German Court Grants Compulsory HIV Drug License

By: Markus Rieck  <http://www.fuchs-ip.eu/team/>

For the first time, the German Federal Patent Court in Munich granted a compulsory license in a preliminary injunction proceeding. The license was awarded to the U.S. company Merck. After the filing of a lawsuit against Merck for patent infringement in Dusseldorf, Merck responded by filing its own lawsuit against the Japanese company Shionogi, demanding a license of Shionogi's patent (EP 1 422 218). The patent protects the HIV drug raltegravir sold by Merck under the name Isentress in Germany. Merck had offered Shionogi a license fee of 10 million US dollars, which Shionogi rejected.

Compulsory licenses can be granted in Germany if the claimant tries without success to obtain a license from the patentee and public interest demands the grant of the license. In cases of emergency, the compulsory license can be granted by way of a preliminary injunction. The availability of an equivalent alternative drug is a factor in the decision to grant a preliminary injunction. In the Merck case, an independent expert advised the court that there was no equivalent alternative drug available for treatment of patients who had previously been treated with Merck’s product Isentress.

The German Federal Patent Court has always been reluctant to grant compulsory licenses. This is only the second decision that granted a compulsory license, and the first that granted the license in a preliminary injunction proceeding.

The decision has not been published, but the German Federal Patent Court has issued a press release <https://www.bundespatentgericht.de/cms/index.php?option=com_content&view=article&id=139:2016-09-01-13-36-42&catid=9:pressemitteilungen&Itemid=79&lang=en>, which states (machine translated) the following:

Intermediate use of AIDS medication granted

1 September 2016

In the proceedings pending before the Federal Patent Court for a provisional judicial order for a usage permit in European patent 1 422 218 (see also press releases of the Federal Patent Court of 27 June 2016 and 27 July 2016), the 3rd Senate of the Federal Patent Court issued judgment of 31 August 2016 Decided to temporarily allow the applicants to use the patent in such a way that they can continue to offer the drug Isentress® with the active substance raltegravir for an antiviral therapy against HIV / AIDS in the Federal Republic of Germany within the scope of the already dispensed forms of administration.

The Senate, after obtaining an expert opinion, has come to the conclusion that the drug is needed by certain groups of HIV-infected and / or AIDS-affected patients for medical reasons and cannot avoid these without considerable health risks on other preparations. This applies in particular to pregnant women, infants and children as well as patients treated for HIV for many years. In doing so, the Senate has also taken into account that an effective risk of infection for third parties is reduced by an effective reduction in viral loads. This is a public interest in granting a compulsory license.

In the opinion of the Senate, the applicants have also substantiated the further prerequisites for granting a compulsory license pursuant to section 24 (1) of the Patents Act. Moreover, the urgency required for the adoption of an interim application pursuant to Section 85 of the Patents Act (Zivilgesetz) is necessary because, in the oral hearing before the District Court of Düsseldorf (court: 4c O 48/15) on 13 September 2016, the sentencing to discontinue the sale of Isentress ® for infringement of the abovementioned European patent.

A written verdict is still pending. The main charge (3 Li 1/16) remains pending.

Az .: 3 LiQ 1/16

NEW TTAB RULES

The USPTO published a Notice of Final Rulemaking in the Federal Register on October 7 2016, at 81 F.R. 69950. It sets forth several amendments to the rules that govern inter partes (oppositions, cancellations, concurrent use) and ex parte appeal proceedings before the TTAB (Trademark Trial and Appeal Board).

For all proceedings, including those already in progress on January 14, 2017, some of the changes are:
• All pleadings and submissions must be filed through ESTTA. Trademark Rules 2.101, 2.102, 2.106, 2.111, 2.114, 2.121, 2.123, 2.126, 2.190 and 2.191.
• Service of all papers must be by email, unless otherwise stipulated. Trademark Rule 2.119.
• Response periods are no longer extended by five days for service by mail. Trademark Rule 2.119.
• Deadlines for submissions to the Board that are initiated by a date of service are 20 days. Trademark Rule 2.119. Responses to motions for summary judgment remain
30 days. Similarly, deadlines for responses to discovery requests remain 30 days.
• All discovery requests must be served early enough to allow for responses prior to
the close of discovery. Trademark Rule 2.120. Duty to supplement discovery
responses will continue after the close of discovery.
• Motions to compel initial disclosures must be filed within 30 days after the deadline
for serving initial disclosures. Trademark Rule 2.120.
• Motions to compel discovery, motions to test the sufficiency of responses or
objections, and motions for summary judgment must be filed prior to the first
pretrial disclosure deadline. Trademark Rules 2.120 and 2.127.
• Requests for production and requests for admission, as well as interrogatories, are
each limited to 75. Trademark Rule 2.120.
• Testimony may be submitted in the form of an affidavit or declaration. Trademark
Rules 2.121, 2. 123 and 2.125.
• New requirements for the submission of trial evidence and deposition transcripts.
Trademark Rules 2.122, 2.123, and 2.125.
• For proceedings filed on or after January 14, 2017, in addition to the changes set
forth above, the Board's notice of institution constitutes service of complaints.
Trademark Rules 2.101 and 2.111.

Macitentan Patents

By: Divya Goyal from GreyB Service (guest author)

Macitentan (trade name Opsumit) is a drug by Actelion for the treatment of Pulmonary Arterial Hypertension (PAH). Macitentan delays progression of PAH.  Macitentan received approval from the FDA in December 2013. Since then 35 other countries have given an affirmation for its usage.

After its approval, in the first quarter of 2015, Opsumit sales were $99.5 million, which further rose to $390.2 million in the first half of 2016.

We at GreyB service studied patents relating to Macitentan.  Actelion currently owns 55% of the total patents for Macitentan. 

What is Macitentan and how it’s exclusive?

Before approval of Macitentan, Tracleer and Letairis were the only two FDA approved endothelin receptor antagonist ETRAs for oral PAH treatment. The problem with these two drugs was their adverse effect on a liver. Also, the phase-III clinical trials of the two drugs were primarily based on 6 minutes walking distance test. Macitentan’s phase-III clinical trial, on the other hand, was based on delaying disease progression.

The structure of Macitentan is derived from Tracleer which has a dual ET_A/ET_B activity. ET_A and ET_B are endothelin receptors whose activation results in raising or lowering blood pressure. It has more affinity to bind to ET_A which increases blood pressure when endothelin binds to it. Also, ET_A is responsible for curing PAH more as compared to ET_B.

Unlike Tracleer that requires two dosages per day, Macitentan requires only one. It also has enhanced oral efficacy and has less severe effects on the live and bile salt transport system. Also, Macitentan is designated as an orphan drug. An orphan drug is that which is used for the treatment of a rare disease.

Key Patents of Macitentan

The patent US7094781 titled Sulfamides And Their Use As Endothelin Receptor Antagonists by Actelion Pharmaceuticals is the key patent of Macitentan which claims its chemical structure. 

• Twenty-one unique patent families are published based on Macitentan.
• Out of these twenty-one unique patent families, only one is the API (active pharmaceutical ingredient) patent i.e. it claims the only the structure of Macitentan.

Macitentan has 21 unique patent families out of which one is the API (active pharmaceutical ingredient) patent. Actelion has protected Macitentan in 23 different countries details of which is in the table below:

Publication Number	Expiry
DK1345920T3	December 18, 2020
ES2260318T3	December 18, 2020
LU92381I2	December 18, 2005
PT1345920E	December 18, 2020
AT323079T	December 18, 2020
EP1345920B1	December 4, 2021
DE60118782D1	December 4, 2021
NO2014014I2	August 31, 2015
HU229403B1	December 04, 2026
KR819668B1	December 18, 2020
CN100432070C	December 18, 2020
IL155805A	December 04, 2021
MY129150A	December 18, 2020
AU2002227984B8	December 04, 2026
NZ525614A	December 04, 2021
ZA200303695A	December 18, 2020
AR35610A1	December 18, 2020
BR200116237A	December 04, 2021
MX2003004780A	December 04, 2021
US7094781B2	October 12, 2022
CA2431675C	December 4, 2021
JP04245130B2	December 04, 2021

In Australia, US and Hungary, Macitentan patents have the expiry date of Dec 2026, Oct 2022, and Dec 2026 respectively. However, in Luxembourg and Norway, Actelion’s patents on Macitentan have expired thus opening the market for generic versions.

Patents by Other Assignees on Macitentan

Other than Actelion, there are patents filed by other assignees on Macitentan that are going to be in effect even after expiration of the key patent. The classification of these patents based on the features they are protecting is provided below.

Distribution of Patents on the Basis of Features

At least 20 patents have been filed by assignees other than Actelion on Macitentan. Out of these 20, 1 patent is on formulation filed by INSERM of France.

Three patents are filed on methods of use. These patents disclose development of Endothelin receptor antagonist in treating other diseases.

There are four patents related to structures in which companies have made attempts to circumvent and develop technologies for different crystalline or amorphous structure of Macitentan.

Sandoz, for example, has a patent application, US20160074398A1 , that discloses a polymorph of Macitentan.

In the rest 12 patents, 5 are on combinations, 5 are on process and 2 are on intermediates.

What are the features Companies Should Avoid when Launching a Generic version of Macitentan

The table below provides the list of feature that different patents protect in different jurisdictions which a company that is trying to launch a generic drug of Macitentan should avoid.

Category		Patent		Assignee		Patent Scope/Protected features	Market Coverage
Formulation		US9265762B2		Actelion Pharmaceuticals		Formulation comprising Macitentan and a filler (lactose monohydrate with microcrystalline cellulose), disintegrant (sodium starch glycolate and polyvinylpyrrolidone), 0.1 to 3% in weight of surfactant (polysorbate) and lubricant (magnesium stearate).	AU, BR, CA, CN, DK, EP, ES, HK, HR, IL, JP, KR, MY, NO, NZ, PT, RU, SI, TW, ZA
Combination		US8999934B2		Board Of Regents, The University Of Texas System		Use of Macitentan with cytotoxic agents for inhibiting an astrocyte mediated protection of a brain metastasis cell.	AU, CA, CN, DK, EA, EP, ES, HR, IL, IN, JP, KR, MA, MX, NZ, PT, SG, SI, TW, US, WO
		US8541433B2		Actelion Pharmaceuticals		Use of Macitentan with paciltaxil for the treatment of ovarian Cancer	AR, AU, CA, CN, DK, EP, ES, HR, JP, KR, MX, PT, RU, SI, TW, US, WO
		EP2670405B1				Use of Macitentan with cytotoxic agents such as temozolomide and paciltaxil for the treatmnet of malignant glioma.	EP, AR, AU, CA, CN, CO, EA, EP, IL, JP, KR, MA, MX, NZ, SG, TN, TW, US, WO
		US8268847B2				Use of Macitentan with PDE5-inhibitory agents to treat disorders involve vasoconstriction.	AR, AU, BR, CA, CL, CN, DK, EP, ES, HK, HR, IL, JP, KR, MA, MX, MY, NO, NZ, PT, RU, SI, TW, WO, ZA
		US8809334B2				Use of Macitentan along with agents having prostacyclin receptor (IP) agonist properties.	AR, AU, BR, CA, CN, EP, IL, JP, KR, MA, MX, NZ, RU, TW, WO
Process		WO2015121397A1		Actelion Pharmaceuticals		Production method for synthesis of Macitentan	EP
		EP2978746A1					CA, CN, KR, TW, US, WO
		KR2016030972A (hyperlink not available)
		CA2915736A1				Production method for synthesis of Macitentan and reaction solvent such as ethylene glycol.	TW, WO
		CN104447572A		Nanjing Nmg-Adds		Production method for synthesis of Macitentan by reacting N- propyl sulfonamide and 5- (4- bromophenyl) -4, 6- dichloropyrimidine.
Intermediates	CN104311492A		Chengdu Climb Pharmaceutical		Disclosure of preparation of intermediates for the production of Macitentan
	CN104897833A				Disclosure of detection of intermediate (N- propylamino sulfonamide), which can be employed for the prodcution of Macitentan.
Structure	WO2014198178A1		Hangzhou Pushai Pharmaceutical Technology		Disclosure of a polymorph of Macitentan and its XRD configurations.
	WO2016009322A1		Sifavitor		Disclosure of amorphous form of Macitentan.
	US20110082151A1		Auspex Pharmaceuticals		Disclosure of deuterium incorporation in the structure of Macitentan.
	US20160074398A1		Sandoz AG		Disclosure of a polymorph of Macitentan and its XRD configurations.			AU, CA, EP, WO
Method of Use	CA2641952C		Actelion Pharmaceuticals		Use of an endothelin receptor antagonist for the treatment of early stage idiopathic pulmonary fibrosis			AU, BR, CN, EP, IL, JP, KR, MX, NO, RU, SG, US, ZA
	EP2509594A1		French Institute of Health and Medical Research (INSERM)		Use of endothelin inhibitor for the treatment of rapidly progressive glomerulonephritis.			US
	WO2015110593A1		Unassigned		Use of ETBR-inhibitor for use in the prevention or treatment of a HCMV infection.

Actelion, no doubt, is the most dominant player of the Macitentan drug segment. It owns 55% of the total patents filed on Macitentan while the rest 45% are filed by different players.  There is one patent by Auspex, a company acquired by Teva, that protects Macitentan molecule. 

Abbvie v. Amgen update (Humira biosimilar lawsuit)

In its complaint regarding Amgen's biosimilar version of the drug Humira, Abbvie alleged that 42 U.S.C. § 262(l)(8)(A) requires Amgen to provide notice to AbbVie “not later than 180 days before the date of the first commercial marketing” of the Amgen biosimilar product, which can only be given after FDA licensure.   AbbVie also requested an order compelling Amgen to comply with the notice of commercial marketing provision set forth in 42 U.S.C. § 262(l)(8)(A).  On October 28, 2016, Amgen stipulated that it will comply with the notice requirements of 42 U.S.C. § 262(l)(8)(A): “The parties agree that paragraph (l)(8)(A), as currently interpreted by the courts, requires Amgen Inc., the subsection (k) applicant, to provide notice to AbbVie Inc., the reference product sponsor, only after ABP 501 (now known as Amjevitaä) is licensed by the FDA and then not later than 180 days before the date of first commercial marketing of Amjevitaä in the United States.” 

The parties have also filed a joint proposed scheduling order, which proposes a trial commencing on November 4, 2019.

Abbvie Inc. v. Amgen Inc., 16-666, U.S. District Court for the District of Delaware (Wilmington). 

HUMIRA FORMULATION PATENT SURVIVES IPR

Abbvie Biotechnology Ltd.’s (Abbvie) strategy to protect the drug HUMIRA from biosimilars relies on a number of patents that claim the liquid formulation of the drug HUMIRA.  Previously, the Patent Trial and Appeal Board (PTAB ) denied Amgen’s IPR petitions to invalidate two of Abbvie’s liquid formulation patents.  U.S. Patent Nos. 8,916,157 and 8,916,158 in IPR2015-01514 and IPR2015-01517.  Coherus Biosciences Inc. (Coherus) petitioned the PTAB to invalidate a related formulation patent that was not previously litigated, U.S. Patent 9,114,166.  The PTAB has also denied Coherus’ petition (IPR2016-01018).

The Patent (U.S. Patent 9,114,166) challenged by Coherus claims a stable liquid aqueous pharmaceutical formulation:

1. A stable liquid aqueous pharmaceutical formulation comprising: a human anti-human Tumor Necrosis Factor alpha (TNFα) IgG1 antibody at a concentration of 50 mg/ml, wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7, and a buffer system; wherein the formulation is isotonic, suitable for single-use subcutaneous injection, and has a pH of 4.0 to 8.0.

Coherus’s (the petitioner) position was that:

Petitioner argues that “the only difference between the formulation components in Example 4 (formula b) [of Relton] and the challenged claims is the presence of a different IgG1 antibody, as opposed to the IgG1 antibody D2E7.” Petitioner then relies on van de Putte for its teaching of D2E7.  Petitioner argues that it was well known that D2E7 effectively treated rheumatoid arthritis when administered as a weekly dose of 20, 40, or 80 mg D2E7 by subcutaneous self-injection. Id. Petitioner further argues that a person of ordinary skill in the art would have had a reason to prepare a stable liquid formulation of D2E7 with a buffer system because liquid formulations were the preferred form of delivering proteins due to the convenience of manufacturing and clinical use.

PTAB’s reasoning for denying the petition was that:

We are not persuaded by this argument and supporting evidence. Petitioner’s argument that Relton’s disclosure of the class of IgG1 antibodies is sufficient guidance for a skilled artisan to prepare a stable, high concentration, liquid formulation of D2E7 is once again belied by the state of the art and Dr. Manning himself. In his book chapter (Chapter 8), Dr. Manning states that “[t]he exquisite sensitivity of protein structure, function, and stability to the primary sequence does not readily lend itself to a generic approach for protein formulation.” He continues, stating “[e]ven for closely related proteins, the relative stability and major pathways for degradation might be quite different.” Dr. Manning’s opinion (from his book) is consistent with Patent Owner’s summary of the state of the art at that time.  For example, Wang explains that, although certain factors have been identified that contribute to the stabilization of proteins, “the structural differences among different proteins are so significant that generalization of universal stabilization strategies has not been successful.”  Accordingly, Wang concludes that “the most formidable challenge in formulating a liquid protein pharmaceutical is to preserve the biological activity of the protein for an acceptable shelf life. Unfortunately, there is no single pathway to follow in formulating such a product. Usually, proteins have to be evaluated on a case-by-case basis.”  Thus, we are not convinced by Petitioner’s argument that Relton’s generic disclosure of IgG1 antibody formulations translates to a reasonable expectation of success in formulating a stable, liquid, high-concentration D2E7 formulation.

Accordingly, we determine that Petitioner has not shown sufficiently that a skilled artisan—without the benefit of hindsight—would have combined van de Putte and Relton to achieve the claimed formulation with a reasonable expectation of success. See Grain Processing Corp. v. Am.- Maize Prods. Co., 840 F.2d 902, 907 (Fed. Cir. 1988) (“Care must be taken to avoid hindsight reconstruction by using ‘the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit.’” (quoting Orthopedic Equip. Co. v. United States, 702 F.2d 1005, 1012 (Fed. Cir. 1983))).