Blocking Patents in Intermediate Chemical Technologies

Ram Vishwakarma
Indian Institute of Integrative Medicine, Jammu National Institute of Immunology, New Delhi

Chemical Intermediates
Combining through chemical bonding, various atoms of the basic building blocks known as elements (such as C, N, O etc) creates a molecule. That molecule is used either as the final entity of choice, or as a starting material for synthesis of more complex molecule.

In patent laws, the term chemical intermediate refers to a building base for a larger molecule, and it can be independently patented.
Whether an inventions smaller parts are held together by chemical bonds: covalent (in case of NCEs) or physical mixture (in case of composition of matter) or by mechanical means (mechanical device or apparatus) is not deemed to be conceptually distinct. However, a chemical intermediate must have value for making product of known utility (drug or device)

Need for Patent Blocking

If an invention (e.g. NCE) is patented and its surroundings have been excluded: Another patent covering the exclusions can block the initial inventor for further developing the market.

Building a patent wall around the product or process is one way to hold back competitors.
This is the essence of bracketing. Such forms of patent blocking may reduce competition but will not block the competitor.

Blocking Patents
Two patents are said to be blocking when one of them cannot be used without infringing the other. If an innovator has patented an NCE, along with the process any further work on this patented product is worthless as: 1. 2. 3. The chemical (product) is patented. Alternative process, if developed, can not be utilized as the final product is patented. Same mechanism can not be used even for final product modifications for producing better product.

In this situation the license to make NCE is worthless without the license to employ the process or vice-versa.

Monopoly or setting territories patent Blocking

To extend monopoly power of an individual patent.
Build wall of patents around leading products defends against imitators and can secure market share.

Use this policy always at all platforms. Patent walls to be used to impose threats of patent infringement. Never disclose the optimal processes for making API.

Patent Thicket
The creation of large numbers of overlapping patents is called a patent thicket.

Create a patent thicket around their important drug products. Patent protection should be done on a wide range of chemical variants and analogs, methods of synthesizing the drug, chemical intermediates in the synthesis, different crystal forms, different finished dosage forms and various methods of use. Therapeutic use of drug exclude others from commercialization the drug for the same treatments.

Big Pharma approach to delay or block Generic entry to market

Use a variety of methods with the objective of delaying or blocking market entry of generics.

Play games in patenting new salt forms too late. Patent drug intermediates that covers a number of routes. Process patents to put generics off. Strongest protection obtained by including a portfolio of patents, each directed towards a different aspect of new drug. Compound patent exclude others from making, using, selling, offering for sale or importing the drug compound.
Tie up or take over the potential generic company

Advantages of Blocking Patents

Use IP rights to protect every aspect of its technology, for all its products, including research methods, supply and distribution channels and marketing. Reap the benefits of selling the product without competition for a finite period (period varies according to country of originmainly, 20 years). Exclusivity is to reward those who have taken the risk and cost of developing a new drug.

Use of the material or process described in patent are legally requested for their permission to do so (cost of licensing).
Preserve market share of a new drug through FDA exclusivity.

Disadvantages of Blocking Patent

Inventive rivalry is good for inventive progress, but too strong patent protection will distort such progress due to patent blocking. The cumulativeness in the innovative processes, a more narrow protection favors secondary inventions but sacrifices the economic incentives.
At times, IPR blocks the free flow knowledge based research in this area (NFkB case).

Failure of the Free Market Policy theory.

FORMULATION OF CIPROFLOXACIN COMPOUND OR SALT

Formulation contains Ciprofloxacin+dry binder based on cellulose+disintegration auxiliary +cross-linked polyvinyl pyrrolidones+a flow-improving agent+lubricant.
Ciprofloxacin -antibacterial It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada and the UK, it is marketed as Ciloxan, Cipro, Cipro XR, Cipro XLCiproxin and most recently Proquin.

CIPROFLOXACIN

Polyvinyl pyrrolidones

Biological activity

Lubricant Dosage Forms Disintegrating auxiliary

Intermediate patent of Ciprofloxacin vs Ra-Hydrogen or (Bayer methyl or ethyl or Schein)

-hydroxy-ethyl group Salts-May be inorganic or organic acids( HCL, HBr, HI, H2SO4, CH3COOH, Sccinic acid, malic acid, phosphonic acid) Organic base-KOH, NaOH, Ca(OH)2, Al(OH)3, pieridine, morpholine, ethyl amine, triethylamine etc

Synthesis of one intermediate of ciprofloxacin

Ciprofloxacin compound or salt or alkali or alkaline earth metal salt

Various analogs of Ciprofloxacin

Process for production of Ciprofloxacin (intermediate chemical used for synthesis) STRUCTURE II 1. Quinoline-carboxylic acid formula a.R-hydrogen b.X-halogen or alkylsulphonyl group(1-4 C) A-Nitrogen or CR3 R3-halogen, nitrile, caboxyl or ester e B-Nitrogen, C-H and A & B can not nitrogen

(II)

Polymorphic form of Atorvastatin hemi calcium salt

3H2O

BLOCKBUSTER DRUG OF PFIZER USEFUL FOR LOWERING SERUM CHOLESTEROL LEVELS

Few Patents of Atorvastatin & Salt Forms

US-5273995-Atorvastatin lactone form & salt preparation & methd of treating mammals including human. US-6121461-Claim form III-methods for preparation & pharmaceutical composition. EP-1535613 -Polymorphic form of atorvastatin calcium US-0287538-Process for preparing amorphous atorvastatin calcium without intermediate isolation of crystal or undefined mixture of crystal and amorphous atorvastatin calcium. US-0276027- Method for production and isolation of novel crystalline forms of atorvastatin free acid; (useful as intermediates to prepare salts of atorvastatin). US-7411075-New atorvastatin calcium form V in anhydrate & hydrate states(Advantage- higher solubility in water than atorvastatin); process for preparation & pharmaceutical composition & dosage forms.

EXPIRY OF FEW PATENTS OF ATORVASTATIN US-4681893 Atorvastatin first disclosed to public. US5969156 (Expiry: Jan 8, 2017): Which covers crystalline Polymorphic Form I, II and IV US6087511 (Expiry: July 16, 2016): A process for the preparation of amorphous Atorvastatin US6274740 (Expiry: July 16, 2016): Process for the preparation of amorphous Atorvastatin or hydrates VICTORY OF PFIZER PATENT

The '893 patent was to expire on May 30, 2006, but Pfizer was granted a patent term extension up to Sept, 2009. Ranbaxy filed an ANDA & challenged basic (DK 171,588) and enantiomer (EP 409,281) patents for generics version with the claim that in 893 a compound is a stereoisomer but Pfizer claimed for only one form. Court rejected this saying it was a writing mistake.

ATORVASTATIN

Atorvastatin Lactone Form

Atorvastatin Calcium salt

Synthesis of Calcium salt of Atorvastatin

LIPITOR

Patent-5,955,611 (Synthesis of Sidenafil)More efficient process than EP-A-0463756

Intermediate precursor (Bis-amide)

Anhydrous sidenafil mono citrate (US0235857 Cyclisation (presence of base, in solvent; H2O2 or peroxide salt; neutralization

Coupling

Sidenafil freebase +Citric acid

SILDENAFIL (WO-A-94/28902) 95%

Scheme for intermediate Bis-amide of Sildenafil

Patent: US 2009/0005395 Synthesis of Sildenafil N-oxide

Prodrug : Sildenafil N-Oxide (Bioreversible derivative of drug) Favorable PK profile than sildenafil

Administered orally Sildenafil N-oxide (Produrg) & rapidly converted in to sildenafil & Ndesmethylsildenafil (active metabolite of sildenafil )

Patent US-0069422 Intermediates of Sildenafil

US Patent-7041826 (New process for preparing intermediate for Antidepressant Mirtazapine)

1-Methyl-3-phenylpiperazine key intermediate of Mirtazapine & other tetracyclic compounds

Reduction

MIRTAZAPINE

Methylation

US Patent-4062848 Used as a starting material for Mirtazapine

4-bezyl-2-oxo3-phenylpiperazine

Novel Piperazine derivative 4-benzyl-1-methyl-2-oxo-3phenylpiperazine

Patent US-5502195 Sulfoxide-carboxylate intermediates of Omeprazole & Lansoprazole

Omeprazole
Useful in gastrointestinal inflammatory diseases

Lansoprazole Similar pharmaceutical activity as omeprazole

Oxidation

Oxidation

Advantage of this step: High purity of sulfinyl compounds

Oxidation, hydrolysis, Carboxylic salts formation, Decarboxylation

Amide analogue (Readily oxidized to corresponding sulfinyl compounds)

US Patent-4876399 TAXOLS PREPARATION & INTERMEDIATES

US-5411984: Water soluble analogs 2-(alanyl)-taxol & 2succinyltaxol

US-4814470 more potent than taxol

TAXOL(Natural) Reported JACS-932325; antitumor activity

Synthesis of 2 Diol taxol intermediate

6 steps

(Commercially available)

2-Diol

Key Intermediate for taxol synthesis

Thank You