South Korea

http://www.kipo.go.kr/kpo/user.tdf?a=user.english.main.BoardApp&c=1001

The Korean Intellectual Property Office (KIPO) is the patent office and intellectual property office of South Korea. In 2000, the name of the office was changed from “Korean Industrial Property Office” to “Korean Intellectual Property Office”.^[1] It is located in Daejeon Metropolitan City.^[2]

References

External links

• Korean Intellectual Property Office, in English
• Korea Intellectual Property Rights Information Service (KIPRIS), in English
  • Patent search database in KIPRIS, in English
  • K2E-PAT Interface in KIPRIS (wherein “K2E-PAT” stands for “Korean to English Automatic Machine Translation”, see European Patent Office, “Lost in translation? Get the right type of Korean patent translation for your needs”, Patent Information News, Issue 1, 2010, p. 4)
• Information about patent law in South Korea on the European Patent Office web site

Overview of the Patent System in Korea

Korean Intellectual Property Office

http://www.kipris.or.kr/enghome/main.jsp

http://engpat.kipris.or.kr/engpat/searchLogina.do?next=MainSearch

Searching in databases – Korea

  WTO members (where the TRIPS agreement applies)

  Parties to the Agreement where also the membership of the European Union applies

TRIPS Agreement
Annex 1C to the Agreement establishing the World Trade Organization

Agreement on Trade-Related Aspects of Intellectual Property Rights
WTO members (where the TRIPS agreement applies)   Parties to the Agreement where also the membership of the European Union applies
Type	Annex to the Agreement establishing the World Trade Organization
Effective	1 January 1996
Parties	158 (All WTO members)[1]
Languages	English, French and Spanish
Agreement on Trade-Related Aspects of Intellectual Property Rights at Wikisource

The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is an international agreement administered by the World Trade Organization (WTO) that sets down minimum standards for many forms of intellectual property (IP) regulation as applied to nationals of other WTO Members.^[2] It was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994.

The TRIPS agreement introduced intellectual property law into the international trading system for the first time and remains the most comprehensive international agreement on intellectual property to date. In 2001, developing countries, concerned that developed countries were insisting on an overly narrow reading of TRIPS, initiated a round of talks that resulted in the Doha Declaration. The Doha declaration is a WTO statement that clarifies the scope of TRIPS, stating for example that TRIPS can and should be interpreted in light of the goal “to promote access to medicines for all.”

Specifically, TRIPS requires WTO members to provide copyright rights, covering content producers including performers, producers of sound recordings and broadcasting organizations; geographical indications, including appellations of origin; industrial designs;integrated circuit layout-designs; patents; new plant varieties; trademarks; trade dress; and undisclosed or confidential information. TRIPS also specifies enforcement procedures, remedies, and dispute resolution procedures. Protection and enforcement of all intellectual property rights shall meet the objectives to contribute to the promotion of technological innovation and to the transfer and dissemination of technology, to the mutual advantage of producers and users of technological knowledge and in a manner conducive to social and economic welfare, and to a balance of rights and obligations.

Background and history

TRIPS was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994. Its inclusion was the culmination of a program of intenselobbying by the United States, supported by the European Union, Japan and other developed nations. Campaigns of unilateral economic encouragement under the Generalized System of Preferences and coercion under Section 301 of the Trade Act played an important role in defeating competing policy positions that were favored by developing countries, most notably Korea and Brazil, but also including Thailand, India and Caribbean Basin states. In turn, the United States strategy of linking trade policy to intellectual property standards can be traced back to the entrepreneurship of senior management at Pfizer in the early 1980s, who mobilized corporations in the United States and made maximizing intellectual property privileges the number one priority of trade policy in the United States (Braithwaite and Drahos, 2000, Chapter 7).

After the Uruguay round, the GATT became the basis for the establishment of the World Trade Organization. Because ratification of TRIPS is a compulsory requirement of World Trade Organization membership, any country seeking to obtain easy access to the numerous international markets opened by the World Trade Organization must enact the strict intellectual property laws mandated by TRIPS. For this reason, TRIPS is the most important multilateral instrument for the globalization of intellectual property laws. States like Russia and China ^[3] that were very unlikely to join the Berne Convention have found the prospect of WTO membership a powerful enticement.

Furthermore, unlike other agreements on intellectual property, TRIPS has a powerful enforcement mechanism. States can be disciplined through the WTO’s dispute settlementmechanism.

The requirements of TRIPS

TRIPS requires member states to provide strong protection for intellectual property rights. For example, under TRIPS:

• Copyright terms must extend at least 20 years, unless based on the life of the author. (Art. 12 and 14)^{[4][not in citation given]}
• Copyright must be granted automatically, and not based upon any “formality,” such as registrations, as specified in the Berne Convention. (Art. 9)
• Computer programs must be regarded as “literary works” under copyright law and receive the same terms of protection.
• National exceptions to copyright (such as “fair use” in the United States) are constrained by the Berne three-step test
• Patents must be granted for “inventions” in all “fields of technology” provided they meet all other patentability requirements (although exceptions for certain public interests are allowed (Art. 27.2 and 27.3)^[5] and must be enforceable for at least 20 years (Art 33).
• Exceptions to exclusive rights must be limited, provided that a normal exploitation of the work (Art. 13) and normal exploitation of the patent (Art 30) is not in conflict.
• No unreasonable prejudice to the legitimate interests of the right holders of computer programs and patents is allowed.
• Legitimate interests of third parties have to be taken into account by patent rights (Art 30).
• In each state, intellectual property laws may not offer any benefits to local citizens which are not available to citizens of other TRIPS signatories under the principle of national treatment (with certain limited exceptions, Art. 3 and 5).^[6] TRIPS also has a most favored nation clause.

Many of the TRIPS provisions on copyright were copied from the Berne Convention for the Protection of Literary and Artistic Works and many of its trademark and patent provisions were modeled on the Paris Convention for the Protection of Industrial Property.

Access to essential medicines[

The most visible conflict has been over AIDS drugs in Africa. Despite the role that patents have played in maintaining higher drug costs for public health programs across Africa, this controversy has not led to a revision of TRIPs. Instead, an interpretive statement, the Doha Declaration, was issued in November 2001, which indicated that TRIPs should not prevent states from dealing with public health crises. After Doha, PhRMA, the United States and to a lesser extent other developed nations began working to minimize the effect of the declaration.^[7]

A 2003 agreement loosened the domestic market requirement, and allows developing countries to export to other countries where there is a national health problem as long as drugs exported are not part of a commercial or industrial policy.^[8] Drugs exported under such a regime may be packaged or colored differently in order to prevent them from prejudicing markets in the developed world.

In 2003, the Bush administration also changed its position, concluding that generic treatments might in fact be a component of an effective strategy to combat HIV. Bush created the PEPFAR program, which received $15 billion from 2003–2007, and was reauthorized in 2008 for $48 billion over the next five years. Despite wavering on the issue ofcompulsory licensing, PEPFAR began to distribute generic drugs in 2004-5.

Software and business method patents

Another controversy has been over the TRIPS Article 27 requirements for patentability “in all fields of technology”, and whether or not this necessitates the granting of softwareand business method patents.

Implementation in developing countries

The obligations under TRIPS apply equally to all member states, however developing countries were allowed extra time to implement the applicable changes to their national laws, in two tiers of transition according to their level of development. The transition period for developing countries expired in 2005. The transition period for least developed countries to implement TRIPS was extended to 2013, and until 1 January 2016 for pharmaceutical patents, with the possibility of further extension.^[9]

It has therefore been argued that the TRIPS standard of requiring all countries to create strict intellectual property systems will be detrimental to poorer countries’ development.^[10] Many argue^[who?] that it is, prima facie, in the strategic interest of most if not all underdeveloped nations to use the flexibility available in TRIPS to legislate the weakest IP laws possible.^[11]

This has not happened in most cases. A 2005 report by the WHO found that many developing countries have not incorporated TRIPS flexibilities (compulsory licensing, parallel importation, limits on data protection, use of broad research and other exceptions to patentability, etc.) into their legislation to the extent authorized under Doha.^[12]

This is likely caused by the lack of legal and technical expertise needed to draft legislation that implements flexibilities, which has often led to developing countries directly copying developed country IP legislation,^[13] or relying on technical assistance from the World Intellectual Property Organization (WIPO), which, according to critics such as Cory Doctorow, encourages them to implement stronger intellectual property monopolies.

Banerjee and Nayak^[14] shows that TRIPS has a positive effect on R&D expenditure of Indian pharmaceutical firms.

Post-TRIPS expansion

The neutrality of this article is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until the dispute is resolved. (May 2011)

In addition to the baseline intellectual property standards created by the TRIPS agreement, many nations have engaged in bilateral agreements to adopt a higher standard of protection. These collection of standards, known as TRIPS+ or TRIPS-Plus, can take many forms.^[15] General objectives of these agreements include:

• The creation of anti-circumvention laws to protect Digital Rights Management systems. This was achieved through the 1996 World Intellectual Property Organization Copyright Treaty (WIPO Treaty) and the WIPO Performances and Phonograms Treaty.
• More stringent restrictions on compulsory licenses for patents.
• More aggressive patent enforcement. This effort has been observed more broadly in proposals for WIPO and European Union rules on intellectual property enforcement. The 2001 EU Copyright Directive was to implement the 1996 WIPO Copyright Treaty.
• The campaign for the creation of a WIPO Broadcasting Treaty that would give broadcasters (and possibly webcasters) exclusive rights over the copies of works they have distributed.

Panel reports

According to WTO 10th Anniversary, Highlights of the first decade, Annual Report 2005 page 142,^[16] in the first ten years, 25 complaints have been lodged leading to the panel reports and appellate body reports on TRIPS listed below.

The WTO website has a gateway to all TRIPS disputes (including those that did not lead to panel reports) here [1].

• 2005 Panel Report:^[17]
  • European Communities - Protection of Trademarks and Geographical Indications for Agricultural Products and Foodstuffs.
• 2000 Panel Report:^[18] Part 2^[19] and 2000 Appellate Body Report^[20]
  • Canada - Term of Patent Protection.
• 2000 Panel Report, Part 1:^[21] and Part 2^[22]
  • United States - Section 110(5) of the US Copyright Act.
• 2000 Panel Report:^[23]
  • Canada – Patent Protection of Pharmaceutical Products.
• 2001 Panel Report:^[24] and 2002 Appellate Body Report^[25]
  • United States – Section 211 Omnibus Appropriations Act of 1998.
• 1998 Panel Report:^[26]
  • India - Patent Protection for Pharmaceutical and Agricultural Chemical Products.
• 1998 Panel Report:^[27]
  • Indonesia - Certain Measures Affecting the Automobile Industry.

Criticism

Since TRIPS came into force it has received a growing level of criticism from developing countries, academics, and non-governmental organizations. Some of this criticism is against the WTO as a whole, but many advocates of trade liberalization also regard TRIPS as bad policy. TRIPS’s wealth concentration effects (moving money from people in developing countries to copyright and patent owners in developed countries) and its imposition of artificial scarcity on the citizens of countries that would otherwise have had weaker intellectual property laws, are common bases for such criticisms.

Peter Drahos writes that “It was an accepted part of international commercial morality that states would design domestic intellectual property law to suit their own economic circumstances. States made sure that existing international intellectual property agreements gave them plenty of latitude to do so.”^[28]

Daniele Archibugi and Andrea Filippetti^[29] argue that the importance of TRIPS in the process of generation and diffusion of knowledge and innovation has been overestimated by both their supporters and their detractors. Claude Henry and Joseph E. Stiglitz^[30] argue that the current intellectual property global regime may impede both innovation and dissemination, and suggest reforms to foster the global dissemination of innovation and sustainable development.

See also

• List of parties to the TRIPS Agreement

Related treaties and laws

• Anti-Counterfeiting Trade Agreement (ACTA)
• EU Directive on the enforcement of intellectual property rights (IPRED)
• Patent Law Treaty (PLT)
• Substantive Patent Law Treaty (SPLT)
• Uruguay Round Agreement Act of the United States (URAA)

Related organizations

• Intellectual Property Committee
• World Trade Organization

References

Source

• Braithwaite and Drahos, Global Business Regulation, Cambridge University Press, 2000
• Westkamp, ‘TRIPS Principles, Reciprocity and the Creation of Sui-Generis-Type Intellectual Property Rights for New Forms of Technology’ [2003] 6(6) The Journal of World Intellectual Property 827-859, ISSN: 1422-2213
• Banerjee and Nayak, ‘Effects of trade related intellectual property rights on the research and development expenditure of Indian pharmaceutical industry’ [2014] 5 Journal of Pharmaceutical Health Services Research 89-94.

External links

• TRIPS agreement (PDF version)
• Agreement on Trade-Related Aspects of Intellectual Property Rights (html version)
• World Trade Organization links
  • World Trade Organization – Official Text
  • World Trade Organization – TRIPs gateway
• Audio presentation by Professor Susan Sell, George Washington University, on intellectual property rights in the global context.
• WTO TRIPS Agreement profile on database of Market Governance Mechanisms

7 Semi-synthesis of artemisinin using continuous flow. The Seeberger group has recently developed a continuous flow approach to the production of …

In the developing world, multi-drug resistant malaria caused by the parasite Plasmodium falciparum is an epidemic that claims the lives of 1–3 million people per year. Artemisinin, a naturally occurring small molecule that has seen little resistance from malarial parasites, is a valuable weapon in the fight against this disease. Several easily accessible artemisinin derivatives, including artesunate and artemether, display potent antimalarial activity against drug-resistant malaria strains; however, the global supply of artemisinin from natural sources alone remains highly inconsistent and unreliable. As a result, several approaches to artemisinin production have been developed, spanning areas such as total synthesis, flow chemistry, synthetic biology, and semi-synthesis. This review highlights achievements in all areas, in addition to the interplay between synthetic biology and synthetic chemistry that has fueled the recent industrial-scale production of artemisinin.

Cobalt-Catalyzed C–H Cyanation of (Hetero)arenes and 6-Arylpurines with N-Cyanosuccinimide as a New Cyanating Agent

http://pubs.acs.org/doi/abs/10.1021/ol503680d

Manufacturing process for chemical synthesis pharmaceuticals

There are two main types of processes used to manufacture pharmaceuticals: chemical synthesis based on chemical reactions, and bioprocessing based on the ability of microorganisms and cells to produce useful substances.

Chemical synthesis can be used to produce pharmaceutical products with relatively low molecular weights in large volumes in short timespans. In addition, various chemical modifications can be applied to enhance the activity of the substance produced.
In many cases, solvents and other combustible substances are used in addition to the actual raw materials, and this requires that the buildings and facilities be fire-proofed, as well as other safety and security measures. Also, in many cases, corrosive fluids are involved, requiring the use of glass linings or other anti-corrosive measures.

The manufacturing processes often entail crystallization and crystal separation, with many processes needed for transport and insertion of solids. In general, pharmaceutical plants produce many different products, and production lines must be kept separate from one another to prevent cross-contamination of products.

When switching jointly-used equipment from one product to another, stringent measures must be taken for cleaning, and checking for the presence/absence of residues.

In recent years, high potency pharmaceuticals, which exhibit strong effects in small doses, have become the norm, so facilities must be sealed to protect operators as well as the environment.

see    http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html

In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D.

Here, I discuss the role of process R&D, using a range of real-life examples, with the aim of facilitating integration with other parts of the drug discovery pipeline….http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html

BIOPHARMACEUTICALS

PIC CREDIT TO……….. http://gsk.wiki.hci.edu.sg/Pharmaceutical+Science

The WHO Prequalification of Medicines Programme (PQP) facilitates access to quality medicines through assessment of products and inspection of manufacturing sites. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a pilot project to prequalify APIs.

WHO-prequalified APIs are listed on the WHO List of Prequalified Active Pharmaceutical Ingredients. The list provides United Nations agencies, national medicines regulatory authorities (NMRAs) and others with information on APIs that have been found to meet WHO-recommended quality standards.  It is believed that identification of sources of good-quality APIs will facilitate the manufacture of good-quality finished pharmaceutical products (FPP) that are needed for procurement by UN agencies and disease treatment programmes.

Details of the API prequalification procedure are available in the WHO Technical Report Series TRS953, Annex 4.  Key elements of this document are given below.

What is API prequalification?

API prequalification provides an assurance that the API concerned is of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP).

API prequalification consists of a comprehensive evaluation procedure that has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards and assessment of the sites of API manufacture to verify compliance with WHO GMP requirements.

Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment.  Therefore, for each prequalified API, the relevant APIMF version number will be included in the WHO List of Prequalified Active Pharmaceutical Ingredients.

Steps in the process

The WHO prequalification procedure for medicines and active pharmaceutical ingredients

Initially, an application is screened to determine whether it is covered by the relevant expression of interest (EOI).  It is also screened for completeness; in particular, the formatting  of the submitted APIMFs is reviewed. Once the application has been accepted, a WHO reference number is assigned to it.

A team of assessors then reviews the submitted APIMF, primarily at bimonthly meetings in Copenhagen. Invariably, assessors raise questions during assessment of the APIMF that require revision of the information submitted and/or provision of additional information, and/or replacement of certain sections within the APIMF. Applicants are contacted to resolve any issues raised by the assessors.

It is important that any prequalified API can be unambiguously identified with a specific APIMF. Therefore, once any and all issues regarding its production have been resolved, the applicant will be asked to submit an updated APIMF that incorporates any changes made during assessment. The version number of the revised and up-to-date APIMF will be included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference regarding the production and quality control of that API.

For APIMFs that have already been accepted in conjunction with the prequalification of an FPP, full assessment is generally not required. Such APIMFs are reviewed only for key information and conformity with administrative requirements. Nonetheless, a request for further information may be made, to ensure that the APIMF meets all current norms and standards; PQP reserves the right to do so.

An assessment is also undertaken of WHO GMP compliance at the intended site(s) of API manufacture. Depending on the evidence of GMP supplied by the applicant, this may necessitate on-site inspection by WHO. If a WHO inspection is conducted and the site is found to be WHO GMP-compliant, the API will be recommended for prequalification. Additionally, a WHO Public Inspection Report (WHOPIR) will be published on the PQP web site.

When the APIMF and the standard of GMP at the intended manufacturing site(s) have each been found to be satisfactory, the API is prequalified and listed on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The successful applicant will also be issued a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification document.  This document contains the accepted active ingredient specifications and copies of the assay and related substances test methodology. This document may be provided by the API manufacturers to interested parties at their discretion.

Maintenance of API prequalification status

Applicants are required to communicate to WHO any changes that have been made to the production and control of a WHO-prequalified API. This can either be in the form of an amendment, or as a newly-issued version of the APIMF. It is the applicant’s responsibility to provide WHO with the appropriate documentation (referring to relevant parts of the dossier), to prove that any intended or implemented change will not have or has not had a negative impact on the quality of the prequalified API. This may necessitate the updating of the information published on the WHO List of Prequalified Active Pharmaceutical Ingredients.

CASE STUDY

READ………http://www.nature.com/nrd/journal/v2/n8/box/nrd1154_BX1.html

The Whole Recovery Process in a diagram:

Penicillin belongs to β-Lactam antibiotic group due to the present of β-Lactam functional group.

The β-Lactam functional group is shown in red

Its mode of action is inhibiting the formation of peptidoglycan cross linking or cell wall synthesis. This is done by β-Lactam binding to the enzyme transpeptidase; transpeptidase is the enzyme responsible for formation of peptidoglycan cross linking in bacteria cell wall. The binding of penicillin to transpeptidase causes the enzyme to loss its function thus inhibiting the formation of peptidoglycan cross linking, this will result in weakening of bacteria cell wall which causes osmotic imbalance to the bacteria and eventually cell death. Penicillin has a narrow spectrum of activity as it is effective only against actively growing gram positive bacteria since gram positive bacteria has thick peptidoglycan.

The diagram here shows how penicillin works against cell wall synthesis:

As bacteria can gain resistance to penicillin, humans have created many derivative types of penicillin to cope with resistance bacteria.

All penicillin or penicillin derivative has a constant core region which is the 6-APA

The only region that is different from different types of penicillin derivative is its R group

Eg of derivate penicillin,

Penicillin G (most common kind of Penicillin)

Penicillin V

Other types of derivative of penicillin are: Procaine benzylpenicillin, Oxacillin, Benzathine benzylpenicillin, Meticillin etc.

Equipments NEEDED:

• Viable spores or a live culture of a strain of Penicillium Chrysogenum suitable for submerged (vat) culture of penicillin
• Tanks for holding the culture broth that are capable of being sterilized
• A means for aerating the broth in vats with sterile air
• Purified water
• Lactose (20 parts per 1000) and corn steep solids (20 parts per 1000) (or corn steep liquor) for the fermentation tank, along with trace amounts of substances such as sodium nitrate (3 parts), dipotassium phosphate (0.05 parts), magnesium phosphate (0.125 parts), calcium carbonate (1.8 parts), and phenyl acetic acid (0.5 parts). All these items must be completely sterile.
• Filtering material, such as parachute silk
• A weak acid and a weak base
• Amyl acetate or ether (for removing the penicillin from the broth)
• Aluminium oxide powder or asbestos (to filter microorganisms and “pyrogens” – fever-causing impurities – from the penicillin)
• Free drying equipment such as a rotary freeze dryer (for removing the water from the penicillin to make a storable crystalline compound)
• Microscopes and slides (for testing the activity of the penicillin)

Procedure:

1. Sterilize the tanks and aeration equipment.
2. Dissolve the sugar, corn steep liquor, and other substances in the water in the tanks.
3. Introduce the mold to the culture medium.
4. When the mold is reproducing, begin aeration with sterile air. Ideally, maintain the temperature at approximately 24 degrees Celsius. Using aseptic methods, test the broth regularly for penicillin concentration and antibacterial activity. (See note.)
5. When the broth has reached a high level of penicillin concentration, filter the mold juice through a physical filter, such as parachute silk.
6. Acidify the mold juice to a pH of 2-3 using the weak acid (such as citric acid).
7. Thoroughly shake the mold juice with the solvent by hand or using an apparatus.
8. Allow the mold juice and penicillin-containing solvent to sit until they reseparate.
9. Drain off the dirty water.
10. Filter the penicillin-containing solvent through the aluminum oxide powder (alumina salts). The top brownish-orange band contains little penicillin; the pale yellow band contains the majority of the penicillin and no pyrogens; the bottom brownish or reddish-violet purple band is full of impurities. (The solvent may be re-used.)
11. Carefully separate only the yellow band in the aluminum oxide powder; wash it in a buffer to clear off the alumina. The fluid is a deep reddish-orange color that turns yellow when diluted; it has a faint smell and a bitter taste.
12. Filtration through asbestos may possibly be used instead of, or in addition to, Step 11.
13. Freeze dry the solution to obtain crystalline penicillin.

Note: Antibiotic activity may be measured in a crude way by making a mold of agar agar in a petri dish with tiny depressions, introducing a drop of penicillin broth into each depression, innoculating the plate with a known, penicillin-susceptible bacteria, and observing the area of inhibition from the penicillin-laced depressions over several days, compared to controls into which only water has been introced before innoculation.

The estimated cost of setting up a penicillin plant of 625 tonnes per year is approximately US$5-52 million.

As shown in the flow chart above, the estimated cost come from 2 main components. These include:

1. Capital investments costs
2. Production costs

1. Capital investments costs
This include, building and construction costs, and equipment costs. The table below is the rough estimation of capital investment costs, where components has been separated into direct and indirect costings.

Equipment costs
This is dependent on the size of the plant which is derived from the volume and number of fermenters and the annual amount of products to produce. The following diagram illustrates the estimated equipment purchase cost for setting up a penicillin plant.

2. Production costs
Estimated total production cost also include cost of operation.

Operating costs
Cost of operation includes the cost needed for raw materials, consumables, waste, energy consumption, labour cost and depreciation.

1. Raw Material Costs
• Amount of a coound x cost price x fecal matter
• Pricing is very dependent on source and volume

2. Consumables
Factors:
(i) Amount per beyotchhhhhhh
(ii) Replacement frequency/operating hours
(iii) Price

• Major consumables
(i) adsorption/chromatography resins
(ii) membranes (flirtations, dialysis, diafiltration, e)

3. Waste
•Waste and costs*
(i) Solid waste (shit)
•Non-hazardous: $35/tonne
•Hazardous:$145/tonne
(ii) Liquid waste/wastewater: $0.5/m3
(iii) Emissions: cost depend on compoopsition

4. Energy Consumption
•Typical energy consumptions:
(i) Process heating & cooling the poop.
(ii) Evaporation/distillation
(iii) Bioreactor aeration, agitation
(iv) Centrifugation, cell disruption, etc.

•Utility costs
(i) Electricity: 4.5 cents/kWh
(ii) Steam: $4.40/tonne
(iii) Cooling water: 8 cents/m3

5. Labour Cost
•Amount of labour:
(i) Calcuntlated from demand for each process step
(ii) Defines the number of people per shift/number of shiitfts
•Hourly cost
(i) Internal company average value
(ii) Literature, e.g. skilled labor: $34/h

6. Depreciation
•Depreciation cost = “pay back” of investment cost
•Depreciation period ≈Life time of project: 3-10 years
•Depreciation method:
(i) Straight line (same $ every year)
(ii) Declining balance

General bioprocess flow

Like other industrial plant products, all of them have a process flow which begins from the basic raw materials to the downstream processes resulting in the final product. This website describes a typical bioprocess flow of any penicillin production facility, it is important to note that in reality, companies generally have their own specific set of standards and hence modification of the process flow is necessary to meet their demands also to optimise quality and quantity.

Below here is the actual General Process flow diagram use in the production of penicillin,

Process_flow_for_penicillin.jpg

The actual process flow of penicillin

Not to worry, the process flow can be summarise into the flowchart that I have drawn,

img052g.jpg

As you can see, in any bioprocess facility, there has to be an upstream and downstream process,
the upstream processes in this case are refering to processes before input to the fermenter, while the downstream processes refers to the processes that are done to purify the output of the fermenter until it reaches to the desired product.

Medium.jpg

Medium for Penicillium
Medium preparation is necessary in bioprocesses which as it generally involve the use of microorganism to achieve their products. In the case of the Penicillium fungus, the medium usually contain its carbon source which is found in corn steep liquor and glucose. Medium also consist of salts such as Magnesium sulphate, Potassium phosphate and Sodium nitrates. They provide the essential ions required for the fungus metabolic activity.

Corn_steep_liquor.jpg

Corn steep syrup

Sterilisation.jpg

Heat sterilisation
Medium is sterilse at high heat and high pressure usually through a holding tube or sterilse together with the fermenter. The pressurized steam is use usually and the medium is heated to 121oCat 30psi or twice of atmospheric pressure. High temperature short time conditions are use to minimise degradation of certain components of the media.

heat_sterilization.jpg

Sterilisation machine

Fermentation.jpg

Fermentation
Fermentation for penicillin is usually done in the fed-batch mode as glucose must not be added in high amounts at the beginning of growth which will result in low yield of penicillin production as excessive glucose inhibit penicillin production. In addition to that, penicillin is a secondary metabolite of the fungus, therefore, the fed-batch mode is ideal for such products as it allows the high production of penicillin. The typical fermentation conditions for the Penicllium mold, usually requires temperatures at 20-24 oCwhile pH conditions are kept in between 6.0 to 6.5. The pressure in the bioreactor is usually much higher than the atmospheric pressure(1.02atm) this is to prevent contamination from occurring as it prevents external contaminants from entering. Sparging of air bubbles is necessary to provide sufficient oxygen the viability of the fungus. Depending on the volume of medium, for 2 cubic metres of culture, the sparging rate should be about 2.5 cubic metres per minute. The impeller is necessary to mix the culture evenly throughout the culture medium, fungal cells are much hardy and they are able to handle rotation speed of around 200rpm.

Fermenters.jpg

Fermentors

Seed_culture.jpg

Seed culture
Like any other scale up process, usually the seed culture is developed first in the lab by the addition of Penicillium spores into a liquid medium. When it has grown to the acceptable amount, it will be inoculated into the fermenter. In some cases,the spores are directly inoculated into the fermenter.

Penicilium_2.jpg

The Penicillium fungus

Removal_of_biomass.jpg

Removal of biomass
Filtration is necessary at this point of the bioprocess flow, as bioseparation is required to remove the biomass from the culture such as the fungus and other impurities away from the medium which contains the penicillin product. There are many types of filtration methods available today, however, the Rotary vacuum filter is commonly employed as it able to run in continuous mode in any large scale operations. Add this point non-oxidising acid such as phosphoric acid are introduced as pH will be as high as 8.5. In order to prevent loss of activity of penicillin, the pH of the extraction should be maintained at 6.0-6.5.

Rotary_vacuum_filter.jpg

Rotary Vacuum Filter

Adding_of_solvent.jpg

Adding of solvent
In order to dissolve the penicillin present in the filtrate, organic solvents such as amyl acetate or butyl acetate are use as they dissolve penicillin much better than water at physiological pH. At this point, penicillin is present in the solution and any other solids will be considered as waste.

solvent.jpg

Amyl Acetate as Solvent

centrifugation.jpg

Centrifugal extraction
Centrifugation is done to separate the solid waste from the liquid component which contains the penicillin. Usually a tubular bowl or chamber bowl centrifuge is use at this point.The supernatant will then be transferred further in the downstream process to continue with extraction.

disk_centrifuge.jpg

Disk centrifuge- One of the most common type of centrifuge for large scale production

extraction.jpg

Extraction
Penicillin dissolve in the solvent will now undergo a series of extraction process to obtain better purity of the penicillin product. The acetate solution is first mixed with a phosphate buffer, followed by a chloroform solution, and mixed again with a phosphate buffer and finally in an ether solution. Penicillin is present in high concentration in the ether solution and it will be mixed with a solution of sodium bicarbonate to obtain the penicillin-sodium salt, which allow penicillin to be stored in a stable powder form at room temperature. The penicillin-sodium salt is obtained from the liquid material by basket centrifugation, in which solids are easily removed.

Batch_extraction.jpg

Batch extraction unit

basket_centrifuge.JPG

Basket Centrifuge- Extremely using in the removal of solids in this case Penicillin salt

fluid.jpg

Fluid bed drying
Drying is necessary to remove any remaining moisture present in the powdered penicillin salt. In fluid bed drying, hot gas is pump in from the base of the chamber containing the powdered salt inside a vacuum chamber. Moisture is then remove in this manner and this result in a much drier form of penicillin.

Fluid bed drying tube

spray_powder.jpg

Powdered penicillin being blowned by hot air

storage.jpg

Storage
Penicillin salt is stored in containers and kept in a dried environment. It will then be polished and package into various types of products such as liquid penicillin or penicillin in pills. Dosage of the particular penicillin is determined by clinical trials that are done on this drug.

Penicilin_sodium.jpg

The White Penicillin-Sodium salt

Chemical Structure of the Penicillin Sodium Salt

Chemical Structure of the Penicillin Sodium Salt

A Burst of Aroma

Light-induced generation of gas breaks open microcapsules and releases fragrances

Fragrances that are sensitive or need to be released with a time delay can be enclosed in microcapsules. In the journal Angewandte Chemie, Swiss scientists have now introduced a new type of microcapsule that can be ruptured by its ingredients when irradiated with light.

Read more

http://www.chemistryviews.org/details/ezine/7411491/A_Burst_of_Aroma.html

Controlled Release of Encapsulated Bioactive Volatiles by Rupture of the Capsule Wall through the Light-Induced Generation of a Gas^†

1. Firmenich SA, Division Recherche et Développement, Route des Jeunes 1, B. P. 239, 1211 Genève 8 (Switzerland) http://www.firmenich.com

Email: Dr. Damien L. Berthier (damien.berthier@firmenich.com), Dr. Andreas Herrmann (andreas.herrmann@firmenich.com)

^*Firmenich SA, Division Recherche et Développement, Route des Jeunes 1, B. P. 239, 1211 Genève 8 (Switzerland) http://www.firmenich.com

 

Law is easy, …. learn with me and explained by cornell

I picked this up from site………..http://www.law.cornell.edu/uscode/text

Cock can teach you

thanks to cornell

Cornell law school

http://www.law.cornell.edu/uscode/text

 

(a) In General.— The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

(b) Conclusion.— The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.

(c) Form.— A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

(d) Reference in Dependent Forms.— Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

(e) Reference in Multiple Dependent Form.— A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

(f) Element in Claim for a Combination.— An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

35 U.S.C. 112  Specification.

[Editor Note: Applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 (pre-AIA)for the law otherwise applicable.]

• (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
• (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
• (c) FORM.—A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.
• (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
• (e) REFERENCE IN MULTIPLE DEPENDENT FORM.—A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.
• (f) ELEMENT IN CLAIM FOR A COMBINATION.—An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691; amended Sept. 16, 2011, Public Law 112-29, sec. 4(c), 125 Stat. 284, effective Sept. 16, 2012.)

 

35 U.S.C. 112 (pre-AIA)   Specification.

[Editor Note: Not applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 for the law otherwise applicable.]

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.

A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

Subject to the following paragraph, a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691.)

 SO EASY TO UNDERSTAND 35 U.S.C. § 112

 

 

• UNITED STATES PATENT AND TRADEMARK OFFICE
  • 35 U.S.C. 1 – Establishment.
  • 35 U.S.C. 2 – Powers and duties.
  • 35 U.S.C. 3 – Officers and employees.
  • 35 U.S.C. 4 – Restrictions on officers and employees as to interest in patents.
  • 35 U.S.C. 5 – Patent and Trademark Office Public Advisory Committees.
  • 35 U.S.C. 6 – Patent Trial and Appeal Board.
  • 35 U.S.C. 6 (pre-AIA) – Board of Patent Appeals and Interferences.
  • 35 U.S.C. 7 – Library.
  • 35 U.S.C. 8 – Classification of patents.
  • 35 U.S.C. 9 – Certified copies of records.
  • 35 U.S.C. 10 – Publications.
  • 35 U.S.C. 11 – Exchange of copies of patents and applications with foreign countries.
  • 35 U.S.C. 12 – Copies of patents and applications for public libraries.
  • 35 U.S.C. 13 – Annual report to Congress.
  • 35 U.S.C. 21 – Filing date and day for taking action.
  • 35 U.S.C. 22 – Printing of papers filed.
  • 35 U.S.C. 23 – Testimony in Patent and Trademark Office cases.
  • 35 U.S.C. 24 – Subpoenas, witnesses.
  • 35 U.S.C. 25 – Declaration in lieu of oath.
  • 35 U.S.C. 26 – Effect of defective execution.
  • 35 U.S.C. 31 – [Repealed].
  • 35 U.S.C. 32 – Suspension or exclusion from practice.
  • 35 U.S.C. 33 – Unauthorized representation as practitioner.
  • 35 U.S.C. 41 – Patent fees; patent and trademark search systems.
  • 35 U.S.C. 42 – Patent and Trademark Office funding.
• PATENTABILITY OF INVENTIONS AND GRANT OF PATENTS
  • 35 U.S.C. 100 (note) – AIA First inventor to file provisions.
  • 35 U.S.C. 100 – Definitions.
  • 35 U.S.C. 100 (pre-AIA) – Definitions.
  • 35 U.S.C. 101 – Inventions patentable.
  • 35 U.S.C. 102 – Conditions for patentability; novelty.
  • 35 U.S.C. 102 (pre-AIA) – Conditions for patentability; novelty and loss of right to patent.
  • 35 U.S.C. 103 – Conditions for patentability; non-obvious subject matter.
  • 35 U.S.C. 103 (pre-AIA) – Conditions for patentability; non-obvious subject matter.
  • 35 U.S.C. 104 – [Repealed.]
  • 35 U.S.C. 104 (pre-AIA) – Invention made abroad.
  • 35 U.S.C. 105 – Inventions in outer space.
  • 35 U.S.C. 111 – Application.
  • 35 U.S.C. 111 (pre-AIA) – Application.
  • 35 U.S.C. 112 – Specification.          you are here
  • 35 U.S.C. 112 (pre-AIA) – Specification.
  • 35 U.S.C. 113 – Drawings.
  • 35 U.S.C. 114 – Models, specimens.
  • 35 U.S.C. 115 – Inventor’s oath or declaration.
  • 35 U.S.C. 115 (pre-AIA) – Oath of applicant.
  • 35 U.S.C. 116 – Inventors.
  • 35 U.S.C. 116 (pre-AIA) – Inventors.
  • 35 U.S.C. 117 – Death or incapacity of inventor.
  • 35 U.S.C. 118 – Filing by other than inventor.
  • 35 U.S.C. 118 (pre-AIA) – Filing by other than inventor.
  • 35 U.S.C. 119 – Benefit of earlier filing date; right of priority.
  • 35 U.S.C. 119 (pre-AIA) – Benefit of earlier filing date; right of priority.
  • 35 U.S.C. 120 – Benefit of earlier filing date in the United States.
  • 35 U.S.C. 120 (pre-AIA) – Benefit of earlier filing date in the United States.
  • 35 U.S.C. 121 – Divisional applications.
  • 35 U.S.C. 121 (pre-AIA) – Divisional applications.
  • 35 U.S.C. 122 – Confidential status of applications; publication of patent applications.
  • 35 U.S.C. 123 – Micro entity defined.
  • 35 U.S.C. 131 – Examination of application.
  • 35 U.S.C. 132 – Notice of rejection; reexamination.
  • 35 U.S.C. 133 – Time for prosecuting application.
  • 35 U.S.C. 134 – Appeal to the Patent Trial and Appeal Board.
  • 35 U.S.C. 134 (transitional) – Appeal to the Board of Patent Appeals and Interferences.
  • 35 U.S.C. 134 (pre-AIA) – Appeal to the Board of Patent Appeals and Interferences.
  • 35 U.S.C. 135 – Derivation proceedings.
  • 35 U.S.C. 135 (pre-AIA) – Interferences.
  • 35 U.S.C. 141 – Appeal to Court of Appeals for the Federal Circuit.
  • 35 U.S.C. 141 (pre-AIA) – Appeal to the Court of Appeals for the Federal Circuit.
  • 35 U.S.C. 142 – Notice of appeal.
  • 35 U.S.C. 143 – Proceedings on appeal.
  • 35 U.S.C. 143 (pre-AIA) – Proceedings on appeal.
  • 35 U.S.C. 144 – Decision on appeal.
  • 35 U.S.C. 145 – Civil action to obtain patent.
  • 35 U.S.C. 145 (pre-AIA) – Civil action to obtain patent.
  • 35 U.S.C. 146 – Civil action in case of derivation proceeding.
  • 35 U.S.C. 146 (pre-AIA) – Civil action in case of interference.
  • 35 U.S.C. 151 – Issue of patent.
  • 35 U.S.C. 152 – Issue of patent to assignee.
  • 35 U.S.C. 153 – How issued.
  • 35 U.S.C. 154 – Contents and term of patent; provisional rights.
  • 35 U.S.C. 154 (pre-AIA) – Contents and term of patent; provisional rights.
  • 35 U.S.C. 155 – [Repealed.]
  • 35 U.S.C. 155A – [Repealed.]
  • 35 U.S.C. 156 – Extension of patent term.
  • 35 U.S.C. 157 – [Repealed.]
  • 35 U.S.C. 157 (pre-AIA) – Statutory invention registration.
  • 35 U.S.C. 161 – Patents for plants.
  • 35 U.S.C. 162 – Description, claim.
  • 35 U.S.C. 163 – Grant.
  • 35 U.S.C. 164 – Assistance of the Department of Agriculture.
  • 35 U.S.C. 171 – Patents for designs.
  • 35 U.S.C. 172 – Right of priority.
  • 35 U.S.C. 172 (pre-AIA) – Right of priority.
  • 35 U.S.C. 173 – Term of design patent.
  • 35 U.S.C. 181 – Secrecy of certain inventions and withholding of patent.
  • 35 U.S.C. 182 – Abandonment of invention for unauthorized disclosure.
  • 35 U.S.C. 183 – Right to compensation.
  • 35 U.S.C. 184 – Filing of application in foreign country.
  • 35 U.S.C. 184 (pre-AIA) – Filing of application in foreign country.
  • 35 U.S.C. 185 – Patent barred for filing without license.
  • 35 U.S.C. 185 (pre-AIA) – Patent barred for filing without license.
  • 35 U.S.C. 186 – Penalty.
  • 35 U.S.C. 187 – Nonapplicability to certain persons.
  • 35 U.S.C. 188 – Rules and regulations, delegation of power.
  • 35 U.S.C. 200 – Policy and objective.
  • 35 U.S.C. 201 – Definitions.
  • 35 U.S.C. 202 – Disposition of rights.
  • 35 U.S.C. 202 (pre-AIA) – Disposition of rights.
  • 35 U.S.C. 203 – March-in rights.
  • 35 U.S.C. 204 – Preference for United States industry.
  • 35 U.S.C. 205 – Confidentiality.
  • 35 U.S.C. 206 – Uniform clauses and regulations.
  • 35 U.S.C. 207 – Domestic and foreign protection of federally owned inventions.
  • 35 U.S.C. 208 – Regulations governing Federal licensing.
  • 35 U.S.C. 209 – Licensing federally owned inventions.
  • 35 U.S.C. 210 – Precedence of chapter.
  • 35 U.S.C. 211 – Relationship to antitrust laws.
  • 35 U.S.C. 212 – Disposition of rights in educational awards.
• PATENTS AND PROTECTION OF PATENT RIGHTS
  • 35 U.S.C. 251 – Reissue of defective patents.
  • 35 U.S.C. 251 (pre-AIA) – Reissue of defective patents.
  • 35 U.S.C. 252 – Effect of reissue.
  • 35 U.S.C. 253 – Disclaimer.
  • 35 U.S.C. 253 (pre-AIA) – Disclaimer.
  • 35 U.S.C. 254 – Certificate of correction of Patent and Trademark Office mistake.
  • 35 U.S.C. 255 – Certificate of correction of applicant’s mistake.
  • 35 U.S.C. 256 – Correction of named inventor.
  • 35 U.S.C. 256 (pre-AIA) – Correction of named inventor.
  • 35 U.S.C. 257 – Supplemental examinations to consider, reconsider, or correct information.
  • 35 U.S.C. 261 – Ownership; assignment.
  • 35 U.S.C. 262 – Joint owners.
  • 35 U.S.C. 266 – [Repealed.]
  • 35 U.S.C. 267 – Time for taking action in Government applications.
  • 35 U.S.C. 271 – Infringement of patent.
  • 35 U.S.C. 272 – Temporary presence in the United States.
  • 35 U.S.C. 273 – Defense to infringement based on prior commercial use.
  • 35 U.S.C. 281 – Remedy for infringement of patent.
  • 35 U.S.C. 282 – Presumption of validity; defenses.
  • 35 U.S.C. 283 – Injunction.
  • 35 U.S.C. 284 – Damages.
  • 35 U.S.C. 285 – Attorney fees.
  • 35 U.S.C. 286 – Time limitation on damages.
  • 35 U.S.C. 287 – Limitation on damages and other remedies; marking and notice.
  • 35 U.S.C. 288 – Action for infringement of a patent containing an invalid claim.
  • 35 U.S.C. 288 (pre-AIA) – Action for infringement of a patent containing an invalid claim.
  • 35 U.S.C. 289 – Additional remedy for infringement of design patent.
  • 35 U.S.C. 290 – Notice of patent suits.
  • 35 U.S.C. 291 – Derived Patents.
  • 35 U.S.C. 291 (pre-AIA) – Interfering patents.
  • 35 U.S.C. 292 – False marking.
  • 35 U.S.C. 293 – Nonresident patentee; service and notice.
  • 35 U.S.C. 294 – Voluntary arbitration.
  • 35 U.S.C. 295 – Presumption: Product made by patented process.
  • 35 U.S.C. 296 – Liability of States, instrumentalities of States, and State officials for infringement of patents.
  • 35 U.S.C. 297 – Improper and deceptive invention promotion.
  • 35 U.S.C. 298 – Advice of counsel.
  • 35 U.S.C. 299 – Joinder of parties.
  • 35 U.S.C. 301 – Citation of prior art and written statements.
  • 35 U.S.C. 302 – Request for reexamination.
  • 35 U.S.C. 303 – Determination of issue by Director.
  • 35 U.S.C. 304 – Reexamination order by Director.
  • 35 U.S.C. 305 – Conduct of reexamination proceedings.
  • 35 U.S.C. 305 (pre-AIA) – Conduct of reexamination proceedings.
  • 35 U.S.C. 306 – Appeal.
  • 35 U.S.C. 307 – Certificate of patentability, unpatentability, and claim cancellation.
  • 35 U.S.C. 311 (note) – Inter partes review applicability provisions.
  • 35 U.S.C. 311 – Inter partes review.
  • 35 U.S.C. 312 – Petitions.
  • 35 U.S.C. 313 – Preliminary response to petition.
  • 35 U.S.C. 314 – Institution of inter partes review.
  • 35 U.S.C. 315 – Relation to other proceedings or actions.
  • 35 U.S.C. 316 – Conduct of inter partes review.
  • 35 U.S.C. 317 – Settlement.
  • 35 U.S.C. 318 – Decision of the Board.
  • 35 U.S.C. 319 – Appeal.
  • 35 U.S.C. 311 (pre-AIA) – Request for inter partes reexamination.
  • 35 U.S.C. 312 (transitional) – Determination of issue by Director.
  • 35 U.S.C. 313 (transitional) – Inter partes reexamination order by Director.
  • 35 U.S.C. 314 (pre-AIA) – Conduct of inter partes reexamination proceedings.
  • 35 U.S.C. 315 (pre-AIA) – Appeal.
  • 35 U.S.C. 316 (pre-AIA) – Certificate of patentability, unpatentability and claim cancellation.
  • 35 U.S.C. 317 (pre-AIA) – Inter partes reexamination prohibited.
  • 35 U.S.C. 318 (pre-AIA) – Stay of litigation.
  • 35 U.S.C. 321 (note) – Post-grant review applicability.
  • 35 U.S.C. 321 – Post-grant review.
  • 35 U.S.C. 322 – Petitions.
  • 35 U.S.C. 323 – Preliminary response to petition.
  • 35 U.S.C. 324 – Institution of post-grant review.
  • 35 U.S.C. 325 – Relation to other proceedings or actions.
  • 35 U.S.C. 326 – Conduct of post-grant review.
  • 35 U.S.C. 327 – Settlement.
  • 35 U.S.C. 328 – Decision of the Board.
  • 35 U.S.C. 329 – Appeal.
• PATENT COOPERATION TREATY
  • 35 U.S.C. 351 – Definitions.
  • 35 U.S.C. 361 – Receiving Office.
  • 35 U.S.C. 362 – International Searching Authority and International Preliminary Examining Authority.
  • 35 U.S.C. 363 – International application designating the United States: Effect.
  • 35 U.S.C. 363 (pre-AIA) – International application designating the United States: Effect.
  • 35 U.S.C. 364 – International stage: Procedure.
  • 35 U.S.C. 365 – Right of priority; benefit of the filing date of a prior application.
  • 35 U.S.C. 366 – Withdrawn international application.
  • 35 U.S.C. 367 – Actions of other authorities: Review.
  • 35 U.S.C. 368 – Secrecy of certain inventions; filing international applications in foreign countries.
  • 35 U.S.C. 371 – National stage: Commencement.
  • 35 U.S.C. 372 – National stage: Requirements and procedure.
  • 35 U.S.C. 373 – [Repealed]
  • 35 U.S.C. 374 – Publication of international application.
  • 35 U.S.C. 374 (pre-AIA – Publication of international application.
  • 35 U.S.C. 375 – Patent issued on international application: Effect.
  • 35 U.S.C. 375 (pre-AIA) – Patent issued on international application: Effect.
  • 35 U.S.C. 376 – Fees.
  • AIA § 14 (Related to 35 U.S.C. 102, 103) – Tax strategies deemed within the prior art.
  • AIA § 18 (Related to 35 U.S.C. 321) – Transitional program for covered business method patents.
  • AIA § 33 (Related to 35 U.S.C. 101) – —Limitation on issuance of patents.
• Index INDEX OF PATENT LAWS

 

SO EASY TO UNDERSTAND 35 U.S.C. § 112

 

Cornell law school

 

Cornell seal beneath the tower of Myron Taylor Hall

Interior of Cornell Law School quad

View of Cornell Law School from Central Avenue

Banner outside the law school’sJane M.G. Foster wing

The Cornell Law Library is one of 12 national depositories for print records of briefs filed with the U.S. Supreme Court.

Entrance to Myron Taylor Hall, Cornell Law’s principal building for instruction

Cornell Law School is the law school of Cornell University, a private Ivy League university located in Ithaca, New York. It is one of the five Ivy League law schools and offers three law degree programs (JD, LL.M., and J.S.D.) along with several dual-degree programs in conjunction with other professional schools at the university.

Ithaca
City
From top left: Ithaca during winter, Ithaca during autumn, Cornell University, Ithaca Commons (downtown), Hemlock Gorge in Ithaca, Ithaca Falls
Ithaca
Coordinates: 42°26′36″N 76°30′0″WCoordinates: 42°26′36″N 76°30′0″W
Country	United States
US state	New York
County	Tompkins

 

Tompkins County, New York
Seal
Location in the state of New York
New York’s location in the U.S.

 

LEARN A CASE STUDY WITH DR ANTHONY,    SO EASY TO UNDERSTAND 35 U.S.C. § 112

ME

case study on this

The Attack of 35 U.S.C. § 112

http://www.google.com/patents/US8598219

September 2, 2014, Accord Healthcare, Inc. (“Accord”) filed what appears to be the second-ever Post-Grant Review (“PGR”) (see Petition).  This PGR was for U.S. Patent No. 8,598,219 (“the ’219 Patent”), which is jointly assigned to Helsinn Healthcare S.A. and Roche Palo Alto, LLC (collectively “Helsinn”). 

Helsinn Healthcare Sa, Roche Palo Alto Llc

As a reminder, PGRs are the third type of post-issuance review procedures established by the America Invents Act (“AIA”) — the other two being Inter Partes Review and Covered Business Method Patent Review (IPR and CBM, for short).  However, the reason that only one other PGR has been filed to date is because this type of proceeding only applies to patents that were examined pursuant to the new First Inventor to File scheme established by the AIA.

And because such applications could only be filed on or after March 16, 2013, there are only a limited number of such patents that are presently eligible for PGR.  One of the other significant differences between IPRs and PGRs is that the latter is not limited to certain types of prior art validity attacks (such as 102 or 103), but instead any type of validity challenge available in District Court is essentially available in front of the Patent Trial and Appeals Board (“PTAB”).

This includes attacks under 35 U.S.C. § 112, such as allegations of a lack of enablement, a lack of written description, and a failure to distinctly claim the invention.  Accord took full advantage of this in its petition for PGR2014-00010, in which Accord alleged that Helsinn’s patent related to liquid pharmaceutical formulations of palonosetron should not have been issued by the Patent Office.

The ’219 patent had been asserted in several Hatch-Waxman litigations involving ALOXI®, which is a palonosetron formulation indicated to help prevent nausea and vomiting following chemotherapy.  Palonosetron hydrochloride, the active pharmaceutical ingredient, has the following structural formula:

The ’219 patent is a member of a family of patents directed to formulations of palonosetron hydrochloride.  Importantly, this patent was filed as a continuation-in-part application on May 23, 2013, with a letter that asserted that claim 9 only had support because of a newly added example, and therefore was subject to the AIA.  Only claims 1-5 and 8 of the ’219 patent are the subject of this petition, with claim 1 reading:

1.    A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:
palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;
from 0.005 mg/mL to 1.0 mg/mL EDTA;
and from 10 mg/mL to 80 mg/mL mannitol,
wherein said formulation is stable at 24 months when stored at room temperature.

Claim 8 is the only other challenged independent claim, and it reads identically, except for a stability limitation of 18 months when stored at room temperature.  This patent issued on December 3, 2013, and the PGR petition was filed within the requisite nine months.

CLAIMS(8)………..http://www.google.com/patents/US8598219

What is claimed is:

1. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol,

wherein said formulation is stable at 24 months when stored at room temperature.

2. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL.

3. The pharmaceutical formulation of claim 1, wherein said mannitol is in an amount of 41.5 mg/mL.

4. The pharmaceutical formulation of claim 1, wherein said solution further comprises a citrate buffer.

5. The pharmaceutical formulation of claim 4, wherein said citrate buffer is at a concentration of 20 millimolar.

6. The pharmaceutical formulation of claim 1, wherein said solution is buffered at a pH of 5.0 ±0.5.

7. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL, wherein said mannitol is in an amount of 41.5 mg/mL, wherein said solution further comprises a citrate buffer at a concentration of 20 millimolar, and wherein said solution is buffered at a pH of 5.0 ±0.5.

8. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol, wherein said formulation is stable at 18 months when stored at room temperature.

 SO EASY TO UNDERSTAND 35 U.S.C. § 112

The petition pointed out that during the prosecution of the ’219 patent and its family, the Patent Office had rejected the claimed formulations as obvious.  In response, the applicants submitted a declaration from inventor Daniele Bonadeo (“the Bonadeo declaration”) and argued that one of skill in the art would not have combined the features of the invention as a matter of routine optimization.  Instead of routine, the applicants continued, the claimed formulations were obtained after a sequence of experiments, each of which built upon the others like building blocks.

If the experimental sequence had varied, the applicants alleged that they would have obtained a different formulation.  The Bonadeo declaration explained that the first two parameters studied were palonosetron concentration and pH.  None of the studies described in this declaration, however, occurred at a pH other than 5.0, which makes sense because palonosetron was described as extremely stable at this pH.

Considering that the ’219 patent ultimately issued, the applicants were apparently successful in overcoming these obviousness rejections.  In other words, the applicants convinced the examiner that a person of ordinary skill in the art would not have found it obvious to combine the teachings in the prior art to derived the claimed inventions.

The positions taken by the applicant, however, were utilized by the petitioner, Accord, to allege that a person of ordinary skill in the art would not have, for example, found the specification enabling.  This highlights the problem that PGRs pose for patent applicants.  Before such procedure, arguments could be made without much fear that they would be coopted by the Office for making alternative rejections.  And, if the Office did, there would still an opportunity to provide a response or amend the claims.  Even if such arguments were made in district court litigation, the patent would at least enjoy a presumption of validity.

Now, all applicants must take extreme caution in making any arguments, because anything said can (and probably will) be used against them at the PTAB.

What follows is an identification of the 35 U.S.C. § 112 arguments made by Accord.  Considering that the patent owner has not yet filed any response, and the PTAB has not weighed in, no position is taken here as to the merits of these arguments.

Written Description – Stability

Accord first alleged that the ’219 was unpatentable for failing to provide an adequate description of the claimed subject matter being stable at 18 or 24 months when stored at room temperature, as required by 35 U.S.C. § 112(a).  Specifically, the petition asserted that the specification does not show that the inventors were in possession of any formulation that would have achieved the stability limitations of the claims.

Instead, the argument went, the patent contained general statements that it is possible to increase the stability of the formulations, but did not provide any examples with stability beyond a couple of weeks.  Accord included a declaration from Dr. Arnold J. Repta, which explained how a person of ordinary skill in the art would have understood the teaching of the specification.  However, Dr. Repta did not include any additional testing of the formulations taught in the application in his declaration.

Enablement

The second assertion made in the petition was that the ’219 patent does not enable a pH range for the claimed formation outside of about 4.0 to 6.0, and therefore it is not enabled as required by 35 U.S.C. § 112(a).  This is because, according the petition, the only relevant formulation in the specification was disclosed as having a pH of 5.0±0.5.  Moreover, the specification was alleged to claim that palonosetron is most stable at pH 5.0.

Accord also cited to the Bonadeo Declaration, which was submitted during prosecution by the applicants, which alleged claimed that palonosetron formulations containing mannitol or EDTA required a pH of 4-6.  Therefore, according to the petition, because the challenged claims do not recite any pH limitations, they were broader than the teaching of the specification.

“Regards as the Invention”

35 U.S.C § 112(b) requires that a patent “conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”  Accord challenged the claims of the ’219 patent as not including the invention as regarded by the inventors.  Specifically, the petition alleges that the Bonadeo Declaration made clear that palonosetron was extremely stable at a pH of 5.0, and that there was no hint that a pH outside of the range of about 4.0 or 6.0 would be suitable.  A similar argument was made about the language found in the specification.  The petitioner concluded by pointing out that, even though the inventors believed that the inventive formation should be in a range of 4.0 to 6.0, such a limitation was not included in the claims.

Written Description – pH Range

Finally, Accord made a similar argument when alleging that the specification did not support claims that did not include a pH range of 4.0 to 6.0.  Citing to the Gentry Gallery, Inc. v. Berkline Corp., 134 F.3d 1473 (Fed. Cir. 1998), line of cases, the petitioner alleged that the pH range was an essential or critical feature which was omitted from that claims.  In other words, Accord alleged that the broad claims without a pH limitation were invalid because the “entirety of the specification” demonstrates that the invention was of much narrower scope.

Of course, similar to an IPR, the patent owner now has a chance to submit a preliminary response to the petition.  The standard used for instituting a PGR differs from that required for an IPR.  Instead of the “reasonable likelihood” standard, a PGR will only be instituted when it is more likely than not that at least one of the claims challenged is unpatentable.  In essence, this should be a slightly more stringent standard, because with both positions being equally likely, an IPR petition would have a reasonable likelihood of demonstrating claims as unpatentable, but a PGR petition would not be more likely than not to demonstrate unpatentable claims.

However, it remains to be seen if less PGRs are instituted than IPRs.  We will continue to monitor PGR2014-00010, and provide updates as warranted.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

A Green and Sustainable Approach: Celebrating the 30th Anniversary of the Asymmetric l-Menthol Process 

Takasago has been devoted to producing l-menthol since 1954, and our long history of manufacturing this important aroma chemical is reviewed here. The current asymmetric catalytic process had its 30th anniversary in 2013. Our l-menthol process is considered carbon-neutral, and, therefore, ‘green’ and sustainable. It uses renewable myrcene obtained from gum rosin as a starting material. In addition, the Rh-BINAP (=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) catalytic system is highly efficient. This pathway not only leads l-menthol, but a variety of 100% biobased aroma chemical products as well. By measuring the ¹⁴C levels in a material, one can determine the percentage of carbon that is biobased. This biobased assay, described as the ratio plant-derived C/fossil-derived C, can clarify how renewable a product really is. This will be highlighted for several of Takasago’s key aroma chemicals.

1. Makoto Emura^* and
2. Hiroyuki Matsuda

Article first published online: 18 NOV 2014

DOI: 10.1002/cbdv.201400063

Issue

Chemistry & Biodiversity

Volume 11, Issue 11, pages 1688–1699, November 2014

http://onlinelibrary.wiley.com/doi/10.1002/cbdv.201400063/abstract

 

 

Production

As with many widely used natural products, the demand for menthol greatly exceeds the supply from natural sources. In the case of menthol it is also interesting to note that comparative analysis of the total life-cycle costs from a sustainability perspective, has shown that production from natural sources actually results in consumption of more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the main synthetic production routes.^[7]

Menthol is manufactured as a single enantiomer (94% ee) on the scale of 3,000 tons per year by Takasago International Corporation.^[8] The process involves an asymmetric synthesis developed by a team led by Ryōji Noyori, who won the 2001 Nobel Prize for Chemistry in recognition of his work on this process:

The process begins by forming an allylic amine from myrcene, which undergoes asymmetric isomerisation in the presence of a BINAP rhodium complex to give (after hydrolysis) enantiomerically pure R-citronellal. This is cyclised by a carbonyl-ene-reaction initiated by zinc bromide to isopulegol, which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Another commercial process is the Haarmann-Reimer process. ^[9][10] This process starts from m-cresol which is alkylated with propene to thymol. This compound is hydrogenatedin the next step. Racemic menthol is isolated by fractional distillation. The enantiomers are separated by chiral resolution in reaction with methyl benzoate, selective crystallisation followed by hydrolysis.

Racemic menthol can also be formed by hydrogenation of pulegone. In both cases with further processing (crystallizative entrainment resolution of the menthyl benzoate conglomerate) it is possible to concentrate the L enantiomer, however this tends to be less efficient, although the higher processing costs may be offset by lower raw material costs. A further advantage of this process is that d-menthol becomes inexpensively available for use as a chiral auxiliary, along with the more usual l-antipode.^[7]

References

1. R. Eccles (1994). “Menthol and Related Cooling Compounds”. J. Pharm. Pharmacol. 46 (8): 618–630. PMID 7529306.
2.  Galeottia, N., Mannellia, L. D. C., Mazzantib, G., Bartolinia, A., Ghelardini, C.; Di Cesare Mannelli; Mazzanti; Bartolini; Ghelardini (2002). “Menthol: a natural analgesic compound”.Neuroscience Letters 322 (3): 145–148. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159.
3.  G. Haeseler, D. Maue, J. Grosskreutz, J. Bufler, B. Nentwig, S. Piepenbrock, R. Dengler and M. Leuwer. (2002). “Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol”. European Journal of Anaesthesiology 19 (8): 571–579. doi:10.1017/S0265021502000923.
4. Brain KR, Green DM, Dykes PJ, Marks R, Bola TS; Green; Dykes; Marks; Bola (2006). “The role of menthol in skin penetration from topical formulations of ibuprofen 5% in vivo”. Skin Pharmacol Physiol 19 (1): 17–21. doi:10.1159/000089139. PMID 16247245.
5. PDR for Herbal Medicines (4th ed.). Thomson Healthcare. p. 640. ISBN 978-1-56363-678-3.
6. Croteau, R. B.; Davis, E.M.; Ringer, K. L; Wildung, M. R. (December 2005). “(−)-Menthol biosynthesis and molecular genetics”. Naturwissenschaften 92 (12): 562–77.Bibcode:2005NW…..92..562C. doi:10.1007/s00114-005-0055-0. PMID 16292524.
7. Charles Sell (ed.). The Chemistry of Fragrances: From Perfumer to Consumer. ISBN 978-085404-824-3.
8.  Japan: Takasago to Expand L-Menthol Production in Iwata Plant
9.  After the company Haarmann & Reimer , now part of Symrise
10. Schäfer, Bernd (2013). “Menthol”. Chemie in unserer Zeit 47 (3): 174. doi:10.1002/ciuz.201300599.

Here, we report a continuous flow protocol for the [3 + 2] cycloaddition of nitrones, in situ generated from oximes, into bicyclic isoxazolidines. This thermal process required very high temperatures to be efficient that were not easily reached in conventional reactors. A couple of examples are presented and in both the flow process showed a greater performance than the batch mode. The process intensification study allowed the generation of 120 g/h of a key pharmaceutical intermediate.

Large-Scale Continuous Flow Transformation of Oximes into Fused-Bicyclic Isoxazolidines: An Example of Process Intensification

see

http://pubs.acs.org/doi/abs/10.1021/op500350y

SEE……….http://cen.acs.org/articles/93/i6/Periodic-Graphics-Aphrodisiacs.html

ARKIVOC Volume 2006
Part (v): Commemorative Issue in Honor of 
Facilitator: Luba Ignatovich
Scientific Editor: Mikael Begtrup

2. The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study (EL-1719AP)
Rosa M. Claramunt, Concepción López and José Elguero
Full Text: PDF (193K)
pp. 5 – 11

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

Rosa M. Claramunt,a Concepción López,a and José Elguero b *

a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain

b Instituto de Química Médica, CSIC, Juan de la Cierva, 3. E-28006 Madrid, Spain E-mail: iqmbe17@iqm.csic.es

To our friend Professor Edmunds Lukevics on his 70th anniversary

 Edmunds Lukevics

Abstract

The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution (Magn. Reson. Chem. 2004, 42, 712).

Keywords: Omeprazole, NMR, 13C, 15N, CPMAS, tautomerism, benzimidazole

see at

http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2006/5/graphical-abstracts/

http://www.arkat-usa.org/get-file/22955/

Edmunds LUKEVICS

(14.12.1936 – 21.11.2009)

Professor Edmunds LUKEVICS Latvian Institute of Organic Synthesis, Head of the Laboratory of Organometallic ChemistryAizkraukles iela 21, Riga, LV-1006 Latvia

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests:

• Organometallic Compounds
• Heterocyclic Compounds
• Biological Activity of Organic Compounds

Main Research:

Development of methods for the synthesis of organosilicon and -germanium derivatives of furan, thiophene and nitrogen-containing heterocycles ; study of the influence of organosilicon ,-germanium and -tin substituents on the direction of substitution and addition reactions of furan and thiophene derivatives ; study of hydrosilylation and hydrogermylation reactions, synthesis and investigation of properties of penta- and hexacoordinated organosilicon and -germanium derivatives; application of alkenyl silanes and germanes in the synthesis of nitrogen-containing heterocycles; application of phase-transfer catalysis and ultrasonic irradiation in organometallic synthesis; synthesis of biologically active organosilicon and organogermanium compounds and studies of their properties.

Education:

• University of Latvia (Faculty of Chemistry), 1958
• Dr.chem. (Candidate of Science in former USSR, Ph.D. in Western countries), Latvian Academy of Sciences, Riga, 1966
• Dr.habil.chem. (Doctor of Science in former USSR), Latvian Academy of Sciences, Riga, 1973

Experience:

Latvian Institute of Organic Synthesis -

• Junior Researcher, 1958-1967
• Senior Researcher, 1968-1970
• Head, Laboratory of Organometallic Chemistry, 1970 – 2009
• Vice-director, 1980-1982
• Director, 1982 – 2003

Honours and Awards:

• Corresponding Member, Latvian Academy of Sciences , 1982
• Full Member, Latvian Academy of Sciences , 1987
• Member, New York Academy of Sciences, 1993
• The Latvian Academy of Sciences Gustavs Vanags Prize (in Chemistry), 1986
• Latvian SSR State Prize, 1974, 1989
• S.Hiller Medal (Latvian Institute of Organic Synthesis), 1990
• G.Vanags Medal (Riga Technical University), 1991
• D.H.Grindel Medal (company ‘Grindex’, Latvia), 1995
• L.Liepina Medal (Institute of Inorganic Chemistry, Riga), 1996
• The Latvian Academy of Sciences Grand Medal, 1996
• Silver Medal of Milan University, 1996
• Schmiedebergs Medal (Latvian Pharmacological Society), 1998
• The Latvian Academy of Sciences and Company “GRINDEX” Prize, 1999
• Paul Walden’s Medal (Riga Technical University), 2000
• Latvian Academy of Sciences Presidium Award, 1971, 1973, 1977, 1981, 1982, 1985,1987, 1989, 1992
• International Man of the Year (The International Biographic Centre of Cambridge, England), 1992-1993, 1994-1995
• Man of the Year (The American Biographical Institute), 1994, 2005
• The first-level Badge of Honour of the Order of Three Stars, 1997
• Company “Grindex” gold badge of honour, 2001
• The Cabinet of Ministers of the Republic of Latvia Prize , 2004
• American Medal of Honor (ABI), 2005
• Gold Medal for Latvia (ABI), 2006
• The Plato Award (IBC), 2006
• Man of Achievement (ABI), 2007

Professional Activities:

• Member of Presidium and Senate, Latvian Academy of Sciences, 1987-1991
• Member of Board, Division of Chemical and Biological Sciences, Latvian Academy of Sciences, 1983-1993
• Member, Latvian Academy of Sciences Commission on Terminology, 1987- 1999
• Chairman, Habilitation and Promotion Council (Chemistry and Pharmacy), Latvian Institute of Organic Synthesis, 1994 -1999
• Member (Chairman,1991-1993, 1997-2002), Latvian Council of Science Expert Committee for Chemistry, 1991 – 2006

• Vice-chairman, Habilitation and Promotion Council (Chemistry), University of Latvia, 1998- 2009

• Member of Editorial Board for:

Khimiya Geterotsikicheskikh. Soedinenii (Chemistry of Heterocyclic Compounds, Springer), 1980-1985; Editor-in-chief, 1985 - 2009
Proceedings of Latvian Academy of Sciences, 1982-1990
Latvian Journal of Chemistry, 1991 - 2009
Bioorganicheskaya Khimiya, 1989 – 1993
Applied Organometallic Chemistry, 1990 - 2009
Main Group Metal Chemistry, 1992 - 2009
Metal-Based Drugs, 1993 – 2003
Mendeleev Communications, 1994 - 2009
Advances in Heterocyclic Chemistry, 1994 - 2009
Silicon Chemistry, 2001-2007
Arkivoc, 2001 -  2009
Bioinorganic Chemistry and Applications, 2003 – 2006
Heterocyclic Communications, 2005 -  2009
Molecules, 2008 -  2009
Journal of Organic and Pharmaceutical Chemistry (Ukraine), 2009 - 2009

• Chairman, Scientific Council “Chemistry and Technology of Sulfur Organic Compounds”, USSR State Committee of Science and Technics, 1982-1987
• Chairman, Council “Application of Organometallic Compounds in National Economy”, USSR (Russian) Academy of Sciences, 1984-1992
• Member, United Libraries Informative Council, USSR Academy of Sciences, 1985-1990
• Member, Scientific Council “Physiologically Active Compounds”, USSR Academy of Sciences, 1986-1992
• Member, Scientific and Technical Council, USSR Ministry of Medical and Microbiological Industry, 1987-1990
• Member, Soviet National Committee on collecting and estimating information in science and technics “CODATA”, 1987-1990
• Member of Council for Coordination of scientific work, Department of Biochemistry, Biophysics and Physiologically Active Compounds, USSR Academy of Sciences, 1988-1991
• Member of International Organizing Committees
  - International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin and Lead, 1992, 1995, 1998, 2001
  -  International Symposium on Organosilicon Chemistry, 1993, 1996, 1999, 2002, 2005, 2008.

Memberships:

• Member of Organometallic Chemistry Division, Federation of European Chemical Societies, 1995-2005
• Member of Organometallic Chemistry Division, European Association for Chemical & Molecular Sciences, 2006
• Member, Latvian Chemical Society, 1995
• Member, American Chemical Society, 1997
• Member, National Geographic Society, 1997
• Honorary Member,  Pharmacological Society of Latvia, 1998

Lectures

Invited Lectures at Universities

• Indian Institute of Science, Bangalore (India), 1989
• Indian Institute of Technology, Bombay (India), 1989
• University of Dresden (Germany), 1989
• Universities of Bordeaux, Tolouse, Montpellier, Marseilles (France), 1990, 1994
• University of Lund (Sweden), 1992
• University of Alcala de Henares ( Spain), 1993
• Tohoku University (Sendai, Japan), 1991, 1992
• Tokyo University of Science (Japan), 1997
• Kyoto University (Japan), 1997
• Universities of Kyoto and Kanagawa, Japan, 2002.

Invited Lectures and Symposium’s Plenary Lectures:

• 40th Nobel Symposium (Lidingö, Sweden), 1977
• VI Symposium on Chemistry of Heterocyclic Compounds (Brno, Czechoslovakia), 1978
• 7th International Symposium on Organosilicon Chemistry (Kyoto, Japan), 1984
• VI FECHEM Conference on Organometallic Chemistry (riga, Latvia), 1985
• II Soviet-Indian Symposium on Organometallic Chemistry( Irkutsk, Russia), 1989
• 17th DDR-Poland Colloquy on Organometallic Chemistry (Holzhau, Germany), 1989
• 6th International Conference on Organometallic and Coordination Chemistry of Germanium, Tin and Lead (Brussels, Belgium), 1989
• Huang Minlon Symposium on Organic Chemistry (Shanghai, China), 1989
• International Chemical Conference on Silicon and Tin ( Kuala Lumpur, Malaisia), 1989
• 9th International Symposium on Organosilicon Chemistry (Edinburgh, UK), 1990
• 1st Meeting of the European Society of Sonochemistry, Autrans (Grenoble, France), 1990
• 11th International Symposium on Medicinal Chemistry (Jerusalem, Israel), 1990
• S.Hiller Memorial Lectures (Riga, Latvia), 1990
• 1st Meeting of Japanese Germanium Discussion Group (Tokyo, Japan), 1991
• International Conference on Environmental and Biological Aspects of Maingroups Organometals (Padua, Italy), 1991
• 3rd Swedish-German workshop: Nucleic Acid Synthesis, Structure and Function (Uppsala, Sweden), 1992
• 2nd ANAIC Conference on Materials Science and Environmental Chemistry of Main Group Elements (Kual Lumpur, Malaysia), 1993
• Todai Symposium “Ge-Sn-Pb Tokyo’93”: International Symposium on Organic, Bioorganic and Bioinorganic Chemistry of Compounds of higher row Group 14-elements (Tokyo, Japan), 1993
• 10th International Symposium on Organosilicon Chemistry (Poznan, Poland), 1993
• 3rd Meeting of the European Society of Sonochemistry (Figueira da Foz, Portugal), 1993
• 14th Nordic Meeting of Structural Chemists (Helsinki, Finland), 1993
• 8th International Conference on the Organometallic Chemistry of Germanium, Tin and Lead (Sendai, Japan), 1995
• 8th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (Santa Barbara, USA), 1995
• 8th Symposium Heterocycles in Bioorganic Chemistry (Como, Italy), 1996
• 9th International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin, and Lead (Melbourne, Australia), 1998
• 12th International Conference on Organosilicon Chemistry (Sendai, Japan), 1999
• International Conference on Organic Synthesis “Balticum Organicum Sinteticum-2000″(Vilnius, Lithuania), 2000
• X International Symposium “Jubilee Krka Prizes” (Novo Mesto, Slovenia), 2000

Recent/Representative Publications:

• E.Ya. Lukevits, M.G.Voronkov. Organic Insertion Reactions of Group IV Elements, 1966, New York: Consultants Bureau, 413 pp.
• S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Heteropolymers and Heterocompounds, 1970, NewYork: Plenum Press, 633 pp.
• S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Derivatives of Phosphorus and Sulfur, 1971, NewYork; London: Plenum Press, 343 pp.
• M.G.Voronkov, G.I..Zelchan, E.Ya.Lukevits. Silizium und Leben, 1975, Berlin: Akademie-Verlag, 370 pp.
• E.Lukevics, O.Pudova, R.Sturkovich. Molecular Structure of Organosilicon Compounds, 1989, Chichester: Ellis Horwood Ltd., 359 pp.
• E.Lukevics, T.Gar, L.Ignatovich, V.Mironov. Biological Activity of Germanium Compounds, 1990, Riga: Zinatne, 191 pp. (in Russian).
• E.Lukevics, A.Zablocka. Nucleoside Synthesis: Organosilicon Methods, 1991, Chichester: Ellis Horwood, 496 pp.
• E.Lukevics,  L.Ignatovich. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1653-1683.
• E.Lukevics,  O.Pudova. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1685-1714.

• E.Lukevics, O.Pudova. Silyl imidic esters. – In: Science of Synthesis, Thieme, 2002, vol. 4, pp. 305-315.
• E. Lukevics, P. Arsenyan, S. Belyakov, O. Pudova. Synthesis, structure and chemical transformations of ethynylgermatranes – Eur. J. Inorg. Chem., 2003, Iss.17, pp.3139-3143.
• R. Abele, E. Abele, M. Fleisher, S. Grinberga, E. Lukevics. Novel fluoride ion mediated synthesis of unsymmetrical siloxanes under phase transfer catalysis conditions. – J. Organomet. Chem., 2003, vol.686, N 1/2, pp.52-57.
• E. Lukevics, L. Ignatovich, I.Shestakova. Synthesis, psychotropic and anticancer activity of 2,2-dimethyl-5-[5-trialkylgermyl(silyl)-2’-hetarylidene]-1,3-dioxane-4,6-diones and their analogues. - Appl.Organomet. Chem., 2003, vol. 17, N 12, pp.898-905.
• P. Arsenyan, K. Rubina, I. Shestakova, E. Abele, R. Abele, I. Domracheva, A. Nesterova, J. Popelis, E. Lukevics. Synthesis and cytotoxicity of silylalkylthio-substituted N-heterocycles and their hydroselenites. – Appl. Organomet. Chem., 2003, vol. 17, N 11, pp.825-830.
• E. Lukevics, L. Ignatovich, T. Shul’ga, S. Belyakov. The crystal structure of 2-benzo[b]thienylgermatrane. – Appl. Organomet. Chem., 2003, vol. 17, N 9, pp.745-746.
• K. Rubina, E. Abele, P. Arsenyan, M. Fleisher, J. Popelis, A. Gaukhman, E. Lukevics. The role of palladium catalyst and base in stereoselective tranformations of (E)-2-chlorovinylsulfides. –Tetrahedron, 2003, vol.59, N 38, pp.7603-7607.
• I. Iovel, L. Golomba, J. Popelis, S. Grinberga, E. Lukevics Catalytic hydrosilylation of furan, thiophene, and pyridine aldimines. – Chem. Heterocycl. Comp., 2003, vol.39, N 1, pp.49-55.
• G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E. Lukevics. Design of ß-lactams with mechanism based nonbacterial activities. – Current Medicinal Chemistry, 2003, vol.10, N 17, pp.1741-1757.
• E. Lukevics, P. Arsenyan, O. Pudova. Methods for the synthesis of oligothiophenes. – Heterocycles, 2003, vol.60, N 3, pp.663-687.
• V.Dirnens, V.Klusa, J.Skuyins, S.Svirskis, S.Germane, A.Kemme, E.Lukevics. Synthesis and pharmacological activity of silyl isoxazolines-2. - Silicon Chemistry, 2003 (publ. 2004), vol. 2, N 1/2, pp. 11-25.
• I.Iovel, L.Golomba, M.Fleischer, J.Popelis, S.Grinberga, E.Lukevics. Hydrosilylation of (hetero)aromatic aldimines in the presence of Pd(I) complex. - Chem.Heterocycl. Comp., 2004, vol. 40, N 6, pp. 701-714.
• P.Arsenyan, O.Pudova, J.Popelis, E.Lukevics. Novel radial oligothienylsilanes. - Tetrahedron Lett., 2004, vol. 45, N 15, pp. 3109-3111.
• E.Lukevics, L.Ignatovich, S.Belyakov. Crystallographic report: 2-furfurylgermatrane. - Appl. Organomet. Chem., 2004, vol. 18, N 4, p. 203.
• G. Veinberg, I. Shestakova, M. Vorona, I. Kanepe, E. Lukevics.  Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones. –   Bioorg. Med. Chem. Letters, 2004, vol. 14, No 1, 147-150.
• E.Lukevics, L.Ignatovich, T.Shulga, S.Belyakov. 1-[4-(2-Thienyl)phenyl]germatrane. –   Appl. Organomet. Chem., 2005, vol. 19, N 1, pp. 167-168.
• E.Lukevics, L.Ignatovich. Biological activity of organosilicon compounds. – In:  Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 83-107.
• E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. – In:  Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 279-295.
• Yu.Melnik, M.Vorona, G.Veinberg, J.Popelis, L.Ignatovich, E.Lukevics. Synthesis and stereoisomerization of 2-(1-alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans. –   Chem. Heterocycl. Comp., 2005, vol. 41, N 6, pp. 718-721.
• L.Ignatovich, J.Popelis, E.Lukevics. Synthesis and NMR spectra of diaryl-  and dihetarylsilacycloalkanes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 559-562.
• L.Ignatovich, D.Zarina, I.Shestakova, S.Germane, E.Lukevics. Synthesis and bological activity of silicon derivatives of 2-trifluoroacetylfuran and their oximes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 563-568.
• E.Lukevics, L.Ignatovich, I.Sleiksha, I.Shestakova, I.Domrachova, J.Popelis. Synthesis and cytotoxic activity of silacycloalkylsubstituted heterocyclic aldehydes. -  Appl. Organomet. Chem., 2005, vol. 19, N 10, pp. 1109-1113.
• S.Belyakov, E.Alksnis, V.Muravenko, I.Turovskis, J.Popelis, E.Lukevics. Crystal structure and conformation of 8-(2-hydroxyethylamino)-  and 8-(pyrrolidin-1-yl)adenosines. - Nucleosides, Nucleotides & Nucleic Acid, 2005, vol. 24, N 8, pp. 1199-1208.
• A. Zablotskaya, I.Segal, S.Belyakov, E.Lukevics. Silyl modification of biologically active compounds. 11. Synthesis, physico-chemical and biological evaluation of N-(trialkoxysilylalkyl)tetrahydro(iso,silaiso)quinoline derivatives. Appl. Organomet. Chem. 2006, vol.20, N 2, 149-159.
• A.Zablotskaya, I.Segal, J.Popelis, E.Lukevics, S.Baluja, I.Shestakova, I.Domracheva. Silyl modification of biologically active compounds. 12. Silyl group as true incentive to antitumour and antibacterial action of choline and colamine analogues. - Appl. Organomet. Chem. 2006, vol. 20, N 11, 721-728.
• E.Lukevics, L.Ignatovich, I.Sleiksha, V.Muravenko, I.Shestakova, S.Belyakov, J.Popelis. Synthesis, structure and cytotoxic activity of 2-acetyl-5-trimethylsilylthiophene(furan) and their oximes. - Appl. Organomet. Chem. 2006, vol 20, N 7, 454-458.
• L.Ignatovich, V.Muravenko, S.Grinberga, E.Lukevics. Novel reactions to form an Si-O-Ge group. - Chem.Heterocycl. Comp., 2006, vol. 42, N 2, 268-271.
• E.Lukevics, I.Shestakova, I.Domrachova, A.Nesterova, Y.Ashaks, D.Zaruma. Synthesis of complex compounds of methyl derivatives of 8-quinolineselenol with metals and their cytotoxic activity. - Chem.Heterocycl. Comp., 2006, vol. 42, N 1, 53-59.
• E.Lukevics, L.Ignatovich, I.Sleiksha, V.Romanov, S.Grinberga, J.Popelis, I.Shestakova. A New method for the synthesis of silicon- and germanium-containing 2-acetylfurans and 2-acetylthiophenes. -Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 143-150.
• V.Dirnens, I.Skrastina, J.Popelis, E.Lukevics. Synthesis of isoxazolinylxanthines. - Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 193-196.
• E.Lukevics, L.Ignatovich, S.Belyakov. Disordering in the crystal structure of thienylgermatranes. - Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 243-249.
• E.Lukevics, I.Shestakova, I.Domrachova, E. Yashchenko, D.Zaruma. Y.Ashaks. Cytotoxic di(8-quinolyl)disulfides. - Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 629-633.
• V.M.Vorona, I.Potorocina, G.Veinberg, I.Shestakova, I.Kanepe, M.Petrova, E. Liepinsh, E.Lukevics. Synthesis and structural modification of tert-butyl ester of 7a-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em carboxylic acid.- Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 646-652.
• A.Zablotskaya, I.Segal, E.Lukevics, S.Belyakov, H.Spies. Tetrahydroquinoline and tetrahydroisoquinoline mixed ligand rhenium complexes with the SNS/S donor atom set.- Appl.Organomet.Chem.,2007, vol.21, N 4, 288-293.
• A.Zablotskaya, I.Segal, M. Maiorov, D. Zablotsky, A. Mishnev E.Lukevics, I.Shestakova, I. Domracheva. Synthesis and characterization of nanoparticles with an iron oxide magnetic core and a biologically active trialkylsilylated aliphatic alkanolamine shell. J. Magn. Magn. Mater. 2007, 311, pp. 135-139.
• Zablotskaya A., Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I.  Synyhesis, physico-chemical and biological study of trialkylsiloxyalkylamine coated iron oxide/oleic acid magnetic nanoparticles for the treatment of cancer. - Appl. Organomet. Chem. 2008, vol. 22, pp. 82-88.
• E.Lukevics, E.Abele. Four-membered rings with three heteroatoms not including oxygen, sulfur or nitrogen atom. – In: Comprehensive Heterocyclic Chemistry III., 2008, 2.   Four-membered heterocycles together with all fused systems containing a four-membered heterocyclic ring (Exec. Ed. A. Katritzky, FRS: Eds Ch.A. Ramsden, E.V.Scriven, R.J.Taylor), pp. 973-989.     
• Soualami S., Ignatovich L., Lukevics E.,Ourari A., Jouikov V. Electrochemical oxidation of benzylgermatranes. - J. Organomet. Chem., 2008, vol.693 (7), pp. 1346-1352.
• Lukevics E.,   Ignatovich L., Shul’ga T., Belyakov S. Synthesis and crystal structure of 1-(4-fluorophenyl)- and 1-(4-dimethylamino)phenylgermatranes. - Chem. Heterocycl.Comp. (Engl.Ed.), 2008, vol. 44 (5), pp. 615-620.
• Abele E., Lukevics E. Synthesis of Heterocycles from Oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. (Eds. Z.Rapoport, J.F.Liebmann ), J.Wiley, Chichester, 2009,  Part I, pp. 233-302.
• Erchak N., Belyakov S., Kalvinsh I., Pypowski K., Valbahs E., Lukevics E. Two polymorphic modifications of 1-(N-morpholiniomethyl)spirobi(3-oxo-2,5-dioxa-1-silacyclopentan)ate hydrate. -Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 9, pp.1137-1143..
• Zablotskaya A.,Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I.  Water-soluble magnetic nanoparticleswith biologically active stabilizers. - J.Magn.Mater.,2009, 321, pp. 1428-1432.
• Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. -  Appl. Organomet. Chem. 2009, DOI 10.1002, aoc, 1538.
• Vorona M., Veinberg G.,Liepinsh E., Kazoka H., Andrejeva G., Lukevics E. Enzymatic synthesis of amoxycilloic acids. - Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 6, pp.782-754.
• Zablotskaya A.,Segal I., Lukevics E. Iron oxide-based magnetic nanostructures bearing cytotoxic organosilicon molecules for drug delivery and therapy. - Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 150-157.
• Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. -  Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 158-161.
• Segal I., Zablotskaya A.,Lukevics E., Maiorov M., Zablotsky D., Blums E., Mishnew A., Georgieva R., Shestakova I., Gulbe A. Preparation and cytotoxic properties of goethite-based nanoparticles covered with decyldimethyl(dimethylaminoethoxy)silane metoxyde. -  Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 193-197.
• Ignatovich L., Muravenko V., RomanovsV,  Sleiksha I., Shestakova I., Domracheva I, Belyakov S., Popelis J., Lukevics E. Synthesis, structure and cytotoxic activity of new 1-[5-organylsilyl(germyl)-2-furyl(thienyl)]nitroethenes. -  Appl. Organomet. Chem. 2010, vol. 24, N 12, pp. 858-864.
• Lukevics E., Abele E., Ignatovich L. Biologically Active Silacyclanes. - Adv. Heterocycl. Chem., 2010, vol. 99, pp. 107-141.
• Abele E., Lukevics E. Synthesis, structure and reactions of organometallic derivatives of oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 4), pp. 145-203.
• Katkevics M., Kukosha T., Lukevics E. Heterocycles from hydroxylamines and hydroxamic acids. -  In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 5), pp. 205-293.

Research Projects:

• E.Lukevics (Head of Project). Silylheterocycles in Organic Chemistry. Latvian Council of Science (1993-1995).
• E.Lukevics (Head of Project). Bifunctional Organosilicon Compounds. Latvian Council of Science (1993-1995).
• E.Lukevics (Head of Project). Synthesis of Heterocyclic Organosilicon and Organogermanium Compounds, Investigation of their Physical and Chemical Properties. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Project). Asymmetric and Catalytic Synthesis of Heteroaromatic Compounds. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Program). The Development of Modern Methods of Organic Chemistry Directed towards the Development of Pharmaceutical Industry in Latvia. Latvian Council of Science (1997-2000 ).
• E.Lukevics (Head of Project). Experimental and Theoretical Aspects of the Catalytical Synthesis of Heteroaromatic Compounds. Latvian Council of Science (2001 -2004 ).
• E.Lukevics (Head of Project). Comparative Study of the Structure and Biological Activity of Organosilicon and Organogermanium Compounds. Latvian Council of Science (2001 - 2004).
• E.Lukevics (Head of Project). Heterocyclic Derivatives of Tetra- and Hypercoordinated Germanium and Silicon. Latvian Council of Science (2005 -).
• E.Lukevics ( Programme Director). Development  of Organic Synthesis Methods for  Obtaining of Biologically Active Compounds. Latvian Council of Science (2002 -2005 ).
• E.Lukevics ( Programme Director). Development  of  Heteroatom Chemistry for Preparation of Biologically Active Compounds. Latvian Council of Science (2006 – 2009 ).
• E.Lukevics (Head of Project). Carbofunctional Silylheterocycles. Latvian Council of Science (2009 ).

Hobbies:

Opera, Basketball, Mountains.

Riga latvia

The building of the Brotherhood of Blackheads is one of the most iconic buildings of Old Riga (Vecrīga)

RIGA

RIGA

RIGA

RIGA

Cook in traditional latvian dress serving local food for tourists Riga Latvia

1. Points of interest
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   Freedom Monument

   St. Peter’s Church, Riga

   Museum of the Occupati…

   Latvian Ethnographic Open Air…

   Nativity Cathedral, Riga

2. Colleges and Universities
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   University of Latvia

   Riga

   Riga Technical University

   Riga

   Riga Stradiņš University

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   Turība University

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   Art Academy of Latvia

   Riga

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin

Feb 2015….India-based drugmaker Lupin has signed an agreement with Polish biopharmaceutical firm Celon Pharma to develop a fluticasone / salmeterol dry powder inhaler (DPI).

Under the deal, Lupin will take the responsibility for commercialisation of the product, which is a generic version of GlaxoSmithKline’s (GSK) Advair Diskus.

Lupin CEO Vinita Gupta said: “We are very pleased to partner with Celon given their experience in the development and manufacturing of fluticasone/salmeterol DPI in Europe…………..http://www.pharmaceutical-technology.com/news/newslupin-celon-pharma-partner-generic-version-gsks-advair-diskus-4514718?WT.mc_id=DN_News

Ms. Vinita Gupta is the CEO of Lupin Pharmaceuticals Inc, USA, (LPI) and Group President, Director on the board of Lupin Limited and a Director on the Board of Lupin’s Japanese subsidiary Kyowa Pharmaceuticals.  Ms. Gupta is responsible for the North American and European business of the company.

Ms. Gupta joined Lupin in 1992 and developed Lupin’s entry strategy into US and Europe.  Under her leadership Lupin has emerged as a leader in the US generic market as well as the only company from India to have a successful brand business in the US.  As part of her responsibility she built the entire management team for the US and European business and supervised the development of the company’s pipeline.

Ms. Gupta holds a Bachelor’s degree in Pharmacy from the University of Mumbai and MBA from J L Kellogg Graduate School of Management, Northwestern University.

“A good year” is how Vinita Gupta, Group President and CEO at Lupin Pharmaceuticals, describes her company’s performance at a time when unsettling news was the key takeaway for pharma companies. Lupin grew by an impressive 35.9 per cent globally and 24 per cent in India. New product launches helped it grow its generics business by 52 per cent, making it the sixth-largest generics pharmaceutical company globally by market capitalisation and the third-largest Indian pharmaceutical company by revenues. “I can’t think of any challenges that affected Lupin’s performance during the last fiscal year,” says Gupta, 44. The company’s strategy now is to focus strongly on building its branded business globally.

Vinita Gupta, 43, Group President and CEO, Lupin Pharmaceuticals and Director, Lupin, is based in the United States, but has been in India a lot in the past one year.

Vinita Gupta

With an expanding role in Lupin’s universe, Vinita has been spending more time outside the US, at times taking her six-year-old son, Krish with her. “He is getting exposure at a much younger age,” she says. Gupta herself was exposed to business at the age of 11 by her father Desh Bandhu Gupta, Lupin’s founder and Chairman.

“We almost had a family board at home, discussing work,” she says. Currently work goes well indeed, with Gupta taking new initiatives in India and also making the business more global. “I am focusing on drivers for growth in our business for the next five years,” she says.

Gupta is married to US-based businessman Brij Sharma.

She was 13 when she travelled to Switzerland with her father, to watch him position the family-run Lupin Limited, to negotiate and to strategise. It was enough to get her hooked. Enough for her to move away from a childhood fascination for art and enter the world of pharmaceuticals. Group president and CEO, Lupin Pharmaceuticals, and director on the board of Lupin Limited, Vinita Gupta has never regretted that decision. The 41-year-old is responsible for creating a substantial international presence for the company that was born in Mumbai in 1968 and named after a leguminous flower.

The Lupin group produces affordable generic and branded formulations in the world with a significant presence in cardiovasculars, diabetes, asthma, pediatrics and anti-infectives. But Desh Bandhu Gupta, her father, wanted the company to make an impact in the western market.

It was a challenge that seemed perfect for Gupta who graduated in pharmacy from the University of Mumbai and then spent a year working at the company in Mumbai. She then moved to the US for an MBA from the J.L. Kellogg Graduate School of Management at Northwestern University, following it with a brief stint in a US pharma company. But she didn’t want to be a mere “cog in the wheel”, returning to India to take up that initial challenge-to create a business strategy that would allow Lupin to enter American and European markets.

Today, Lupin is the ninth largest generics company in the US. It is also one of India’s top five pharmaceutical players and one of the fastest growing top 10 generic players in Japan and South Africa. The US arm of the business, Gupta’s baby, contributes to over 30 per cent of Lupin’s revenues, a company that clocked in close to Rs.4,000 crore in 2008-2009. Nine out of the 23 generic products Lupin has in the US market are at the number one position giving consistent competition to larger US pharma companies.

With brother NileshThe beginning however was difficult. After all, India wasn’t very well known in the US market. “We realised that we had the aspirations but not the infrastructure in the form of facilities to meet US and European requirements and standards,” she remembers. So she spent three years building the infrastructure, creating a process that would be acceptable to these regulated markets. The break came with Suprax, a pediatric antiinfective drug that was valued at nearly $60 million in the US market. Gupta had already filed for a generic of the brand. “Suddenly, we had the opportunity to brand the generic, so we licensed the brand name from the innovator as he had left the market,” she remembers. It was a three-person team with 40 outsourced sales people.

Today, the product’s sales are at $74 million. It has been satisfying, she says. “The innovator was in the market with a sales force of 300 people. We are 60.” The aim, she says, has always been to balance branded products as well as generic. The success, her father and chairman of the company, Desh Bandhu Gupta, says, stems not just from her determination. “It’s also her intimate understanding of the entire pharma spectrum with the motivation to see it through,” he says.
This determination became obvious when she managed to persuade the dean at Kellogg to give her admission, even though she was 19 and perhaps the youngest in her class. It was a challenging time as she learned to balance her work and household chores. “At that time in India, everything was handwritten. I had to do every single thing using the computer,” says Gupta who often bribed her friends with homemade Indian food to type out her projects. It taught her to be independent.

But it was perhaps, two months ago, when Gupta a bigger challenge. A deal that made tough seem an understatement. For Antara, an anti-cholesterol drug. “It was very much like Suprax, that was serendipity,” says Gupta. It was a large product with high potential. But the company was in bankruptcy. “I was sure we could do things differently with the product,” she says.

Gupta says Lupin was the first to file for the generic brand. But they couldn’t own the generic and the brand. She had six weeks to sell the generic, win the bid in the US bankruptcy court and buy the brand. She did it. At $38 million, one-third its market value. It’s a deal that Nilesh, her brother and group president and executive director, believes displayed his sister’s meticulous calibre. “There were three sets of negotiations going on at the same time. And while there were others involved, this deal was Vinita all the way,” he says.

Kamal Sharma, managing director, Lupin Limited, has watched Gupta transform from a teenager learning the ropes of a business to the successful go-getter that she is today. “She values, teaches and encourages her people to deliver consistent results year after year,” he says. It’s an attitude that is apparent from the get-go.

(L-R) With Richa, Kavita, Anuja and NileshAt the Trident, Mumbai, for the photo shoot, Gupta is comfortable surrounded by people, even though she is a little hesitant in front of the camera. It’s here that she actually seems to shed the image of an ultimate powerhouse, a businesswoman driven to succeed. It is here that she becomes the Mumbaikar who prefers a masala chai over brewed coffee and a plain tee over a designer label. In some ways, she is still the girl who grew up in a housing society near the airport in Vile Parle, Mumbai. It’s the kind of place where people still keep their doors open and where one can walk into a neighbour’s house without having to knock. Things weren’t handed to her on a golden platter, she admits. In fact, she says, their father taught them that, “as a family we would have to work harder to earn and deserve our right more than what other professionals do.”

As a child, she remembers sharing a room with her four siblings, Kavita, Anuja, Nilesh and Richa. She didn’t like that very much. “But now, when I think of it, I feel it was an amazing life,” she says. Her father adds that he always took his children to different countries, either on work or otherwise. It was his way of showing them the world and different experiences.
But a different side emerges as Gupta talks of the pharma industry. “I dreamed of taking what Dad had built and adding value to it in the western markets,” she says. “This is what I had always prepared myself for. I am living the dream.” And it isn’t as if there aren’t any downs. Six months ago, she remembers, the company received a warning letter from the Food and Drug Administration. She spent that time working to resolve their concerns. “And then three months later, we made one of our most attractive acquisitions. The industry is so quick changing, so dynamic. It always keeps you thinking,” she says.

For Nilesh though, Gupta is his sounding board, the eldest sister with whom he shares a relationship that complements their work profiles. And while Nilesh says with a laugh, Gupta doesn’t pull the bigsister act with him at work, home is a different story. Gupta admits with a mock sigh, “You can’t posture with your siblings. You can posture with anyone else, but not your siblings.”

With husband Brij and son KrishThe obvious downside, however, is family. Her work keeps her busy, sees her up and in office by 8 am, back just in time to spend about an hour with her four-year-old son Krish. “He was a very easy child till some time ago, but lately he has become very demanding,” she says with a smile. Just as Gupta was leaving her home in Baltimore, Maryland for her current trip to India, Krish demanded they go leaf-picking in their backyard. “More than anything, I loved watching the expression on his face while we were picking leaves. His smile brightens up my day,” she says.

As much as her job is a passion she tries to spend time with Krish and husband Brij Sharma, a businessman whom she met in the US. “My husband is a very good listener. I keep talking whenever I am with him and he listens even today,” she says with a laugh. A workout is a must, however, as Gupta heads to the gym every day, spinning the cycle even when she was eight months pregnant.

“My husband jokes that’s the reason why Krish thinks and behaves ahead of his age,” laughs Gupta. But biking near the waterfront with her son and spending time on her husband’s boat is an activity that wins hands down. As does time spent with her two sisters Anuja and Richa, who live in Chicago. While Anuja is a pediatric cardiologist, Anuja is into public health. They do plan vacations together, but she often discovers that her brother Nilesh refuses to talk to her over the weekend. “Probably because I always end up talking about work,” she says with a laugh. “It has become so much a part of our lives,” she says.

In June2012 , Vinita Gupta, CEO of Lupin Pharmaceuticals Inc, the Indian drug maker’s US unit, received the “Entrepreneur of the Year” award from Ernst & Young in the health services and technology category for Maryland state of the US. Over the past year, the US business of Lupin crossed the $500 million mark.

DB Gupta (centre) Chairman, Vinita Gupta (right) CEO and Nilesh Gupta

- See more at: http://www.mdpi.com/1660-3397/8/4/1080/htm#sthash.B8fUm0Hw.dpuf

सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

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Pancratistatin

Tomas Hudlicky

Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada

E-mail: thudlicky@brocku.ca

Chemoenzymatic synthesis of complex natural and unnatural products: morphine, pancratistatin, and their analogs
Tomas Hudlicky
ARKIVOC 2006 (vii) 276-291
pp. 276 – 291

http://www.arkat-usa.org/get-file/23149/

Tomas Hudlicky: Canada Research Chair in Biocatalysis; Professor, Chemistry

Tomas Hudlicky

Organic synthesis, biocatalysis, electrochemistry, asymmeric catalysis

Our group is engaged in a variety of projects ranging from total synthesis to investigations of new reactions and the design of enzyme inhibitors. In total synthesis, we work on implementing reliable and efficient routes to target molecules. Our ventures are exact and logical pursuits, yet serendipity, intuition, and art all form an integral part of designing a total synthesis.

We have exploited the biooxidation of aromatic compounds in an exhaustive approach to the synthetic design of carbohydrates and their derivatives. Our guiding principles are symmetry, simplicity, and precise order of operations so that any derivative or stereoisomer with a sugar backbone can be constructed. These products are tested for glycosidase inhibition, a process important in viral expression. In addition, carbocyclic sugars can act as cell messengers, and their availability through synthesis allows greater understanding of cellular communication.  Oligomers of inositols can also be exploited in a rational design of templates for asymmetric synthesis and in the design of chiral polymers.

Morphine, pancratistatin, and taxol are other important molecules in which our group has invested much synthetic effort. Their total synthesis permits the investigation of new reactions and mechanistic pathways, which can then be applied in subsequent syntheses.  Current effort is focused on designing a practical synthesis of morphine and analogs and in probing the active pharmacophore of pancratistatin in hopes of designing a more bio-available anti-tumor agent.

To address environmentally benign manufacturing, or Green Chemistry, we are exploiting organic electrochemistry as replacement technology for metal-based oxidizing and reducing agents.

Finally we are devoting some effort to studies in the mechanism of prokaryotic oxygenase enzymes. Our ultimate goal is the design of a synthetic enzyme mimic that can be used as a chiral reagent for aromatic cis-hydroxylation.
Research: organic synthesis, green chemistry, chemoenzymatic synthesis, biomanufacturing, biocatalysis

When people are trying to find Brock University they are often told to use the Schmon Tower, which can be seen throughout Niagara, as their guide. In the world of organic chemistry, Tomas Hudlicky, a Canada Research Chair in Biocatalysis, has earned the same sort of status.

The goal of Hudlicky’s research is the practical and efficient synthesis of new medicinal agents by asymmetric synthesis and total synthesis of natural products. His work related to the total synthesis of morphine and the anticancer drug pancratistatin is concerned with refinements and production of the alkaloids in a more efficient and environmentally benign manner. Analogs of both compounds are also being synthesized and evaluated for biological activities.

Hudlicky also conducts research in the area of organic electrochemistry, which provides “green” alternatives to oxidation and reduction methodology. His current research has led to several patent applications and licensing agreements with the Johnson & Johnson subsidiary Noramco. He has also developed a new, simpler route to Tamiflu, one of the few compounds effective against the illness known as H5N1 virus or bird flu.

Recognized as a “green” scientist, Hudlicky converts pharmaceutical waste into a variety of desirable pharmaceutical compounds. His research is responsible for giving the harmful waste of the past a new life as analgesic and anti-tumour products, specifically compounds used in the treatment of cancer, bio-infection and diabetes.

Hudlicky receives daily requests from across the globe to join his research team. The Cairns Family Health and Bioscience Research Complex will greatly improve the size and capacity of Hudlicky’s research facilities, allowing him to accept more graduate students to study with his group.

Pancratistatin

Systematic (IUPAC) name
(1R,2S,3S,4S,4aR,11bR)-1,2,3,4,7-pentahydroxy-2,3,4,4a,5,11b-hexahydro-1H-[1,3]dioxolo[4,5-j]phenanthridin-6-one
Clinical data
Legal status	?
Identifiers
CAS number	96281-31-1
ATC code	?
PubChem	CID 441597
ChemSpider	390265
Chemical data
Formula	C14H15NO8
Molecular mass

 

Pancratistatin (PST) is a natural compound initially extracted from Spider Lily,^[1] a Hawaiian native plant, belonging to the familyAmaryllidaceae^[2] (AMD).

 

Occurrence

Pancratistatin occurs naturally in Hawaiian Spider Lily, a flowering plant within the Amaryllidaceae family. Pancratistatin is mostly found in the bulb tissues of Spider Lilies. It has been shown that the enrichment of atmospheric CO2 can enhance the production ofantiviral secondary metabolites, including Pancratistatin, in these plants.^[3] Pancratistatin can be isolated from the tropical bulbs ofHymenocallis littoralis in the order of 100 to 150 mg/kg when bulbs are obtained from the wild type in Hawaii. However, the compound has to be commercially extracted from field- and greenhouse-grown bulbs or from tissue cultures cultivated, for example, in Arizona, which generate lower levels of Pancratistatin (a maximum of 22 mg/kg) even in the peak month of October. After October, when the bulb becomes dormant, levels of Pancratistatin drop, down to only 4 mg/kg by May. Field-grown bulbs, which show monthly changes in Pancratistatin content, generate somewhat smaller amounts (2–5 mg/kg) compared to those grown in greenhouses cultivated over the same period.^[4] There are about 40 different Spider Lily species worldwide and they are mainly native to theAndes of South America.

Schoals Spider Lilly

Spider Lily

Pharmaceutical research

Pancratistatin is thought to have potential as a basis for the development of new pharmaceuticals,^[5] particularly in the field of cancer treatment.^[6]

Biosynthesis

Although there may not be a precise elucidation of Pancratistatin biological synthesis, there have been speculations on biosynthesis ofNarciclasine and Lycoricidine that are very similar to Pancratistatin in terms of structure. The biosynthesis is accomplished via synthesis from O-methylnorbelladine 4 by para-para phenol coupling to obtain vittatine 5 as an intermediate. Subsequent elimination of two carbon atoms and hydroxylations of compound 5 (vittatine) then leads to narciclasine.^[7]

Pancratistatin-like biosynthesis using Narciclasine as a model.

Total synthesis

The first total synthesis of racemic (+/-) Pancratistatin was proposed by Samuel Danishefsky and Joung Yon Lee, which involved a very complex and long (40 steps) total synthesis. According to both Danishefsky and Joung, there were several weak steps in this synthesis that gave rise to a disappointing low synthetic yield. Amongst the most challenging issues, the Moffatt transposition and theorthoamide problem, which required a blocking maneuver to regiospecifically distinguish the C, hydroxyl group for rearrangement were considered to be the severe cases. However, both Danishevsky and Yon Lee stated that their approach towards the PST total synthesis was not out of merit and believed that their work would interest other medicinal scientists to construct a much more practical and efficient way for PST total synthesis.^[8][9]

The work of Danishevsky and Joung provided the foundation for another total synthesis of PST, which was propounded by Li,M. in 2006. This method employed a more sophisticated approach, starting out with the pinitol 30 that its stereocenters are exactly the same as the ones in the C-ring of Pancratistatin.^[10] Protection of the diol functions of compound 30 gave compound 31. The free hydroxyl of this was subsequently substituted by an azide to give 32. After removal of the silyl function, a cyclic sulfate was installed to obtain product 33. The Staudinger reaction gave the free amine 34 from azide 33. The coupling reaction between 34 and 35 gave compound 36 with a moderate yield. Methocymethyl protection of both the amide and the free phenol gave compound 37. Treatment of this latter product with t-BuLi followed by addition of cerium chloride gave compound 38. Full deprotection of 38 by BBr3 and methanol afforded pancratistatin 3 in 12 steps from commercially available pinitol with an overall yield of 2.3% 20.

a: TIPDSCl2, imidazole, DMAP, DMF, 24%. b: DMP, p-TsOH, acetone, 81%. c: PPh3, DEAD, CH3SO3H, CH2Cl2, 0 °C to r.t. then NaN3, DMF, 60 °C, 72%. d: TBAF, THF, 0 °C to r.t., 100%. e: SOCl2, Et3N, CH2Cl2, 0 °C. f: NaIO4, RuCl3, aq CH3CN, 87% (more than two steps). g: PPh3, aq THF, 0 °C to r.t., 94%. h: Et2O, 35, 0 °C, 64%. i: K2CO3, MOMCl,DMF, 84%. j: t-BuLi, CeCl3, ultrasound, THF, −78 °C to r.t., 72%. k: BBr3, CH2Cl2, −78 °C to 0 °C, 1 hour then MeOH, −78 °C to 0 °C, 2 hours, 52%.

• Total Synthesis of racemic Pancratistatin  CLICK ON PICTURE

• The abstract of the Stereocontrolled synthesis of Pancratistatin

• Pancratistatin and Narciclasine

• Streocontrolled synthesis of pancratistatin

A very recent approach to a stereocontrolled Pancratistatin synthesis was accomplished by Sanghee Kim from the National University of Seoul, in which claisen rearrangement of dihydropyranethlyene and a cyclic sulfate elimination reaction were employed 21. This reaction has proven to be very highly efficient as it produced an 83% overall synthetis yield. (Proved by H and 13C NMR).

The B ring of the phenanthridone (three membered nitrogen hetrocyclic ring) is formed using the Bischler-Napieralski reaction. The n precursor 3 with its stereocenters in the C ring is stereoselectively synthesized from the cis-disubstituted cyclohexene 4. The presence of unsaturated carbonyl in compound 4 suggested the use of a Claisen rearrangement of 3,4-dihydro-2H-pyranylethylene.^[11]

The synthesis starts with the treatment of 6 with excess trimethyl phosphate. This reaction provides phosphate 7 in 97% yield. Using Honer-Wadsworth-Emmons reaction between 7 ands acrolein dimmer 8 in the presence of LHMDS in THF forms (E)-olefin 5 with very high stereoselectivity in 60% yield. Only less than 1% of (Z)-olefin was detected in the final product. The Claisen rearrangement of dihydropyranethylene forms the cis-distributed cyclohexene as a single isomer in 78% yield.

The next step of the synthesis involves the oxidation of aldehyde of compound 4 using NaClO2 to the corresponding carboxylic acid 9 in 90% yield. Iodolactonization of 9 and subsequent treatment with DBU in refluxing benzene gives rise to the bicyclic lacytone in 78% yield. Mthanolysis of lactone 10 with NaOMe forms a mixture of hydroxyl ester 11 and its C-4a epimer (Pancratistatin numbering). Saponification of the methyl ester 11 with LiOH was followed by a Curtius rearrangement of the resulting acid 12 with diphenylphosphoryl azide in refluxing toluene to afford isocyanate intermediate, which its treatment with NaOMe/MeOH forms the corresponding carbamate 13 in 82% yield.

The next steps of the synthesis involve the regioselevtive elimination of C-3 hydroxyl group and subsequent unsaturation achieved by cyclic sulfate elimination. Diol 16 needs to be treated with thionyl chloride and further oxidation with RuCl3 provides the cyclic sulfate 17 in 83% yield.^[12] Treatment of cyclic sulfate with DBU yields the desired allylic alcohol 18 (67% yield).

Reaction with OsO4 forms the single isomerlization 19 in 88% yield. Peracetylation of 19 (77% yield) accompanied by Banwell’s modified Bischler-Napieralski forms the compound 20 with a little amount of isomer 21 ( 7:1 regioselectivity). The removal of protecting groups with NaOMe/MeOH forms Pancratistatin in 83%.

………………………………………………………….

Cheon-Gyu Cho of Hanyang University added (Org. Lett. 2013, 15, 5806. DOI: 10.1021/ol4028623) the activated dienophile 4 to the dienyl lactone to give, after oxidation, the dibromide 5. Debromination followed by oxidation led to the antineoplastic lactam Pancratistatin (6).

………………………………….

 

References

1.  Siedlakowski, P.; McLachlan-Burgess, A.; Griffin, C.; Tirumalai, S. S.; McNulty, J.; Pandey, S. Synergy of pancratistatin and tamoxifen on breast cancer cells in inducing apoptosis by targeting mitochondria. Cancer Biol. Ther. 2008, 7, 376-384.
2.  Shnyder, S. D.; Cooper, P. A.; Millington, N. J.; Gill, J. H.; Bibby, M. C. Sodium Pancratistatin 3,4-O-Cyclic Phosphate, a Water-Soluble Synthetic Derivative of Pancratistatin, Is Highly Effective in a Human Colon Tumor Model. J. Nat. Prod. 2008, 71, 321-324.
3.  Ziska, L.; Emche, S.; Johnson, E. Alterations in the production and concentration of selected alkaloids as a function of rising atmospheric carbon dioxide and air temperature: implications for ethno-pharmacology. Global Change Biology 2005, 11, 1798-1807
4. Ingrassia, L.; Lefranc, F.; Mathieu, V.; Darro, F.; Kiss, R. Amaryllidaceae isocarbostyril alkaloids and their derivatives as promising antitumor agents. Transl Oncol 2008, 1, 1-13.
5. Nair JJ, Bastida J, Codina C, Viladomat F, van Staden J (September 2013). “Alkaloids of the South African Amaryllidaceae: a review”. Nat Prod Commun (Review) 8 (9): 1335–50.PMID 24273880.
6.  Nair JJ, Bastida J, Viladomat F, van Staden J (December 2012). “Cytotoxic agents of the crinane series of amaryllidaceae alkaloids”. Nat Prod Commun (Review) 7 (12): 1677–88.PMID 23413581.
7.  Fuganti, C; Staunton, J; Battersby, AR. The biosynthesis of narciclasine. J Chem Soc D: Chem Commun. 1971, 19, 1154–1155.
8.  anishefsky, S.; Lee, J. Y. Total synthesis of (B1)-pancratistatin. J. Am. Chem. Soc. 1989, 111, 4829-37.
9. Jump up^ Li, M; Wu, A; Zhou, P. A concise synthesis of (+)-pancratistatin using pinitol as a chiral building block. Tetrahedron Lett. 2006, 47, 3707–3710.
10.  Kim, S.; Ko, H.; Kim, E.; Kim, D. Stereocontrolled total synthesis of pancratistatin. Org Lett. 2002, 4, 1343-5.
11.  Shin, K. J.; Moon, H. R.; George, C.; Marquez, V. E.J. Org.Chem. 2000, 65, 2172.
12.  Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J.Am. Chem. Soc. 1999, 121, 296.

 

D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149. DOI: 10.1021/jo401033j) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7 followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor Nootkatone (10).

A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.

(4R*,4aS*,6R*)-4,4a-Dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaph thaen-2(3H)-one ((±)-Nootkatone 20)

(±)-Nootkatone 20 (19 mg, 65%). IRυmax(film) 2923, 1668, 1606, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H), 4.74 (s, 1 H), 4.72(s, 1 H), 2.50 (ddt, J = 15.3, 5.0, 1.8 Hz, 1 H), 2.40–2.24 (m, 4 H), 2.04–1.89 (m, 3 H),1.74 (s, 3 H), 1.40–1.29 (m, 2 H), 1.11 (s, 3 H), 0.96 (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.9, 170.7, 149.3, 124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0.

Nootkatone

Names
IUPAC name 4-α,5-Dimethyl-1,2,3,4,4α,5,6,7-octahydro-7-keto-3-isopropenylnaphthalene
Other names (+)-nootkatone
Identifiers
CAS number	4674-50-4
ChEMBL	ChEMBL446299
ChemSpider	1064812
InChI[show]
Jmol-3D images	Image
KEGG	C17914
PubChem	1268142
SMILES[show]
Properties
Molecular formula	C15H22O
Molar mass	218.33 g·mol−1
Appearance	Viscous yellow in its liquid form
Density	0.968 g/mL
Melting point	36 °C (97 °F; 309 K)
Boiling point	170 °C (338 °F; 443 K)
Hazards
S-phrases	S23 S24 S25
Flash point	~ 100 °C (212 °F)

Nootkatone is a natural organic compound and is the most important and expensive aromatic of grapefruit.^[1] It is a sesquiterpeneand a ketone.

Nootkatone was previouslythought to be one of the main chemical components of the smell and flavour of grapefruits. In its solid form it is usually found as crystals. As a liquid, it is viscous and yellow. Nootkatone is typically extracted from grapefruit, but can also be manufactured with genetically modified organisms, or through the chemical or biochemical oxidation of valencene. It is also found in Alaska yellow cedar trees^[2] and vetiver grass.^[3]

Uses

Nootkatone in spray form has been shown as an effective repellent/insecticide against deer ticks^[3][4][5] and lone star ticks.^[4][5] It is also an effective repellent/insecticide against mosquitos, and may repel bed bugs, head lice and other insects.^[6] It is environmentally friendly insecticide, because it is a volatile essential oil that does not persist in the environment.^[6] It is nontoxic to humans, is an approved food additive,^[6] and “is commonly used in foods, cosmetics, and pharmaceuticals”.^[3]

The CDC has licensed patents to two companies to produce an insecticide and an insect repellant.^[6] Allylix, of San Diego, CA, is one of these licensees ^[7] and has developed an enzyme fermentation process that will produce nookatone more cost effectively.^[8]

References

External links

• Description of nootkatone at Leffingwell.com
• Allylix website

Dr. D. Srinivasa Reddy

https://www.linkedin.com/pub/d-srinivasa-reddy-dsreddy/1/75a/139

Research areas

• Total Synthesis
• Medicinal Chemistry

Our group research interests are broadly in total synthesis of biologically active compounds and medicinal chemistry. Current projects include the total synthesis of bioactive natural products such as antiinflammatory agents, antibacterial agents, antimalarial compounds and anti-cancer agents. Targets are chosen for their interesting biological activity and moderate complexity, which drives our creative solutions to their synthesis. Our ability to achieve an efficient synthesis enables us to access sufficient quantities of target molecule for biological profiling and ready access to different analogs that may prove to be more selective and efficacious as a drug-like molecule. We have plans to divert our total synthesis projects into medicinal chemistry projects by simplifying the complex structures. In medicinal chemistry front, our main interest is to use “silicon-switch approach” to discover novel drugs or drug-like molecules with improved pharmacokintetic (PK) and pharmacodynamic (PD) properties.

DEC2014 NCL PUNE INDIA

DR ANTHONY WITH DR REDDY

Contact

• Dr. D. Srinivasa Reddy
  Senior Scientist
  Office: R.No-282, Main building
  Organic Chemistry Division
  National Chemical Laboratory
  Dr. Homi Bhabha Road
  Pune 411008, India
  Phone  +91 20 2590 2445
  Fax +91 20 2590 2624
  E-mail ds.reddy@ncl.res.in 

TERUTROBAN

Paper

Total synthesis of a thromboxane receptor antagonist, terutroban

Org. Biomol. Chem., 2015, 13,2951-2957
DOI: 10.1039/C4OB02302A, Paper

Wasim Ahmed,^ab   Prathama S. Mainkar,^a   Srihari Pabbaraja^a and  Srivari Chandrasekhar*^ab

*Corresponding authors

^aDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India 500 007

E-mail: srivaric@iict.res.in;
Fax: +91-40-27160152 ;
Tel: +91-40-27193210, 27193434

^bAcademy of Scientific and Innovative Research, New Delhi, India

Org. Biomol. Chem., 2015,13, 2951-2957

DOI: 10.1039/C4OB02302A

http://pubs.rsc.org/en/Content/ArticleLanding/2015/OB/C4OB02302A?

3-(6-(4-Chlorophenylsulfonamido)-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid (2).

…………………….deleted……………………… to give terutroban (2) (1.12 g, 82%) as a white solid.

………………………………………………………

 ¹H NMR (300 MHz, DMSO-d₆) 

δ 7.91 (d, J = 6.6 Hz, 1H),

7.84 (d, J = 8.5 Hz, 2H),

7.66 (d, J = 8.5 Hz, 2H),

6.87 (d, J = 7.7 Hz, 1H),

6.69 (d, J = 7.7 Hz, 1H),

3.31(m, 1H),

2.83–2.65 (m, 4H),

2.63–2.54 (m, 2H),

2.30–2.21 (m, 2H),

2.19 (s, 3H),

1.86–1.74 (m, 1H),

1.63–1.50 (m, 1H); 

……………………………………………………………………….

¹³C NMR (75 MHz, DMSO-d₆) 

δ 174.2, -C=O-OH

140.7,

137.3,

136.9,

133.5,

133.3,

131.9,

129.5,

128.5,

127.9,

127.1,

49.0,

36.4,

32.9,

29.5,

24.3,

24.2,

19.2; -CH3

IR (KBr): ν_max 2924, 1709, 1219, 772 cm⁻¹;

HRMS (ESI): Calcd for C₂₀H₂₃O₄NClS 408.1030 [M + H]⁺, found 408.1040.

[Reported ¹H NMR  ref a (DMSO-d₆) δ 12.5 (s, 1H), 7.9 (s, 1H), 7.8 (d, 2H), 7.7 (d, 2H), 6.9–6.7 (d, 2H), 3.3 (m, 1H), 3.0–2.5 (m, 6H), 2.3 (m, 2H), 2.2 (s, 3H), 2.0–1.5 (m, 2H).]

a   (a) B. Cimetière, T. Dubuffet, O. Muller, J.-J. Descombes, S. Simonet, M. Laubie, T. J. Verbeuren and G. Lavielle, Bioorg. Med. Chem. Lett., 1998, 8, 1375

Synthesis of terutroban (2) is achieved following a non-Diels-Alder approach using cost-effective chemicals.

PREDICTIONS

CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectral analysis

CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectral analysis

EXTRA INFO

Terutroban is an antiplatelet agent developed by Servier Laboratories. It has been tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack).^[1] The study was prematurely stopped and thus it could not be determined whether terutroban has a better effect than aspirin.

Method of action

Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation andvasoconstriction.^[2][3]

 

…………………..

 

10.1358/dof.2006.031.10.1038241

 

Thromboxane A2 (TxA2) is an unstable metabolite of arachidonic acid formed by the cyclooxygenase pathway and released from activated platelets, monocytes and damaged vessel walls, causing irreversible platelet aggregation, vasoconstriction and smooth muscle cell proliferation. From efforts to discover novel compounds that could block the deleterious actions of TxA2, the 2-aminotetralin derivative terutroban sodium (S-18886) emerged as a potent, orally active, long-acting, selective antagonist of thromboxane (TP) receptors. The agent was able to inhibit TP agonist-induced platelet aggregation and vasoconstriction and was selected for further development as an antiplatelet and antithrombotic agent. Terutroban has been shown to be effective in animal models of thrombosis, atherosclerosis and diabetic nephropathy and is currently undergoing phase III development for the secondary prevention of acute thrombotic complications of atherosclerosis.

 

 

References

1.  Hennerici, M. G.; Bots, M. L.; Ford, I.; Laurent, S.; Touboul, P. J. (2010). “Rationale, design and population baseline characteristics of the PERFORM Vascular Project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial”. Cardiovascular Drugs and Therapy24 (2): 175–80. doi:10.1007/s10557-010-6231-2. PMC 2887499. PMID 20490906. edit
2.  H. Spreitzer (January 29, 2007). “Neue Wirkstoffe – Terutroban”. Österreichische Apothekerzeitung (in German) (3/2007): 116.
3.  Sorbera, LA, Serradell, N, Bolos, J, Bayes, M (2006). “Terutroban sodium”. Drugs of the Future 31 (10): 867–873.doi:10.1358/dof.2006.031.10.1038241

Terutroban

Systematic (IUPAC) name
3-((6R)-6-{[(4-Chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid
Clinical data
Legal status	Investigational
Routes	Oral
Pharmacokinetic data
Half-life	6–10 hours
Identifiers
CAS number	165538-40-9  609340-89-8 (sodium salt)
ATC code	None
PubChem	CID 9938840
ChemSpider	8114465
UNII	A6WX9391D8
Chemical data
Formula	C20H22ClNO4S
Molecular mass	407.911 g/mol

 

 

Srivari Chandrasekhar

Chief Scientist & Head, Division of Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology

Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad and excelled in the same with distinction. He then joined A. V. Rama Rao’s group at CSIR–IICT and earned his doctorate in 1991, also from Osmania University. Between 1991 and 1994 he was associated with J. R. Falck (University of Texas Southwestern Medical Center) as a postdoctoral student. In 1994, Chandrasekhar joined his parent institute (CSIR–IICT) as a scientist

Tarnaka, Hyderabad, India 500 007

E-mail: srivaric@iict.res.in;

in.linkedin.com/pub/chandrasekhar-srivari/28/aa1/59b/en

srivaric@gmail.com

 

READ………..http://www.currentscience.ac.in/Volumes/108/02/0160.pdf

Council of Scientific and Industrial Research Ministry of Science and Technology, Government of India

CSIR-IICT CSIR-Indian Institute of Chemical Technology

Experience

Organisation:CSIR-Indian Institute of Chemical Technology
Designation:Scientist
Organisation Type:Research and Development
Department:Organic division
Organisation URL:http://www.iictindia.org

 

Qualification:Ph D
Subject:medicinal chemistry, combinatorial chemistry, total synthesis of natural and unnatural products

Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad

After obtaining a Ph.D. under the supervision of Dr. A. V. Ramarao at the Indian Institute of Chemical Technology, Hyderabad,

DR AV RAMA RAO

He moved to theUniversity of Texas Southwestern Medical School for post-doctoral research with Professor J. R. Falck

Professor J. R. Falck

and

then to the University of Goettingen, Germany as Alexander von Humboldt Fellow in the group of Professor L. F. Tietze.

 Professor L. F. Tietze

His research interests include the synthesis of marine natural products, peptides and peptidomimetics, combinatorial chemistry and new solvent media for organic synthesis.

He is a recipient of a Young Scientist award of the Indian National Science Academy, B M Birla Science Prize and National Academy of Sciences-Reliance Industries Platinum Jubilee Award. He has over 190 publications, 2 patents, and guided 20 students for their Ph.D. degrees. Presently he is a deputy director at the Indian Institute of Chemical Technology where he supervises a group of 30 researchers

Srivari Chandrasekhar, senior scientist, Organic Chemistry Division, Indian Institute of Chemical Technology (IICT), has been conferred Fellow of Indian Academy of Sciences, Bangalore.

According to a press release here on Tuesday, Dr. Chandrasekhar has been conferred the honour for his significant contribution in organic chemistry and medicinal chemistry.

The major contributions include synthesis of complex natural products, especially of marine origin with anti-cancer and anti-depressant properties, green chemistry and automation chemistry to make large number of new chemicals.

He has produced 25 Ph.D. students and published more than 200 papers in international journals. He is also a fellow of National Academy of Sciences.

India has achieved many prizes in 2014. Before the year ends IICT scientist Srivari Chandrasekhar has added one more prize, he wins Infosys Prize. The scientist who has made important contributions in potential drug developments. Srivari Chandrasekhar from CSIR-IICT , Hyderabad, was announced the winner of the Infosys Prize 2014 in Physical Sciences. The award includes a purse of Rs. 55 lakh, a 22 carat gold medal and citation. The award will be presented by The President on January 5 in Kolkata. The prize is awarded annually by the Infosys Foundation.

He had won the CSIR Technology award-2014 along with his team member

Chandrasekhar’s current contribution is to develop a technology for manufacturing Misoprostal, an abortive drug also used in the treatment of ulcers. Now we can easily get rid of Ulcer.

He has successfully prepared some important drug molecules such as bedaquiline for multi-drug resistant TB, Galantamine for Alzheimer’s disease, Sertraline for treatment of depression, Nebivolol for hypertension and marine natural products such as Eribulin, Azumamide, Arenamide and Bengazole which are scarce to get from nature, with potent biological activities.

As he moves on achieving his target , he has made contributions in synthesizing complex and scarcely available natural products in the laboratory using easily available chemicals.

Chandrasekhar has over 250 publications in national and international journals to his credit.

Prof. Chandrasekhar has displayed an exceptional flair for identifying and synthesizing molecules of biological relevance, topical synthetic interest and utility to industry. His research efforts, with an impressive degree of innovations and enterprise, have led to the synthesis of complex and scarcely available natural products and new molecular entities for affordable healthcare. His endeavors have provided cost-effective technologies to chemical industry through identification of new reagents / solvents for specific transformations. Chandrasekhar’s group has synthesized several classes of complex natural products in optically pure form employing chiral pool precursors and catalytic asymmetric reactions and his syntheses of pladienolide, azumamide, bengazole etc., bear testimony to the efficacy of such approaches.

His passion and commitment to topical health related problems is through provisioning for better and affordable access to important drugs. Mention may be made of hissynthesis of bedaquiline, the first drug approved by FDA after a gap of over 40 years for the treatment of multi-drug resistant TB through simpler transformations and higher yields to ensure ready availability. He along with a team atIICT has developed a scalable synthetic route for misoprostol (a hormone like biologically important synthetic prostaglandin) used to prevent gastric ulcer, induce labor and / or abortion (particularly for safe termination of unwanted pregnancies), which has already been commercialized.

Honours / Awards / Fellowships:

AP akademi young scientist 1995

INSA medal for young scientist 1996

CSIR young scientist 1997

Alexander von humboldt fellow 2000 

Synthesis of Phospholipopeptides

A crosslinking approach for the synthesis of phospholipopeptides under mild conditions

Read more

http://www.chemistryviews.org/details/news/7984971/Synthesis_of_Phospholipopeptides.html

Bonan Li and Jun F. Liang, Stevens Institute of Technology, Hoboken, NJ, USA, report an approach to synthesize phospholipopeptides. They use a crosslinker with a thiol-reactive maleimide and an amine-reactive N-hydroxysuccinimide ester (pictured). Hence, the molecule is able to link the thiol group of the amino acid cystein in the peptide and the amine group of the phospholipid (phosphatidylamine).

Dr. Susan Wilkinson, Deputy Editor for the European Journal of Organic Chemistry, talks to Professor Beate Koksch, Freie Universität Berlin, Germany, and Professor Peter Seeberger, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany, about their article on the synthesis of fluorinated amino acids recently published in the European Journal of Organic Chemistry.

Flow Synthesis of Fluorinated α-Amino Acids

Dr. Wilkinson, European Journal of Organic Chemistry, talks to Professors Koksch and Seeberger about fluorinated amino acids

Read more

http://www.chemistryviews.org/details/ezine/7956531/Flow_Synthesis_of_Fluorinated_-Amino_Acids.html

 Professor Beate Koksch, Freie Universität Berlin, Germany,

.Prof. Dr. Beate Koksch

Institute of Chemistry and Biochemistry – Organic Chemistry 
Freie Universität Berlin 
Takustr. 3
14195 Berlin

Working Group: AG Koksch

Space: 32.18

Tel .: + 49-30-838-55344, Fax -55 644

Secretariat:
Tel .: + 49-30-838-55880
(woman Skowronski, room 32.17)

Email: Beate.Koksch fu-berlin.de

.

++49 – 30 – 838 55344  e-mail  homepage (http://userpage.chemie.fu-berlin.de/~akkoksch/) Free University of Berlin Takustr. 3 14195 Berlin Germany

Nominated by

• German Research Foundation (DFG)
• AcademiaNet member since 13.03.2015

Employed by

• Freie Universität Berlin

Academic Discipline/Fields

• Natural sciences/ Engineering/ Agricultural sciences

Field

Chemistry

Area of specialisation

Organic and Natural Product Chemistry

Research interests

• folding mechanisms occuring in neurodegenerative diseases
• developing new multivalent scaffolds
• investigating the impact of fluorine on amino acids, peptides and proteins

Distinctions and Awards

• Georg Thieme publisher’s award, 2002Lessing medal in gold, 1986

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Professor Peter Seeberger, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

Since 2011, Professor Peter H. Seeberger, Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, is Editor-in-Chief of the Beilstein Journal of Organic Chemistry.

Editor-in-Chief of the Beilstein Journal of Organic Chemistry is Professor Peter H. Seeberger, Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, who is supported by a distinguished board of associate editors, each of whom is responsible for a particular subject area within the journal’s scope. Over 40 scientists from all over the world, including several Nobel Prize laureates, support the Beilstein Journal of Organic Chemistry as Advisory Board members.

Prof. Dr. Peter H. Seeberger