5. A method for the treatment of a human patient with breast cancer characterized by overexpression of ErbB2 receptor, comprising administering an effective amount of a combination of an anti-ErbB2 antibody which binds epitope 4D5 within the ErbB2 extracellular domain sequence, a taxoid, and a further therapeutic agent, to the human patient.

16. A method for the treatment of a human patient with ErbB2 overexpressing breast cancer, comprising administering a combination of an antibody that binds epitope 4D5 within the ErbB2 extracellular domain sequence, a taxoid and a further growth inhibitory agent, in the absence of an anthracycline derivative, to the human patient in an amount effective to extend the time to disease progression in the human patient.