Patents....Merits of applying in India

 Flowchart of the Process from Application to Grant of a Patent
INDIA

Merits of applying in India

Applying for intellectual property rights in India has the following merits to it.

(1) India is one of the four BRICs countries, attracting attention as a market where high economic growth in the near future is likely.

(2) Because India accepts applications in English, the applicant can use applications in Europe or the United States to apply and thereby save on translation expenses.

(3) Because India is a member of the Paris Convention, the applicant may claim priority when filing a patent granted in Japan.

(4) India is a member of the Patent Cooperation Treaty (PCT) and accepts national phase applications under the PCT.

2. Patents

• 2.1 Duration

Patent rights in India last for twenty years from the application date (India Patent Act Section 53). However, unlike in Japan, there is no system for lengthening the duration of pharmaceutical product inventions, et cetera.

• 2.2 Inventions Subject to Protection

Section 3 of the Indian Patent Act gives specific examples of “things that are not patents.” In India, material patents are acknowledged, but “the mere discovery of a new form of a known substance” (India Patent Act Section 3[d]). Regarding already-known derivatives such as salts, unless they substantially differ in efficacy from known substances, they are considered equivalent to the known substances.

Software itself will not be awarded a patent, but software that is combined with some form of hardware may pass.

India does not have a utility model system.

• 2.3 Application

Figure 1 shows the flow of a patent application from the opening of an application to registration of a patent. Here follows a simple explanation of each stage.

- Application -

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese patent application.

Because India is a member of the PCT, the applicant may specify India in a PCT international application.

Within six months of application, the applicant must submit information on foreign applications (India Patent Act Section 8 [1], India Patent Rules 12 [1A]). If before the grant or rejection of grant of a patent, the Controller requests particular details concerning the processing of the application in other countries, the applicant must submit such details (India Patent Act Section 8 [2], Patent Rules 12 [3]).

- Publication of the Application -

An application is published eighteen months from either the date of application or the priority date of the relevant application (India Patent Rules 24). If an applicant wishes to acquire patent rights early, he or she should utilize the early publication system (India Patent Act Section 11 [2]).

- Request for Examination -

The applicant must make a request for examination within forty-eight months of the priority date of the relevant application or of the application date (India Patent Rules 24B). If the request is not made within this period, the India Patent Office will treat the application as if it had been withdrawn (India Patent Act Section 11 [B]).

- Examination -

If the examiner finds any objections to granting a patent, a First Examination Report is issued. If the applicant responds to this office action, the examiner will examine the application again. If no reason is found for rejection, a decision to grant the patent is made.

If the applicant does not revise the application so that grant of a patent is possible within twelve months (the Acceptance Period) after the First Examination Report is sent, the application will be treated as abandoned (India Patent Act Section 21 [1], India Patent Rules 24 [B]).

If an application is rejected, the applicant may file a request for re-examination (under India Patent Act Section 77 [f]) or appeal (under India Patent Act Section 117A).

(Procedures that the Applicant May Take during the Examination Period)

(a) Amendment

With permission from the Controller, the applicant may amend the application (India Patent Act Section 57). However, the Controller will not recognize an amendment when the amended specification claims or describes things that were not substantially disclosed or indicated in the specification prior to the amendment, or when the claims of the amended specification will not completely fit within the parameters of the pre-amendment specification’s claims (India Patent Act Section 59).

(b) Divisional Application

If a patent has not yet been granted, the applicant may divide the application at any time (India Patent Act Section 16).

(c) Interview with the Examiner

The applicant may seek to have an interview with the examiner after the examiner has begun to examine the application. According to representatives in India, an interview with the examiner is an extremely effective measure.

- Opposition to Grant of a Patent Prior to the Granting of the Patent -

After the publication of a patent application, if a patent has not been granted, anyone may register an opposition to the patent grant with the Controller (India Patent Act Section 25 [1]).

• 2.4 After Grant of a Patent

Following the grant of a patent and up to one year after the announcement of the grant of the patent, anyone privy to the matter may register an opposition to the grant (India Patent Act Section 25 [2]).

Apart from an opposition to the grant of a patent, one may file an application to have the patent revoked (India Patent Act Section 64).

The patentee must give a working statement regarding exploitation of the patent annually (Indian Patent Act Section 146, India Patent Rules 131 [2]).

A patented invention that has not been exploited in India’s territory within three years after the granting of the patent may be cause for grant of a compulsory license (India Patent Act Section 84).

If two years have passed since the order for the first licensing of a compulsory license and the patented invention is still not being exploited in India’s territory, the patent may be revoked (India Patent Act Section 85).

3. Designs

• 3-1. Duration

The duration of a design is ten years from its registration date and may be extended only once for five more years (India Designs Act Section 11). Note that the registration date is treated as the date of application for registration (India Design Act Section 5 [6]).

• 3.2 Designs Subject to Protection

Section 2(d) of the India Designs Act defines design: “‘design’ means only the features of shape, configuration, pattern, ornament or composition of lines or colours applied to any article . . . by any industrial process or means . . .”

Section 2(a) of the India Designs Act defines article: “‘article’ means any article of manufacture and any substance, artificial, or partly artificial and partly natural and includes any part of an article capable of being made and sold separately.” Furthermore, “partial designs” which cannot be sold independently of a whole design are not protected.

• 3.3 Application

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese right.

A request for examination is not necessary (India Designs Act Section 5).

If the examination results in a rejection decision, the applicant may appeal to the High Court (India Designs Act Section 5 [4]).

• 3.4 After Grant of a Design

Anyone privy to the matter may file an application to have the design right revoked (India Designs Act Section 19).

4. Trademarks

• 4.1 Duration

Trademarks are protected for ten years. Trademark protection may be extended with an application for renewal.

• 4.2 Trademarks Subject to Protection

In addition to product trademarks, service marks are protected (India Trademark Act Section 2 [1] [zb]).

There is a system for organizational trademarks (Section 61).

Three-dimensional shapes and color combinations are also protected (Section 2 [1] [m]).

• 4.3 Application

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese right. However, India is not a member of the Madrid Protocol.

As in Japan, India follows the one application, one trademark policy, but within one application the applicant may specify multiple sections (India Trademark Act Section 18).

The applicant may pay an additional fee to request an early examination (India Trademark Rules Section 38 [1]).

If the result of the examination is a rejection decision, the applicant may make an appeal (under India Trademark Act Section 91).

India has a system for challenging trademarks, and for the three months after the trademark is announced, anyone may register an objection to the trademark grant (India Trademark Act Section 25 [1]).

• 4.4 After Registration

In renewal examinations, whether or not the trademark is actually being used is not judged.

Anyone privy to the matter may request a trial for invalidation of a trademark (India Trademark Act Section 57).

If a trademark is not used for five years and three months, it may be subject to a trial for cancellation for non-use (India Trademark Act Section 47).

When the agent or representative of an owner of the a registered trademark files a registration or other paperwork in his or her own name without receiving a power of attorney, the owner of the trademark may register an objection against this paperwork (India Trademark Act Section 146). However, the owner must do so within three years of knowing of the problem.

[Bibliography]

1. International Association for the Protection of Intellectual Property (AIPPI) Japan. Investigation report on India’s intellectual property protection systems and their operation statuses. 2007.

2. “The influence of India’s Patent Act revisions.” In Patento 61, No. 2 (2008), 42-48.

3. Third International Committee. Points to remember when acquiring patents in countries of Asia and Oceania. Revised edition. Resource No. 332. May 2006.

New inventors are often looking for a short overview of the patent process. Ordinarily sending inventors to the United States Patent and Trademark Office(USPTO) web site is like sending someone into a great quagmire.

But there is a nice flow cart with links directing viewers to pertinent information regarding each step of the process for getting a utility patent on the USPTO web page.

Process for Obtaining a Utility Patent in US

Process for the preparation of optically pure indeno [5,4-b] furan derivatives WO 2008062468 ..Ramelteon

The present invention relates to process for the preparation of (-)-(S)-N-[2- (l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (RAMELTEON) (I) in its pure isomeric form and free from its enantiomeric isomer.

1

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTl and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTl or MT2 receptors, and high selectivity for human MTl and MT2 receptors compared to the

MT3 receptor.

Ramelteon is a selective melatonin receptor agonist that has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complain of some type of insomnia and 20 million Americans suffer from chronic insomnia. It is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, leading to impairment of next day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. Ramelteon is the first and only prescription sleep medication that has shown no evidence of abuse and dependence, and as a result, has not been designated as a controlled substance by the DEA. Its approval also allows physicians to prescribe ramelteon for long-term use in adults. Ramelteon provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. However, clinical comparisons with other hypnotic agents are not available and will be needed to better differentiate these products.

Our objective is to prepare either racemic Ramelteon (±)-l or it's intermediate 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (+)-(2) and separations of desired isomers of either (1) or (2) using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

United State patent 6,034,239 reports formation of chiral intermediate (-)-(S)-N- [2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)]ethylamine (S)-2 by the catalytic asymnjetric hydrogenation of 2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethylamine (3) in the presence of catalytic amount of BINAP -ruthenium complex in approximately 89% ee followed by purification by preparing acid salt and its condensation with propionyl chloride to get Ramelteon (1) in pure form.

An alternate process for preparing Ramelteon is reported in JMC, 45,

4222-4239 (2002). Herein the exo double bond of the intermediate (A) was asymetrically reduced using (S)-2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (binap)- Ru complex as the catalyst to obtain enantiomerically pure compound (B). Compound (B) is subsequently converted to (S)-(-) Ramelteon (1) through intermediate steps of Claisen condensation, ozonolysis and finally cyclization.

Thus both the above process uses expensive catalyst and involves very sophisticated reaction conditions which make them commercially less viable. Therefore, there exists a need to develop a process for obtaining Ramelteon in an enantiomerically pure form which is cost effective, uses easily available reagents, is scalable with ease and overall commercially more viable. We herein disclose such a process. The process is provided in the following Scheme 1 below:

A process for preparing enantiomerically pure Ramelteon (S)-I comprising the steps of i) reacting a compound of formula (2) either in racemic or enantiomerically pure form with propionyl chloride (4) to obtain Ramelteon (1) with retention of configuration;

Process for the preparation of optically pure indeno [5,4-b] furan derivatives
WO 2008062468 A2......http://www.google.com/patents/WO2008062468A2?cl=en

Reference
1	*	RIVARA ET AL: "Reassessing the melatonin pharmacophore-Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 10, 15 May 2006 (2006-05-15), pages 3383-3391, XP005364989 ISSN: 0968-0896
2	*	T. YAMANO ET AL: "Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation" TETRAHEDRON ASYMMETRY, vol. 17, no. 2, 23 January 2006 (2006-01-23), pages 184-190, XP002481301 NLELSEVIER, AMSTERDAM.
3	*	UCHIKAWA O ET AL: "Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 45, 1 January 2002 (2002-01-01), pages 4222-4239, XP002990691 ISSN: 0022-2623 cited in the application

Intermediates and processes for the synthesis of Ramelteon US 20080242877

ROZEREM® (Ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. The empirical formula for Ramelteon is C₁₆H₂₁NO₂, and its molecular weight is 259.34. Ramelteon is freely soluble in methanol, ethanol, dimethylsulfoxide (DMSO), 1-octanol and is highly soluble in water and aq. buffer. Ramelteon has the following chemical structure:

Ramelteon is the active ingredient and sold under the brand name of ROZEREM®. Ramelteon is approved by the United States Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset.

Different processes for preparing (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide i.e. Ramelteon are disclosed in U.S. Pat. No. 6,034,239, JP 11080106, JP 11140073 and WO 2006/030739.

U.S. Pat. No. 6,034,239 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11080106 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11140073 discloses the following processes for the preparation of an intermediate of Ramelteon:

PCT Publication No. 2006/030739 discloses the following processes for the preparation of an intermediate of Ramelteon:

The present invention provides additional processes for preparation Ramelteon and intermediates thereof.

Synthesis of Ramelteon (I) 
Example 10

The hydrochloride salt of compound of formula XIII (100.0 gm, 418 mmol) is suspended in the THF at 4000 ml, triethyl amine (116.0 ml, 836 mmol) is added and the reaction is cooled to 10° C. or less. Propionyl chloride (74 ml, 836 mmol) is added dropwise followed by agitation at 25-35° C. for 2-3 hrs. Then 1000 ml, of water is added and the THF is distilled off under reduced pressure. It dissolved in ethyl acetate and wash twice with 10% brine solution. Dry the organic layer with sodium sulfate, distill off under vacuum and product is isolated. Dry the product under vacuum.

Intermediates and processes for the synthesis of Ramelteon
US 20080242877 A1......http://www.google.com/patents/US20080242877

Process for the preparation of ramelteon WO 2010055481

Ramelteon (1) is a melatonin receptor agonist with both high affinity for melatonin MTi and MT₂ receptors and selectivity over the MT₃ receptor.

Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTi or MT₂ receptors, and high selectivity for human MTi and MT₂ receptors compared to the MT₃ receptor.

Ramelteon has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complains of some type of insomnia, and 20 million Americans suffer from chronic insomnia, which is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, often leading to impairment of next-day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. 

Ramelteon has also been prescribed for long-term use in adults, provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. United States Patent No. 6,034,239 discloses the formation of chiral intermediates (S)-(- )-N-[2-(l,6,7,8,-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (sometimes referred to as compound S-2 or intermediate compound S-2) by the catalytic asymmetric hydrogenation of 2- (l,2,6,7,-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine (compound 3 in the reaction scheme shown below) in the presence of a catalytic amount of BINAP-ruthenium complex in approximately 89% e.e. (enantiomeric excess). 

Following the catalytic reaction, the product is purified by preparing acid salts and acylated with propionyl chloride (compound 4 in the reaction scheme shown below) to obtain ramelteon (compound 1 in the reaction scheme shown below) in its pure (S) isomer form.

|S)*2

An alternate process for preparing ramelteon is disclosed in the Journal of Medicinal Chemistry, Vol. 45, pp. 4222-4239 (2002), wherein the exo double bond of intermediates (A) shown below was asymmetrically reduced using (S)-2, 2'-bis-(diphenylphosphino)-l, 1 '- binaphthyl (binap)-Ru complex as the catalyst to obtain the enantiomerically pure compound (B). Compound (B) is subsequently converted to ramelteon (1) through the intermediate steps of Claisen condensation, ozonolysis and cyclization.

m Both of the above processes uses expensive catalyst and give poor enantioselectivity. Additionally, these processes are expensive due to the need to perform multiple purifications steps in order to achieve an enantioselectivity of at least about 99% or greater of the desired isomer.

PCT Patent Publication No. WO 2008/062468 A2 discloses the following process for the preparation of ramelteon:

RAMELTEON

WO 2008/062468 teaches that separation of the enantiomers of intermediate (2) may be accomplished by: i) optical resolution of the racemic amine intermediate (2) by preparing acid salts with chirally pure acids; or ii) chromatographic techniques using chiral and/or achiral stationary phases for batch process, super critical or sub critical chromatography and/or continuous process chromatography. 

Although WO 2008/062468 mentions the possible use of optical resolution with chirally pure acids, there is no further teaching, discussion or disclosure of this method. WO 2008/062468 does, however, provide detailed descriptions of chromatographic methods for separating the isomers of intermediate compound (2). 

The disclosed chromatographic process suffers the following disadvantages:

• Preparative chromatography is time consuming & expensive;

• Highly sophisticated instrumentation required; • Not commercially feasible.

PCT Patent Publication No. WO 2008/106179 discloses a process for the preparation of ramelteon that involves the following reaction steps:

wherein X= O-alkyl or NH₂ and chiral reduction of the compound of formula IV in the presence of Ru-BINAP complex under hydrogen atmosphere in an organic solvent.

IV V

The process disclosed in WO 2008/106179 is similar to the process disclosed in United States Patent No. 6,034,239 and the Journal of Medicinal Chemistry, Vol. 45 in that a Ru-BINAP complex is employed.

Resolution of racemic mixtures via reaction with optically active acids and the subsequent crystallization of the resulting salts is preferably employed when the chiral carbon of the racemic compound is an alpha carbon {i.e., one carbon removed) to the functional group forming the acid addition salt.

 As the distance between the chiral carbon of the racemic compound to the functional group of the racemic compound increases to beta (i.e., two carbon removed) & gamma (i.e., three carbon removed), the resolution of the diastereomeric salt becomes more difficult and not very useful.

Ramelteon has a chiral center at the gamma carbon, which makes the separation of the isomer with an optically active acid quite a daunting task. Similarly, N-[2-(l, 6, 7, 8,- tetrahydro-2H-indeno [5, 4-b]furan-8-yl)]ethylamine (compound T), an intermediate useful in the production of ramelteon has a chiral center at the gamma carbon which would lead a skilled artisan to believe that optical resolution with an optically active acid could prove difficult.

http://www.google.com/patents/WO2010055481A1?cl=en

Inventors	Manjunath Narayan Bhanu, Chandrasekhar Sinha, Bhupesh Aher, Amol Bandal, Atul Parab, Less «
Applicant	Watson Pharma Private Limited

The present invention further includes a process for the synthesis of ramelteon that comprises the step of separating N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl)]ethylamine (compound 2) into its isomers using an optically active acid to achieve high enantioselectivity of the desired isomer. This embodiment may further include the step of acylating the substantially pure enantiomer, (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)]ethylamine (compound (S)-2) using a suitable acylating agent, such as propionyl chloride) to provide (S)-7V-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propionamide (ramelteon or compound 1) substantially free of the (R)-isomer.

One embodiment of the present invention for the preparation of ramelteon is shown below in Scheme 1.

Example 2

Preparation of (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)ethyl] propionamide (ramelteon)

Triethyl amine (15.15 g, 0.15 mol) and propionyl chloride (13.66 g, 0.15 mol) were added to a solution of S-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)]ethylamine (25 g, 0.12 mol) (compound (S)-2) (prepared in Example 1) in dichloromethane and stirred at room temperature for 2 hours. 75 mL water was added to the reaction mixture, and the layers were separated. The dichloromethane layer was concentrated under reduced pressure and purified from a mixture of acetone and hexane to give (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan- 8-yl) ethyl] propionamide (compound 1) having a chiral purity of 99% or greater enantioselectivity.