Merck v. Gilead: $2.54 billion verdict

A federal jury in Delaware awarded Merck $2.54 billion in royalties over Gilead's Sovaldi and Harvoni hepatitis C drugs for infringing Merck's patent. The jury awarded Merck a royalty rate of 10% on total sales of $25.4 billion. The verdict can be found here: http://bit.ly/2gRtMqw

AMGEN V. HOSPIRA: “AN ISOLATED . . . ISOFORM” IS LIMITED TO ONE, AND DEPENDENT CLAIM TO MULTIPLE ISOFORMS IS INVALID

In Amgen v. Hospira[1], a patent infringement lawsuit (U.S. Patent No. 5,856,298) over the biosimilar version of Amgen’s Epogen (epoetin alfa), the parties disputed the meaning of the term "an isolated ... isoform" in claim 1:

1. An isolated biologically active erythropoietin isoform having a single isoelectric point and having a specific number of sialic acids per molecule, said number selected from the group consisting of 1-14, and said isoform being the product of the expression of an exogenous DNA sequence in a non-human eucaryotic host cell.

8. A composition consisting essentially of two or three erythropoietin isoforms according to claim 1. 

Amgen proposed that "an isolated ... isoform" allows for mixtures of at least one isoform.  Hospira proposed that the language allows for mixtures of only one isoform. 

The District Court (Richard Andrews) first discussed the case law regarding the meaning of the term ‘a’ or ‘an’ in a claim: “That 'a' or 'an' can mean 'one or more' is best described as a rule, rather than merely as a presumption or even a convention. The exceptions to this rule are extremely limited: a patentee must 'evince[] a clear intent' to limit 'a' or 'an' to 'one'. . .  An exception to the general rule that 'a' or 'an' means more than one only arises where the language of the claims themselves, the specification, or the prosecution history necessitate a departure from the rule."

Despite stating that the exceptions to this rule (limiting ‘a’ or ‘an’ to only one) are extremely limited, the District Court found that the exception applied “because the plain language evinces a clear intent to claim only one isoform. The claim language reads ‘an isolated ... isoform.’ Plaintiff's reading would render the word ‘isolated’ superfluous. Plaintiff's reading would equate the phrase ‘an isolated .. . isoform’ with ‘an isoform.’”  The District Court further emphasized that Claim 1 was amended during prosecution to read "[a]n isolated ... isoform."  The purpose of the amendment was "to further clarify that an erythropoietin isoform represents a homogeneous preparation."

After finding that Claim 1 requires only one isoform, the District Court found Claim 8 to be invalid since it contradicts Claim 1 's limitation that the isoform is "isolated." Claim 8 requires a mixture "consisting essentially of two or three" isoforms.  Claim 8 thus improperly narrows Claim 1.

The District Court did not discuss the doctrine of claim differentiation, and how the multiple isoforms of Claim 8 would imply that Claim 1 is not limited to a single isoform. 

The Opinion can be found here:

http://www.ded.uscourts.gov/sites/default/files/opinions/rga/2016/november/15-839.pdf

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[1] Amgen v. Hospira, No. 15-cv-839 (D. Del., filed Sept. 18, 2015).

HERCEPTIN IMMUNOCONJUGATE IPR (KADCYLA BIOSIMILAR INTER PARTES REVIEW)

In view of Hospira’s <http://biopharmapatent.blogspot.com/2016/12/hospira-has-filed-petition-for-inter.html> and Mylan’s http://biopharmapatent.blogspot.com/2016/11/mylans-herceptin-ipr-biosimilar-inter.html recent IPR (Inter Partes Review) petitions of patents covering the drug HERCEPTIN^®, we look back at a previously decided IPR (IPR2014-00676) proceeding relating to a patent that covers immunoconjugates of the drug HERCEPTIN^®. 

On October 27, 2015, the PTAB (Patent Trial and Appeal Board) found the claims of U.S. Patent No. 8,337,856, relating to immunoconjugates of an anti-ErbB antibody to be patentable.  The ‘856 Patent covers immunoconjugates of the humanized anti-ErbB2 antibody known as HERCEPTIN^®, linked to a maytansinoid toxin.  The Patent covers the drug KADCYLA^® (ado-trastuzumab emtansine).

The Petitioner (Phigenix Inc.) argued that an ordinary artisan would have had reason to substitute the mouse monoclonal antibody in the immunoconjugate of the prior art (Chari 1992) with huMAB4D5-8 (HERCEPTIN^®) in particular because it was known that (1) humanized antibodies were preferred over mouse counterparts for clinical applications, (2) huMAB4D5-8 had been FDA approved for use to treat breast tumors in humans, and (3) clinical studies indicated that huMAB4D5-8 worked well in combination with microtubule-directed chemotherapy agents for the treatment of breast cancer.

Patent Owner (Genentech, Inc. and ImmunoGen, Inc.) argued that the prior art indicated that HERCEPTIN^® -maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of toxicity in normal human liver tissue in patients.  The Patent Owner pointed to Pai-Scherf 1999, which describes a Phase I clinical study of human patients receiving an immunoconjugate (erb-38) comprising a portion of the anti-HER2 monoclonal antibody e23 fused to a truncated form of Pseudomonas exotoxin A. Although the Pai-Scherf group “initiated the study in humans based on ‘excellent antitumor activity and acceptable animal toxicities,’” it nonetheless observed unacceptable hepatotoxicity in all patients in the treatment group.  Pai-Scherf 1999 indicates that, in a clinical study, human patients experienced “hepatic injury” when exposed to erb-38.  Pai-Scherf 1999 discloses that the “toxicity of erb-38 is most likely due to the presence of erbB2 on hepatocytes, not detected by immunohistochemical staining in earlier publications.”

In response, Petitioner contended that Pai-Scherf 1999 was not relevant because it described the use of a “fusion protein,” not an antibody-drug conjugate.  The PTAB disagreed, stating that although the reference disclosed clinical studies using a single-chain immunoconjugate comprising a portion of an antiHER2/erbB2 antibody and a truncated form of a toxin, Pai-Scherf 1999 discusses generally the “targeting of tumors with antibodies to erbB2 armed with radioisotopes or other toxic agents.” 

The PTAB held that the ordinary artisans would not have had a reasonable expectation that any immunoconjugate, much less the claimed Herceptin^®- maytansinoid immunoconjugate in particular, would be useful to treat solid tumors in humans. 

HERCEPTIN PROTEIN PURIFICATION IPR (BIOSIMILAR INTER PARTES REVIEW)

Hospira has filed a petition for an IPR (IPR2016-0183) (inter partes review) of Genentech’s U.S. Patent No. 7,807,799, which is directed to methods of purifying antibodies.  The claims of the '799 Patent cover any protein that has a CH2/CH3 region, including Genentech’s trastuzumab (Herceptin^®).  The Patent Trial and Appeal Board (PTAB) has not yet made a decision on the petition.  The ’799 Patent claims a method of purifying a protein which comprises a CH2/CH3 region by carrying out protein A affinity chromatography at a temperature in the range of about 10 °C to about 18 °C.  Hospira mainly relies on the following two references for teaching the limitations of the claims of the ‘799 Patent:

Claim Limitations	WO 95/22389
1. A method of purifying a protein which comprises a CH2/CH3 region	A method for the purification of an IgG antibody . . .
comprising subjecting a composition comprising said protein to protein A affinity chromatography	A method for the purification of an IgG antibody . . . comprising sequentially subjecting the medium to (a) Protein A affinity chromatography.
at a temperature in the range from about 10 °C to about 18 °C.	The process in its most preferred embodiment consists of three purification steps (Protein A affinity, cation exchange, and hydrophobic interaction chromatography) . . . All steps are carried out at room temperature (18 – 25 °C).
5. The method of claim 1 wherein the protein is an antibody.	A method for the purification of an IgG antibody . . .

Claim Limitations	Van Sommeren (22 Preparative Biochemistry 135 (1992))
1. A method of purifying a protein which comprises a CH2/CH3 region	The purification of immunoglobulins (IgG) . . .”
comprising subjecting a composition comprising said protein to protein A affinity chromatography	The purification of immunoglobulins (IgG), in particular mouse monoclonal antibodies (mabs), using affinity chromatography with protein A as ligand is very popular . . .
at a temperature in the range from about 10 °C. to about 18 °C.	The effect of temperature, 4°C versus ambient temperature (AT) (20-25°C), was studied for the mabs OT-hCG-1C, 4D, 3A, 6A and 7B and OT-HIV-4A and 4B . .
2. The method of claim 1 further comprising exposing the composition subjected to protein A affinity chromatography to a protease inhibitor	Whether or not degradation of the IgG molecule occurs, depends among other factors on pH and subclass of the mab. However, if required, the activity of cathepsin D can be inhibited by addition of pepstatin A
5. The method of claim 1 wherein the protein is an antibody.	The purification of immunoglobulins (IgG) . . .

ANDAs: TEVA DOES NOT INFRINGE NASONEX POLYMORPH PATENT

After filing of an ANDA by Teva for a generic version of Nasonex (mometasone furoate), Merck responded by filing a patent infringement suit based on U.S. Patent No. 6,127,353 (‘353 Patent).[1]  The ‘353 Patent claims a monohydrate crystalline form of the active ingredient in Nasonex.  Teva’s formulation was made with another crystalline form, but Merck argued that Teva’s crystalline form converted to the patented crystalline form over the two year shelf life of Teva’s product. 

On November 16, 2016, Judge Robinson of the U.S. District Court of Delaware found the '353 Patent to be valid, but not infringed by Teva.

The court first addressed the validity of the ‘353 Patent.  Teva asserted that the ‘353 Patent was invalid for double patenting based on the Federal Circuit’s holding in “Gilead,”  which held that a later-issued but earlier-expiring patent can serve as a double-patenting reference against an earlier issued but later-expiring patent.  Gilead Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208, 1212 (Fed. Cir. 2014).  Recently, the holding in “Gilead” was relied on to invalidate a patent covering the drug Remicade.[2]  In this case, a terminal disclaimer was required to revive another related application during prosecution (relating to the amount of time during which the application was abandoned, not to the subject matter of the claims). The parties disputed whether the patent that issued from the revived application qualified as a double patenting reference because it expired before the '353 patent.  The court held that the '353 patent was not invalid for double patenting since the patents-at-issue were from the same family, were examined by the same examiner at the PTO, and that “[t]his is not an instance of a patentee seeking to extend the patent term with ‘sequential’ applications.” 

After finding the patent to be valid,[3] the court found that Teva’s product did not infringe the ‘353 Patent.  The question for infringement was whether Teva's ANDA product (an aqueous suspension made with prior art anhydrous form) contained any patented monohydrate during the product's shelf life.  

Merck’s expert tested several of Teva’s batches after their expiration dates (2.5 years and 4 years after expiration).  Merck’s expert testified that Teva’s crystals changed to the patented crystals but did not know when these crystals formed, and "the testing did not tell us anything about whether [the patented monohydrate] was present before expiry." Instead, the testing of the expired samples only revealed that the patented crystals appeared at some point between when it was manufactured and when it was tested.  The court concluded that the expired samples were not representative of the ANDA product and that without testimony (or evidence) of when the monohydrate crystals formed in the expired products, the conclusory statements provided by Merck’s expert did not establish infringement.

Regarding Teva’s commercial batches, Merck’s expert allowed the crystals from Teva’s product to dry before performing single crystal X-ray diffraction (SCXRD) analysis.  Merck’s expert explained that he was not able to harvest the monohydrate crystals from a wet slide like he had from the samples of the expired batches.  (For the expired batches, Merck’s expert gave the bottle containing the product a small shake in order to disperse the suspension inside the spray bottle and sprayed a sample on a clean glass slide. He selected a particular crystal using optical microscopy; withdrew the crystal; mounted it onto a MiTeGen loop; and performed SCXRD on the crystal).  The parties disputed whether the drying of the slides promoted crystal growth.  Merck’s expert testified that he "viewed lots of slides where they were drying and ...noticed no formation of new crystals of any sort, including [the monohydrate]." He testified that "[d]rying itself doesn't provide a crystal. It's not part of our standard crystallographic practice. It doesn't happen."  Teva’s expert disagreed, testifying that when Merck’ expert allowed the wet slides to dry over extended period of time, he provided an uncontrolled experiment, which was actually conducive to formation of the monohydrate.

Merck’s expert testified that following a "learning period," he was confident in his ability to visually distinguish (with optical microscopy) between the monohydrate and anhydrous crystals. In summarizing his findings, he testified that he had identified "dozens and dozens" of monohydrate crystals in Teva’s products.  Teva’s expert disagreed with the reliance on visual observation alone, testifying that such observation "has to be coupled with X-ray crystallography of that same crystal in order to have any confidence of the chemical identity in the solid form of that crystal."

Merck also presented the testimony of Teva's 30(b)(6) deposition witness who testified that he could see a peak at 1710 cm^-1 in Raman spectroscopy (corresponding to a peak characteristic of the monohydrate).  The court, relying on case law,[4] concluded that at least three peaks on a spectra must be used to identify material based on accepted practices, and that Teva’s internal testing did not establish the presence of the monohydrate in Teva's product.

The court found that Teva did not infringe the ‘353 Patent since “the literature and the experts consistently pair optical microscopy with another measurement method before conclusively distinguishing polymorphs. . . the court finds that Merck has not established, by a preponderance of the evidence, the presence of [monohydrate] in Teva's ANDA product during its two-year shelf life.” At no point during his testing of Teva’s commercial batch did Merck’s expert harvest a monohydrate crystal from a wet slide, and only relied on crystals from slides which he had dried.

The court’s Order can be found at < https://www.docdroid.net/OqaCSNc/merck-opinion-nov-16-2016.pdf.html>.

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[1] Merck Sharpe & Dohme Corp. v. Teva Pharmaceuticals USA Inc., case number 1:14-cv-00874, U.S. District Court for the District of Delaware.

[2] <https://www.pharmapatentsblog.com/2016/10/05/judge-grants-gilead-motion-to-invalidate-remicade-patent/>

[3] The District Court also dismissed Teva’s position that the ‘353 Patent lacked written description support

[4] Schering Corp. v. Apotex Inc., 2012 WL 2263292 (D.N.J. June 15,2012).

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.