Cefdinir is a third-generation oral cephalosporin antibiotic sold under the brand names Cefzon and Omnicef

As of 2008, cefdinir, as Omnicef, was the highest-selling cephalosporin antibiotic in the United States, with more than US$585 million in retail sales of its generic versions alone.^[1]

It was discovered by Fujisawa Pharmaceutical Co., Ltd. (now Astellas) and introduced in 1991 under the brand name Cefzon.^[2][3]Warner-Lambert licensed this cephalosporin for marketing in US from Fujisawa.^[4] Abbott obtained U.S. marketing rights to Omnicef (cefdinir) in December 1998 through an agreement with Warner-Lambert Company.^[5] It was approved by FDA on Dec 4, 1997.^[6] It is available in US as Omnicef by Abbott Laboratories and in India as Cednir by Abbott, Kefnir by Glenmark and Cefdiel by Ranbaxy.

The ongoing patent battle relating to Cefdinir polymorphism and crystalline forms is described from a scientific point of view. This case study illustrates some of the strategies adopted by generic bulk manufacturers to challenge originator's patents on polymorphic forms. 

The filing of patents claiming new crystalline forms, usually 4−6 years after the original product patent, is a typical strategy applied by such companies to extend patent protection. This patent protection approach by big pharma forces generic bulk producers to discover and file patents on new polymorphs if they want to market the drug after expiry of the product patents. 

Polymorphism is of paramount importance due to its effect on some physical characteristics of powders such as melting point, flowability, vapour pressure, bulk density, chemical reactivity, apparent solubility and dissolution rate, and optical and electrical properties. In other words, polymorphism can affect drug stability, manipulation, and bioavailability

The patent strategy adopted by Fujisawa to protect the life cycle of Cefdinir (1) was based on the filing of a second patent, several years after the product patent, covering the commercialised anhydrous crystalline form of the drug. As a consequence, to overcome the Cefdinir (1) patent protection of the U.S. and Japanese markets, generic bulk producers had to discover a new crystalline form, with the same bioavailability as the marketed one. 

The situation, with competition among several companies, resulted in the generation of a patent “tangle”. In addition to overcoming the Fujisawa patent, the principal aim of generic bulk producers was to generate a competitive market advantage by protecting their new crystal form.

This patent extended the protection of Cefdinir (1) marketed in the United States up to December 2011, 9 years after the expiration of the patent covering the structure........Abbott US2005/0059818

An invention must:

A. be novel.

B. not be obvious for a person skilled in the art

C. be useful.

D. contain sufficient details to allow others to reproduce the invention.

Crystalline form patents represent a small but very important segment of product patents because of the possibility to extend the medicine market protection, thus delaying competition from generic firms. We think that for these specific types of patent applications, the following basic rules should be applied:

1. The crystalline form cannot be characterised by a single technique.

2. When a pharmaceutical application or advantage is claimed to justify the usefulness of the patent application, volatile impurities must comply with ICH guidelines,23 and the new crystalline form must be sufficiently stable to be used as a medicine.

3. A new polymorph must have an advantage over the one previously described. All the patent applications described in this paper do not show a clear advantage of the claimed polymorph with respect to Fujisawa's anhydrous form. The claiming of a crystalline form or solvate without a clear understanding of the usefulness is common to several patent case studies. From our direct experience, an interesting example is Cabergoline (Parkinson's disease):  the originator and generic companies claimed up to 14 crystalline forms and solvates.24 What is the meaning of all these patent applications? Where is the advantage with respect to the previously reported crystalline forms or solvates?

Figure The priority filing dates of all the patents claiming Cefdnir crystalline forms are reported.

Astellas Pharma Inc. (アステラス製薬株式会社 Asuterasu Seiyaku Kabushiki-gaisha^?) is a Japanese pharmaceutical company, formed on 1 April 2005 from the merger of Yamanouchi Pharmaceutical Co., Ltd. (山之内製薬株式会社 Yamanouchi Seiyaku Kabushiki-gaisha^?) and Fujisawa Pharmaceutical Co., Ltd. (藤沢薬品工業株式会社 Fujisawa Yakuhin Kōgyō Kabushiki-gaisha^?).

Polymorphisms and Patent, Market, and Legal Battles:  Cefdinir Case Study

Walter Cabri ,*^† Paolo Ghetti , Giovanni Pozzi , and Marco Alpegiani

Antibioticos S.p.A., Research & Development, Strada Rivoltana km 6/7, 20089 Rodano, Milano, Italy

Org. Process Res. Dev., 2007, 11 (1), pp 64–72

DOI: 10.1021/op0601060

 http://pubs.acs.org/doi/abs/10.1021/op0601060

References

1.  "2008 Top 200 generic drugs by retail dollars"  PDF (399.4 KB). Drug Topics (May 26, 2009). Retrieved on July 24, 2009.
2.  http://www.astellas.com/en/corporate/news/detail/astellas-filed-lawsuit-against.html
3.  http://wenku.baidu.com/view/a2ef6330b90d6c85ec3ac6fa.html
4.  http://www.elsevierbi.com/publications/the-pink-sheet/52/005/comprecin-has-excellent-chance-to-reach-us-market-this-year-dupont-prophenytoin-crosslicense-deal?p=1
5.  http://www.globenewswire.com/newsarchive/mrx/pages/news_releases.html?d=94045
6. http://www.drugs.com/mtm/cefdinir.html
7.  http://www.toku-e.com/Assets/MIC/Cefdinir.pdf
8.  "Omnicef capsules Patient Information" (PDF). Abbott Laboratories. February 2004. Archived from the original (PDF) on 2006-11-18. Retrieved 2006-11-24.

External links

• Medline Plus: Cefdinir

//////

WO 2015104605.new patent on Rivaroxaban, Wockhardt Ltd

Process for preparing rivaroxaban - comprising the reaction of a thioester compound and its salts with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.

WO-2015104605

SHUKLA, Jagdish Dattopant; (IN).
YADAV, Ramprasad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

Wockhardt Ltd

The synthesis of (II) via intermediate (I) is described (example 7, page 15)

4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

A PROCESS FOR PREPARING RIVAROXABAN OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF Field of Invention The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The novel thioester intermediate represented by formula II Formula II or a pharmaceutically acceptable salt thereof, wherein R is leaving group. Background of the invention The drug compound having the adopted name "Rivaroxaban" has chemical name, 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)-2-thiophenecarboxamide; and has the structural formula I, Formula I The commercial pharmaceutical product XARELTO® tablets, contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases. U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof. The process of US '456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3- { [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)-dione, which on cyclization using Ν,Ν-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban. Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908. The reported processes suffers one or the other problems like lower yield, use of carcinogenic reagents like hydrobromic acid at elevated temperature, longer reaction time, and the like. Therefore, there is a need to develop a simple and industrially feasible process for Rivaroxaban and its intermediates or a pharmaceutically acceptable salt thereof.

Wockhardt Ltd chairman Habil Khorakiwala

process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof

Formula IIA

with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,

Formula III

Formula I

EXAMPLE 7: One pot process for Rivaroxaban

The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.

Yield: 10.0 gm

Purity: 99.3 %

EXAMPLE 8: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.

EXAMPLE 9: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015104605&recNum=7&maxRec=57790&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

////////

Selin Sinem Erciyas

Selin Sinem Erciyas Selin is a partner specializing in Patent, Life Sciences and Trademark Law. She has been involved in a number of advisory and litigation IP matters and has handled hundreds of contentious and non-contentious oppositions and court actions involving patents and trademarks. Selin has led on a number of patent infringements, declaration of non-infringement and nullity actions.  She is a graduate of Ankara University and holds an LL.M. degree in European and International Commercial Law from the Ludwig-Maximilians University of Munich.  She worked at the European Patent Office as a trainee lawyer in International and Legal PCT Affairs Department. She is a member of Ankara Bar Association.   selin.yalincakli@gun.av.tr   https://tr.linkedin.com/pub/selin-sinem-yalıncaklı-erci̇yas/3/b43/a59

SELIN SINEM ERCIYAS

Tel:

Work +90 312 213 86 37

Email:

selin.yalincakli@gun.av.tr

WORK DEPARTMENT

Intellectual Property, Life Sciences, Commercial Litigation.

POSITION

Selin Sinem Erciyas is partner in Intellectual Property Department, specializing in Patent Law and Life Sciences issues. Selin has been involved in a number of advisory and litigation matters on all fields of IP and handled hundreds of both contentious and non-contentious administrative oppositions and court actions involving patents and trademarks. Selin took responsibility in a number of patent infringement actions, declaration of non-infringement actions and nullity actions. She represents number of multinational pharmaceutical companies before the Ministry of Health in relation with regulatory issues and assists these pharmaceutical companies in regulatory examinations before the MOH. Selin is a counsel to the Association of Research-Based Pharmaceutical Companies (AIFD). She represented the AIFD at the commission meetings of the Turkish Parliament on the draft Patent Law in Turkey. Selin represented AIFD and EFPIA before the Turkish Government and EU Delegation to Turkey in relation with patent and regulatory matters.

CAREER

Gün+Partners 2006 - to date Trainee Lawyer – European Patent Office- International and Legal PCT Affairs Department- 2006.

LANGUAGES

Turkish, German, English.

MEMBER

Ankara Bar Association, AIPPI, FICPI, GRUR, MARQUES.

EDUCATION

Ludwig Maximilians University of Munich (LL.M Eur.- European and International Commercial Law 2005) Ankara University (Faculty of Law- LL.B- 2002) Arı College -1998.

Selin Sinem Yalıncaklı ERCİYAS

GÜN + PARTNERS

KORESEHITLERI CAD 17, ZINCIRLIKUYU, 34394 ISTANBUL, TURKEY

Aysel Korkmaz

Aysel Korkmaz Aysel is a managing associate specializing in the Patent and Dispute Resolution. She is currently working on patent litigation ranging from infringement to negative clearance actions, data protection and exclusivity particularly in the pharmaceuticals and machinery sectors.  She also advises on insurance and reinsurance litigation and disputes, particularly high level construction and fire claims. She represents London Reinsurers in relation to the fire at the Cargo Building at the Istanbul airport.  She is a graduate of Yeditepe University in Istanbul and holds an LL.M. in International Commercial and Business Law from University of East Anglia in the UK and she has been a member of the Istanbul Bar Association since 2005.   aysel.korkmaz@gun.av.tr https://tr.linkedin.com/pub/aysel-korkmaz/b5/a2a/977/en + 90 (212) 354 00 34

East Anglia Üniversitesi, Norwich, İngiltere (Yüksek Lisans, Uluslar arası Ticaret Hukuku, 2007)
Yeditepe Üniversitesi, Hukuk Fakültesi, İstanbul (Lisans, 2004)
Akyurt Sağlık Meslek Lisesi, Ankara (1999)

Experience

Managing Associate

Gün + Partners

April 2008 – Present (7 years 4 months)

Education

University of East Anglia

Master of Laws (LL.M.)

2006 – 2007

Yeditepe University

Bachelor of Laws (LL.B.)

.........

Zydus Cadila Healthcare Ltd, WO 2015102017, New patent lorcaserin

Processes for the preparation of lorcaserin
Zydus Cadila Healthcare Ltd
WO 2015102017, 09 July2015 

Applicants:	CADILA HEALTHCARE LIMITED [IN/IN]; Zydus Tower, Satellite Cross Roads Ahmedabad – 380 015 Gujarat (IN)
Inventors:	DWIVEDI, Shriprakash Dhar; (IN). SHAH, Alpeshkumar Pravinchandra; (IN). GAJJAR, Samir Rameshbhai; (IN). KHERA, Brij; (IN)

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.
On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol
Useful for treating obesity.
The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed.  Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.
In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)
U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.
U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form
I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.
The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.
International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.
International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.
U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.
International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.
see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription


Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.
100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.
Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.
Example-9: Preparation of crystalline Form I lorcaserin hydrochloride
50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

/////////