Gliptins Global Competition, Will Impact India Too

Global market for diabetes drugs exceeds over $21 billion in 2006 and is still expanding rapidly due to the high prevalence of diabetes and lifestyle changes (WHO index) with India estimated to lead in numbers of diabetic population closely followed by China and the US. Such figures not only pushed drug research companies to expand their R&D pipelines for anti-diabetic drug candidates but also fuelled the competitive race among the drug companies to capture this cut-throat yet money-spinning segment and introduce new therapeutically superior drugs before the rivals’ potential drugs. One such area is emergence of new class of oral hypoglycemics which block enzyme dipeptidyl peptidase IV, particularly known as Dipeptidyl Peptidase IV (DPP IV) inhibitors. Also referred as Gliptins, DPP IV inhibitors are emerging drug class for the treatment of Type II diabetes. According to the industry analysts, DPP IV inhibitors has therapeutic and market potential to achieve blockbuster status.

Indian Patent Pipeline

Gliptins global competition is also reflecting in India, with mail-box applications pending with Indian Patent Office for most of the gliptins including Vildagliptin, Sitagliptin, Saxagliptin, Denagliptin and indigenously invented Melogliptin. Drug companies had surely done their homework over India’s diabetes facts & figures, and strategically moved to file patent applications in India. Let’s have a quick patent check for some of the important gliptins pending with/granted by Indian Patent Office.

To be continued …

Patent Circle Building Gravity

Brett Trout of BlawgIT lately posted his Patent Meme mentioning that “there are lots of blogrolls out there, but almost all include non-patent related blogs or patent blogs which have not been updated for months.” Stating, “if only I could have a link to all the important patent law blogs in one place”, Brett listed down his important patent law blogs which also include Patent Circle. This is obviously a great feeling and a sense of pride that fellow US patent attorney recognize Patent Circle as one of the important patent law blogs and includes in likes of Patent Baristas (my favourite), Patent Docs (top-class), Orange Book Blog (not to be missed), Patently-O (extraordinary) and Patent Prospector (best in the class). Thank you Brett for recognizing and including Patent Circle in your invaluable p-meme!

Not only fellow bloggers are recognizing the spirit of Patent Circle, but also India’s leading business newspapers are keeping track of our interesting posts. India’s premier business newspaper Economic Times has lately covered a story on antiretroviral drug Etravirine, which brought into notice by one of our earlier posts. Earlier, another leading business newspaper Business Standard covered a story on global pharma seeking cancer drug patents, which was also moved by one of our earlier post. Even, Business Standard covered an exclusive story on bloggers driving India’s IPR regime and recognized Patent Circle as one of the blog for separating the wheat from the chaff in the flood of intellectual property related information.

We would like to thank all our readers for their support, encouragement and involvement. We are committed to contribute to the area of patents, will continue to bring latest updates, critical analysis and unbiased stories from the world of patents and will keep building presence of India’s first patent law blog on the global platform. We surely appreciate your views, comments and suggestions on any of our posts. Your feedback not only helps identifying our low points but also encourage pushing the envelope to make Patent Circle a reliable and authentic source. If you feel Patent Circle has managed to build a niche and has contributed to add value to your knowledge and information base, please do let us know at chhonkar.varun@gmail.com or seemasingh.patentlawyer@gmail.com.

Ranbaxy Filed Post-Grant Opposition for Valganciclovir

Ranbaxy has filed a post-grant opposition at Chennai Patent Office under section 25(2) of the Patents Act, 1970 against the grant of Indian Patent No. 207232 (read our earlier post) to Roche for Valganciclovir, questioning the validity of the patent on ground of enhanced efficacy under section 3(d). Earlier, during pre-grant opposition period Mumbai-based NGO Lawyers Collective contested the patent grant but the Chennai Patent Office later granted patent without hearing the opposition filed by Lawyers Collective. The ‘232 patent is having priority prior to 1995, which probably makes Valganciclovir a pre-1995 drug compound to be patented in India.

USD 20 billion going off-patent

About 11 leading drugs, including four blockbuster drugs worth USD 29 billion are going off-patent this year in the US reports Reghu Balakrishnan from Financial Express. For full story read A $20 billion American generic market awaits Indian players.

Merck Generic Promotion

Just came across an interesting article about Merck’s promotional strategy to consolidate generic space for Fosamax, before its key indication patent expired. Read The Wacky World of Generics: Fosamax Edition.

Patent Granted for Anti-inflammatory Drug Lumiracoxib

Novartis has received an Indian Patent No. 208639 for anti-inflammatory drug Lumiracoxib against the mail-box application no. 1927/MAS/1998 filed on August 27, 1998 claiming early priority from US provisional application dated August 28, 1997. In November 2006, Lumiracoxib, marketed as Prexige received marketing approval from all European Union countries through a common procedure called MRP, but later on December 13, 2007 the European Medicines Agency recommended the withdrawal for Prexige from all EU market. Earlier, on September 27, 2007, the US Food and Drug Administration issued a not approvable letter for Lumiracoxib, requiring additional safety data. Lumiracoxib, a COX-2 selective inhibitor is broadly covered within the markush compound structure described in the US Patent No. 6,291,523. The corresponding European Patent EP 1 007 505 already been granted Supplementary Protection Certificate in most of the contracting states, running exclusivity till September 2018. The drug is also recalled in Australia, New Zealand, Philippines, and Canada. In January 2006, Novartis received Drug Controller General of India (DCGI) approval to import and market Prexige, but later announced to drop marketing plans for Lumiracoxib in India due to the growing concerns about its adverse side effects.

Patent Granted for Antiretroviral drug Etravirine

United States Food & Drug Administration lately approved a new antiretroviral drug Etravirine chemically 4-[[6-amino-5-bromo-2-[(4-cyanophenyl) amino] -4-pyrimidinyl] oxy] -3, 5-dimethylbenzonitrile marketed by Tibotec Pharmaceuticals Ltd. (a subsidiary of Johnson & Johnson) under the brand name Intelence. Etravirine (clinically known as TMC125) is broadly covered within markush pyrimidine structure described in US Patent Nos. 6,878,717 (indication patent) and 7,037,917 (basic compound patent), and also granted an Indian Patent No. 204028 against the mail-box application no. IN/PCT/2001/00436/MUM filed on April 20, 2001 claiming early priority from US provisional application dated November 10, 1998. Etravirine was designed by Belgian scientists to reduce drug resistance, partly by making a flexible molecule that can fit in the active pocket of HIV’s reverse transcriptase in different ways, even when the shape of that pocket changes because of viral mutations that would defeat other drugs (read).

Adieu to Fosamax, Camptosar Next to go Off-patent

Merck & Co. bids adieu to blockbuster osteoporosis drug Fosamax, which finally runs out patent protection, putting end Merck’s windfall $ 1.9 billion US market. Teva & Barr Laboratories launched the generic versions of Fosamax after receiving final approval from the US Food and Drug Administration and will jointly share 180-day market exclusivity. Under an agreement deal with Merck, Watson will launch an authorized generic to compete and share market space with Teva and Barr. Pfizer’s anti-cancer drug Camptosar worth over $ 500 million US sales is next to lose patent protection for its drug compound Irinotecan hydrochloride on February 20. In October 2007, Dabur Pharma received the tentative approval for generic Irinotecan from the US FDA.

Ignoring not the solution

Just came across an interesting article by D Ravi Kanth ‘Drug Capitalism’ pointing out the concern for affordable drugs to poor consumers, but what really caught my attention is, what Kanth pointed to be moot issue, whether the gap between those who invest billions of dollars to develop new medicines and those who need them most, particularly, the poorest of the poor, is bridgeable.

Undeniably, this is the core issue that need utmost attention across the globe including India, but unfortunately the issue is made diluted by raging politics over ‘Patients or Patents’.

Watson Authorized Generic For Merck's Osteoporosis Drug

Merck’s blockbuster osteoporosis drug Fosamax will lose patent protection tomorrow with the expiration of Orange Book listed US Patent No. 4,621,077, losing significant $ 1.6 billion US market to generic competition. Earlier in January, Merck announced to sign a deal for an authorized generic but did not disclose the name of its partner. Finally, it is Watson Laboratories that will be selling the authorized version of Fosamax. Barr Pharmaceuticals and Teva Pharmaceutical Industries are also expected to launch generic versions Fosamax this week.

Wockhardt Received Patent For Antibacterial NCE

Mumbai-based biotech company Wockhardt has recently received an Indian Patent No. 213142 for antibacterial NCE against the mail-box application no. 3/MUMNP/2005 filed on July 10, 2003. The published abstract of the application (u/s 11A of the Patents Act, 1970) reads as –

The present invention provides agents having high antimicrobial activity for preventing and treating infectious diseases. Thus, the present invention provides novel cyano-(substituted)-methylenepiperidinophenyl oxazolidinone derivatives, processes for making the compounds, as well as antimicrobial compositions containing said derivatives as active ingredients and methods of treating bacterial infections with the said derivatives.

Referring corresponding PCT publication WO2004007489, the antibacterial compounds are cyano-(substituted)-methylenepiperidinophenyl oxazolidinones. Interestingly, Wockhardt is having a strong research pipeline for anti-bacterial drug targets, with few already in clinical trails which include phase II WCK 771 (arginine salt of S (-) nadifloxacin), phase I WCK 2349 (oral prodrug of WCK 771), phase I WCK 1152 (enantiomer of another drug target WCK 919). Wockhardt’s other antibacterial drug targets in preclinical trails include WCK 2370, WCK 2664, WCK 1734, WCK 919 and WCK 1153 (enantiomer of WCK 919).

Merck dropped Melogliptin

Yet another indigenously discovered and invented anti-diabetic clinical drug candidate lost strategic and financial backup from the research-based company with Merck backing out to support co-development and commercialization of Glenmark’s phase II drug candidate Melogliptin (GRC 8200). The decision came after Merck’s decision to re-focus its portfolio and not to invest further in diabetes research and development. Earlier in 2003 and 2004, Novo Nordisk backed out from Dr. Reddy’s phase III anti-diabetic drug Ragaglitazar (DRF-2725) due to risk assessment and phase II anti-diabetic drug Balaglitazone (DRF-2593) due to lack of competitive advantage. Also, in 2003 Novartis discontinued development of anti-diabetic drug (DRF-4158) which Dr. Reddy’s out-licensed to Novartis in 2001. Later Dr. Reddy’s entered into co-development and commercialization agreement with Rheoscience for Balaglitazone, which is currently in final phase of clinical trial. Schwarz Pharma, in 2004, discontinued development of Ranbaxy phase II prostate drug Pamirosin (RBx 2258) whereas last year Medicines of Malaria Venture (MMV) lost interest in Ranbaxy’s phase II anti-malaria drug Arterolane.

Deals Still in Progress

In 2004, Torrent out-licensed a cardiac drug molecule (TRC 4XXX) to Novartis and Glenmark out-licensed an asthma drug Oglemilast (GRC 3886) to Forest Labs.

Cytopia Received Patent for JAK Kinase Inhibitors

Australian-based biotech drug discovery company Cytopia Pty Ltd. has lately received an Indian Patent No. 214081 (the ‘081 patent) for disubstituted pyrazine compounds having protein kinase, particularly Janus kinase (JAK) inhibitory activity. The ‘081 patent is issued against the mail-box application no. 1743/KOLNP/2004 dated November 17, 2004, claiming earliest priority from an Australian provisional application dated May 23, 2002. The published abstract of the Indian application (u/s 11A, the Patents Act, 1970) reads as –

"A compound of the general formula (I) or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof is described. A method of treating protein kinase-associated disease states using the compound of formula (I) is also described."

Referring corresponding US Patent No. 7,259,179, the disubstituted pyrazine compounds are used to treat protein kinase-associated disorders which result from aberrant protein kinase activity, in particular JAK activity and/or which are alleviated by inhibition of one or more of these enzymes. Further referring that the term ‘JAK’, ‘JAK kinase’ or ‘JAK family’ refers to protein tyrosine kinases which posses characterizing features of JAK1, JAK2, and JAK3.

Cytopia has few other pending applications with Indian Patent Office for drug targets in same class of JAK inhibitors to treat immune diseases and cancer.

1. 1748/KOLNP/2004 – Protein Kinase Inhibitors
2. 845/KOLNP/2006 – Selective Kinase Inhibitors
3. 616/KOLNP/2006 - Azole-based Kinase Inhibitors

In June 2006, Cytopia signed a licensing deal with Novartis to develop JAK3 inhibitor compounds for the prevention of transplant rejection and the treatment of multiple indications of autoimmune diseases. Under the deal Novartis will pay Cytopia approximately $ 9.5 million over three years including an up front payment and research funding. Over the life of deal Cytopia may also become eligible to receive development, regulatory and sales milestones which could total approximately US $ 205 million if an agreed number of multiple indications are successfully commercialized. Cytopia will also receive royalties on product sales.

Cytopia lately announced that its lead JAK2 inhibitor compound CYT387 demonstrated potent activity in cells isolated from patients with myeloproliferative disorders (MPDs). Till date, none of Cytopia’s JAK inhibitors is in any phase of clinical trials, but Cytopia’s anti-cancer lead drug CYT997 has already received IND status by the US FDA and likely to reach phase II trials. CYT997 belongs to class of cancer drugs known as Vascular Targeting Agents (VTAs) and is modified version of another compound CYT490. The application no. 847/KOLNP/2006 for CYT997 is pending with Kolkata Patent Office and was published in the Patent Office Journal in April last year.

Novartis Strategic Move

In a major development, the Thai Government has decided not to issue a compulsory license on anti-cancer drug Imatinib Mesylate after Novartis strategically agreed to provide free Imatinib to cancer patients’ having a household income less than 1.7 million baht (US $ 51,515) per year under the government-sponsored Universal Health Insurance Programme. The drug will be provided free through the Glivec International Patient Assistance Programme (GIPAP) managed by Max Foundation. Describing the agreement as “win-win situation” for patients and the company, Dr. Vichai Chokevivat, advisor to the public health minister and chairman of the Public Health Ministry’s committee on compulsory license, praised Novartis for its decision. According to Chokevivat, the Universal Health Insurance Programme covers 48 million people of Thailand’s 63 million people. He further pointed out two other healthcare schemes – the social security scheme for employees of private companies and the healthcare scheme for civil servants - could afford Imatinib at market price (3,600 baht per tablet) for their patients. This strategic decision will not only allow Novartis to avoid enforcement of compulsory license, but also continue selling patented Glivec to patients in Thailand who can afford the market price.

Although Novartis made no comment on the deal, but obviously the decision has great strategic value. Firstly, the patent for Imatinib will not be overridden by the compulsory license and secondly, generics will not be allowed in Thailand. The later having the more strategic significance, as it will keep generics off-market till patent expires. Remember, the strategic value of patent protection is to keep competition out of the market. The whole episode will surely bring some praise to Novartis philanthropy and keep Generics note of such strategies, it can surely work out in favour of research-companies and make them poor-patients’ better friends (free drugs hmm … interesting).

Your Comments

Subsequent to our post on Tarceva Patent Litigation Analysis IV, Patent Circle received a very informative email from one of the readers, who also happens to be one of my friends in patent profession. I reproduce the email below, and would surely be interested to hear what other readers have to say about it. Such efforts by readers will surely make a difference and do help in shaping patent practice in India.

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"Is Erlotinib a derivative of Gefitinib?

1. I agree with your 29th Jan posting.

2. Erlotinib is not a derivative of Gefitinib.

3. It is not even analogue so to say.

4. Since chronologically Erlo came before Gefi, hence one may quote Erlo while describing Gefi.

In fact while I write this note, one interesting fact came to my mind.

Can one call Aceclofenac a derivative of diclofenac?

Yes. It can be (& it is) derived from Diclofenac. But it is not an analogue of diclofenac.

Why?

Because, although both are antiinflammatory, their mechanism of action is different.

Hence even structural similarity not necessarily ensures that the structures would be analogous.

Imagine Aceclofenac product patent application comes to Indian patent office.

Just because Aceclofenac is an "ester' derivative of diclofenac, would you reject it pending rigorous proof of 25-30%plus efficacy vs Diclofenac?

No. Section 3(d) wording is extremely loose and legally reckless.

Derivative: Two structures should be related by simple transformations (bio or chemical) say by 2 to 3 steps. Their functional group transformation should be short easily demonstrable or part of the common knowledge in that field. Shortness is the key. Otherwise all aromatic compounds can be termed as "derivatives" of benzene: that is absurd.

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Analogue: Two facets: Structural: Inspite of structural changes, function is same. Functional: Some property verifying agent like a bio-surface/lectin certifies the functional closeness. Analogue should always be seen in the light of external/third party/biosurface/or some property verifying agent."

Patent Circle Exclusive: Tarceva Patent Litigation Analysis IV

Does Derivative include Structural Analogues?

What is a derivative? Does derivative encompass compounds chemically similar to and synthesized from a known compound? Or does derivative also include structural analogues of a known compound? According to Oxford Advanced Learner’s Dictionary, ‘derivative’ is a word or thing that has been developed or produced from another word or thing, whereas ‘analogue’ is a thing that is similar to another thing. Giving plain dictionary meaning, a derivative is a compound chemically similar to and synthesized from a known compound, which mean that Erlotinib is a derivative of Gefitinib stands fallacious. But it would not be incorrect to state that Erlotinib is a structural analogue of Gefitinib.

In pharmaceuticals, often a new drug class is researched into a family of structural analogues sharing same chemical backbone structure, but such analogues are not necessarily derivatives of other analogue(s) in the same class. It would be absurd if word ‘derivative’ used under section 3(d) read to include structural analogues.

Is Erlotinib a selection invention? To be continue…

Patent Circle Exclusive: Tarceva Patent Litigation Analysis III

Is Erlotinib a derivative of Gefitinib?

Although Erlotinib and Gefitinib have same 4-anilinoquinazoline base structure, but significantly differs in substituents attached at quinazoline and anilino rings. In both Erlotinib and Gefitinib, quinazoline ring is unsubstituted at the 2-, 5- and 8-positions and have anilino substituent at the 4-position and a substituent attached at the 6- and 7-positions.

In Gefitinib, 6-position of quinazoline ring is substituted with 3-morpholinopropoxy and 7-position with methoxy group and anilino ring is substituted with Fluorine and Chlorine, whereas in Erlotinib 6- and 7-positions of quinazoline ring are substituted with 2-methoxy-ethoxy group and anilino ring is substituted with ethynyl radical. It is well recognized in chemistry that a derivative is a compound formed from a parent compound by replacement of one atom with another atom or group of atoms, but retaining essential elements of the parent compound, for example, Flumezapine and Olanzapine belonging to same family of thienobenzodiazepines and sharing same thienobenzodiazepine base structure.

Anyone with a reasonable understanding of organic chemistry would be able to judge that Erlotinib structurally is not a derivative of Gefitinib, even though sharing same 4-anilinoquinazoline base structure. Erlotinib differs structurally from Gefitinib, by substitution of an ethynyl radical for fluorine and chlorine atoms in Gefitinib at anilino ring and substitution of 2-methoxy-ethoxy groups for 3-morpholinopropoxy and methoxy group at the 6- and 7-positions. Then do Erlotinib need to show improved efficacy under section 3(d) of the Act over Gefitinib? According to the explanation provided therewith section 3(d), any derivative of known substance to be patentable under the Act need to differ significantly in properties with regard to efficacy. Considering that Erlotinib is structurally not a derivative of Gefitinib, triggering section 3(d) efficacy requirement will absolutely be excessive.

Does derivative include structural analogues? To be continue…

Patent Circle Exclusive: Tarceva Patent Litigation Analysis II

Erlotinib is reported to be a derivative of gefitinib, and this argument likely to heat up in Tarceva patent litigation. Cipla certainly will contest the validity of the ‘203 patent under section 3(d) of the Act and possibly extend to post-grant opposition under clause (f) of section 25(2) of the Act. Considering lack of know-how in dealing such complex validity, Indian Courts surely have a tough task ahead, and need to be diligent and detailed in delivering judgment.

Quinazoline Family

Quinazoline is a compound made of fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Gefitinib and Erlotinib belongs to a class of 4-anilinoquinazoline derivatives, an anilino (phenylamino) group attached at the 4-position of quinazoline. Over the years, compounds belonging to 4-anilinoquinazoline family are reported to be useful as an analgesic and anti-inflammatory agent and in the treatment of cancer.

Gefitinib is broadly covered within the markush 4-anilinoquinazoline structure of US Patent No. 5,457,105 (genus patent), and particularly covered within the markush 4-anilinoquinazoline structure of US Patent No. 5,770,599 (species patent). Both genus and species patents are issued to Zeneca and currently listed with the Orange Book. Erlotinib is broadly covered within the markush 4-anilinoquinazoline structure of US Patent No. 5,747,498 (the ‘498 patent). The markush 4-anilinoquinazoline structures are represented below –

Above markush structures have similar 4-anilinoquinazoline base structure, which in fact structurally resembling to anti-cancer markush 4-anilinoquinazolines disclosed in European Patent No. 0 520 722 (‘the 722 patent) issued to Imperial Chemical Industries (ICI) and markush 4-anilinoquinazolines disclosed in US Patent No. 4,464,375 (the ‘375 patent) issued to Sankyo having analgesic and anti-inflammatory properties.

According to the literature citation taken from the genus patent, none of the public disclosure (till that date) reported quinazoline derivative to have anti-cancer properties arising from receptor tyrosine kinase inhibitory properties, and most of the know quinazoline derivatives were reported to possess analgesic, anti-inflammatory, bronchodilator, hypotensive or anti-malarial properties, or tested for antiarrythmic properties. The application for genus patent was filed August 02, 1994 having foreign priority from British patent applications with earliest dated January 20, 1992. Doing some extra-research over the prior art literature, the ‘722 patent seems to be the first patent literature to report and mark a major breakthrough and discovery of new class of 4-anilinoquinazolines for cancer treatment. The ‘722 patent claims priority from British patent applications with earliest dated June 28, 1991. This, in fact, technically suggest that both Gefitinib and Erlotinib are chemical variations of markush 4-anilinoquinazolines disclosed in the ‘722 patent.

Following ICI discovery of new class of 4-anilinoquinazoline inhibitors, AstraZeneca invented first 4-anilinoquinazoline anti-cancer drug candidate Gefitinib, marketed as Iressa followed by Pfizer’s Erlotinib and Glaxo’s Lapatinib (marketed as Tykerb).

Is Erlotinib a derivative of Gefitinib? To be continue …

Happy Republic Day

Patent Granted for Hydrate form of Rosiglitazone Maleate

GlaxoSmithKline has received an Indian Patent No. 213203 (the ‘203 patent) for a novel hydrate form of Rosiglitazone Maleate against the mail-box Application No. IN/PCT/2000/00076/MUM filed December 14, 1998 claiming earliest priority from British patent application dated December 16, 1997. The ‘203 patent titled ‘Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil) amino) ethoxy] benzyl] thiazolidine-2, 4-dione maleic acid salt’ is lately published in the Patent Office Journal Issue No. 04/2008. Abstract of IN/PCT/2000/00076/MUM reads as –

A hydrate of 5-[4-[2-(N-methyl-N-(2-pryidyl) amino) ethoxy] benzyl] thiazolidine-2, 4-dione, maleic acid salt, characterised in that it: (i) contains water in the range of from 0.2 to 1.1% w/w, and (ii) provides an infrared spectrum containing peaks at 764 and 579 cm-1; and/or (iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Figure II; a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of such a compound or composition in medicine.

Rosiglitazone Maleate, globally marketed as Avandia is patented anti-diabetic drug in US and EU valid till October 2015 and September 2014 respectively. Although not sure exactly in what form claims are issued by the Mumbai Patent Office, but certainly would be interested knowing that. For close reference, refer equivalent US Patent Nos. 6,664,278 and 7,045,633.