‘Dose’, ‘Dosage’, ‘Dosage Form’ And ‘Dosage Regimens’: Patentability In India.
Ordinarily, new formulations, dosages or synergistic combinations should, in principle, face no difficulty with the question of novelty, inventive step, and industrial application. Patent eligibility of new formulations and synergistic combinations of drugs was never questioned. However, patent eligibility of dosages/or dosage regimens does come under the scanner of the patent offices and courts. Though many dosage regimes patents are being granted in many jurisdictions, enforcing such patents for these types of inventions has always been difficult.
Earlier patentability of the dosage form suffered a roadblock due to its lack of industrial application. Additionally, it was understood to be only a form of medical method that is excluded from the patent grant on the grounds that these inventions would unjustifiably limit the doctor’s choice of clinical practices. Another reason for refusing patents on dosage form is that it is only a new use for a known substance or a second use. In India, dosage patents have remained a grey area mainly because they were considered to qualify as nonpatentable methods of treatment under section 3(i).
Since a new dosage regimen for a given known drug needs to balance patient compliance, therapeutic efficacy, and side effects of said drug, it falls under the suspect list of exclusions under section 3(d) as well. It is seen by the patent examiner as a new use of known substance bar from patentability in India under section 3(d). On the flip side, obtaining a dosage patent may help extend the market exclusivity of an approved drug beyond the lifetime of the patent that protects the drug. On the downside, this has been criticised by generic drug manufacturers as an attempted evergreening of expired patents. In many jurisdictions, patents on dosage regimens are granted if they meet the requirement of novelty inventive step and industrial applicability.
‘Dose’, ‘Dosage’, ‘Dosage Form’ and ‘Dosage regimen’
The terms ‘dose’, ‘dosage, and ‘dosage regimen’ are used interchangeably, but each term has a specific meaning. The term ‘Dose’ stands for the predetermined amount of the drug administered at one time to produce a certain degree of biological response in a patient. Additionally, the dose of a drug is governed by its inherent potency.
The term ‘Dosage’ means the predetermined amount and rate of administration of a drug recommended by a doctor for a patient. So, ‘Dosage’ is the prescribed administration of a predetermined amount, number, and frequency of doses of a drug over a specific period of time. The term ‘Dosage Form’ connotes the physical form containing active pharmaceutical ingredients (API) combined with selected additional ingredients (excipients) and is meant to be delivered to sites of action within the body by different routes of drug administration.
The ‘Dosage form’ is called unit doses and drug products. They are in the form of Tablets, Capsule, Pellets, Pill, and Lozenges (Solid Dosage forms), or Solutions, Suspension, Emulsion, Elixir, Linctus, Syrups (Liquid Dosage Forms) or Ointment, Cream, and Paste (Semisolid Dosage Forms) or Aerosol, and Insufflations (Gaseous Dosage Forms). Simply stated in simple words, “Dosage Form’ is that physical form in which a precise mixture of API (active pharmaceutical ingredients) and excipients are presented to help easy administration, deliver to sites of action, achieve rapid onset of action, and improve bioavailability, etc.
The last term, ‘Dosage Regimen,’ represents the frequency at which the drug doses are given to any patient to maintain a steady-state serum concentration. ‘Dosage Regimen’ means the dose of the drug and dosing interval. Simply said, it stands for the schedule of doses of a therapeutic agent per unit of time. A dosage regimen is meant for the systematised dosage schedule in personalised medicinal practice.
Therapy vs Therapeutic Application
It is generally understood that the concept of “therapy” or “therapeutic application” includes the treatment of a particular illness or disease with a specified chemical substance or composition in a specified human or animal subject in need of such treatment. Therapeutic Applications are applications comprised of prevention, treatment, or prophylaxis of human disease. Once a new chemical entity (NCE) is found as a therapeutic agent for curing a particular disease, its indications and contraindications are found through clinical trials. Prescribing and modification of drug regimens used for administering a particular medicament appear to be, in the first place, part of the typical activities and duties of the doctor in attendance in exercising his professional skills. However, the therapeutic application of a particular medicament in a specific dose to meet the special patient requirement is emerging as a best practice of personalised medicinal therapy.
Patenting Opportunities for ‘dose’/’dose units’, ‘Dosages forms’ and ‘Dosage regimen’
Dose/dose units!
There appears to be no difficulty in obtaining patent for doses in India and many such patents are allowed after considering their novelty and inventive step. A representative list of few granted cases is given below.
| Patent No | Subject Matter |
| 202523 | Delta Tetrahydrocannabinol (Delta Thc) Solution Metered Dose Inhalers and Methods of Use |
| 210943 | Antitubercular Pharmaceutical Composition in Fixed Dose Combination Comprising Four Drugs |
| 211746 | A Pharmaceutical Composition Comprising Orally Deliverable Dose Units of Celecoxib |
| 216316 | Sustained Release Matrix for High-Dose Insoluble Drugs” |
| 221584 | A Pharmaceutical Composition Comprising One or More Discrete Solid Orally Deliverable Dose |
| 224086 | Pharmaceutical Preparations for Propellant-Driven Metered Dose Inhalers |
Dosage Form
Similarly, many patents on dosage forms were granted in India. The list of a few cases given below proves this point.
| Patent No | Subject Matter |
| 204612 | Dosage Form for Treatment of Diabetes Mellitus |
| 204983 | Extended-Release Oral Dosage Composition |
| 204989 | Controlled Release Solid Dosage Formulation of Pharmaceuticals for Oral Administration |
| 207193 | Methotrexate Topical Semisolid Dosage Form (Gel) |
| 207985 | Pharmaceutical Dosage Form |
| 208718 | A Pharmaceutical Composition in Solid Unit Dosage Form |
| 210282 | A Dosage Form for Controlled Delivery Of |
| 210351 | An Excipient Composition and Method of Preparation of Solid Dosage Form |
| 210957 | Formulation And Dosage Form for Increasing Oral Bioavailability of Hydrophilic Macromolecules |
| 211143 | Stabilised Pharmaceutical Oral Solid Dosage Compositions |
| 211304 | A Low Dosage Pharmaceutical Composition |
| 211749 | Bilayer Sustained Release Oral Dosage Composition Comprising Desloratadine and A Nasal Decongestant |
| 213027 | A Novel Oral Dosage Form to Be Delivered to The Stomach |
| 213311 | Formulation And Dosage Form for Increasing Oralbio Availability of Hydrophilic Macromolecules |
| 213697 | A Sustained Release Oral Solid Dosage Form |
| 214054 | Pharmaceutical Compositions Comprising Misprostol for Vaginal Suppository Dosage Form and Process for Preparation Thereof |
| 216233 | An Orally Administrable Solid Dosage Form Comprising a Ribavirin Compacted Composition and A Method of Producing the Same |
| 216605 | A Controlled Release Dosage Form for Oral Administration |
| 218867 | A Pharmaceutical Composition in The Form of An Oral Dosage |
| 220907 | Oral Dosage Form Containing a Pde 4 Inhibitor as An Active Ingredient and Polyvinylypyrrol Idon as Excipient |
| 222626 | Pharmaceutical Dosage Form of Amorphous Nelfinavir Mesylate |
| 222973 | A Pharmaceutical Oral Dosage Form Comprising of a Novel Combination of Aceclofenac, Paracetamol and Serratiopeptidase |
| 225738 | A Pharmaceutical Composition in Oral Unit Dosage Form |
| 226499 | Compressed Oral Pharmaceutical Dosage Form, With an Enteric Coating, Which Contains an Acid Labile Benzimidazole Compound |
| 227217 | Saquina Vir Mesylate Oral Dosage |
| 229827 | A Liquid Oral Dosage Formulation Comprising Water, 5-Methyl -2 -(2′ – Chloro6′-Fluoroanilino)Phenylacetic Acid |
| 231264 | Pharmaceutical Dosage Form and Method for The Production Thereof |
| 232053 | A Fast-Dispersing Solid Dosage Form |
| 234284 | Pharmaceutical Dosage Units |
| 234522 | An Oral Dosage Form and Method for The Preparation of The Same |
| 234665 | Pharmaceutical Composition as Solid Dosage Form and Method for Manufacturing Thereof |
| 235545 | A Pharmaceutical Composition, A Pharmaceutical Dosage Unit and A Pharmaceutical Pack Thereof |
| 235728 | Pharmaceutical Composition Comprising a Pharmaceutically Acceptable Dosage Of DSPA |
| 235833 | A Stabilised Pharmaceutical Composition in Solid Dosage Form |
| 237273 | A Solid Oral Dosage Form Comprising Valsartan |
| 238564 | A Non-Effervescent Dosage Form Intended to Be Swallowed Directly, Such as A Swallow Tablet or Capsule Formulation |
| 239596 | Dosage Form Containing Pantoprazole as Active Ingredient |
This clearly shows that patents on dosage forms are allowed in India if they meet the requirement of novelty and inventive steps under section 2 (1) (j) and (ja).
Is the Dosage regimen method of treatment?
Position In Europe
If we see earlier rejections of dosage patents in Europe, we will find that in decision T0317/95, where a claim for the combination of a bismuth-containing agent and an H2-receptor blocking agent in which the administration of the said 2 agents was done within 5 minutes of each other was questioned. The European Board of Appeal (EBA), in this case, found that.
“determination of the best individual treatment schedule, in particular the prescribing and modification of drug regimens used for administering a particular medicament (…), appear to be in the first place part of the typical activities and duties of the doctor in attendance in exercising his professional skills” [emphasis added]
In another decision, T0056/97, EBA citation T0317/95 rejected the claim for the same reasons and emphasised that it had:
“difficulty in seeing claim 1 as more than an unsuccessful attempt to obtain protection for a method of therapeutic treatment of the human or animal body”
The board, in this case, found a claim for the use of a thiazide diuretic having a predetermined diuretic effective dose, wherein a dosage unit was established that was 7–25% by weight of the predetermined diuretic effective dose in granted EP 0 154 009 patent, not more than an unsuccessful attempt to obtain protection for a method of therapeutic treatment of the human or animal body by couching it in the form of a “Swiss-type claim”[Emphasis added ].
Claim 1 of EP 0154009 is in dispute as worded as the Swiss claim was:
Claim 1:- “Use of a thiazide diuretic having a predetermined diuretic effective dose for the manufacture of a non-diuretic anti-hypertensive composition comprising a unit dosage amount of the thiazide diuretic insufficient to achieve effective diuresis, but sufficient to achieve anti-hypertension, said amount being within the range of 7-25% by weight of the predetermined diuretic effective dose;”
Dependent claims 2 to 11 claimed specific elaborations of that use.
Position in India
The position relating to non-patentability of the method of treatment in India is governed by section 3(i), which is more or less like Article 52(4) and (5) of EPC, which says that:
“any process for the medical, surgical, curative, prophylactic, [diagnostic, therapeutic] or other treatment of human beings or any process for a similar treatment of animals to render them, free of disease or to increase their economic value or that of their products”.
Articles 52 and 53 (c) (4) of EPC read s as follows
52: Novelty
(4) Paragraphs 2 and 3 shall not exclude the patentability of any substance or composition, comprised in the state of the art, for use in a method referred to in Article 53(c), provided that its use for any such method is not comprised in the state of the art.
(5) Paragraphs 2 and 3 shall also not exclude the patentability of any substance or composition referred to in paragraph 4 for any specific use in a method referred to in Article 53(c), provided that such use is not comprised in the state of the art.
EPC 53 (c)(4) “methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.”
In a patent application [1369/KOLNP/2009] filed by Takeda Pharmaceutical Company Limited, the Kolkata office rejected the patent for the invention relating to the method of administering compounds used to inhibit dipeptidyl peptidase IV as well as treatment methods based on such administration inter alia on the ground falling under the method of treatment exception under section 3(i). In this case, the applicant seeks a patent for the use of the claimed compound [2-6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHYL-4-FLUORO- BENZONITRILE] by way of a single dosage formulation.
The Controller refused the patent as the specification clearly reveals that the field of the instant invention relates to the method of administering compounds to inhibit dipeptidyl peptidase IV as well as the method of treatment only, which is not patentable u/s 3(i) of the Act. Aside from this ground, the Controller also found that the revised claim 1 and all dependent claims (2 to 8) cannot be considered to involve an inventive step or to have overcome the non-patentability criteria imposed under sections 3(d) and 3(e) of the Patents Act. The Controller also rejected the claim of the applicant that the compound is a succinate salt form, which is novel, holding the same to be not patentable under Sections 3(d) and 3(e).
Coverage of Dosage Regimens
If we look at the dosing regimens patterns, we will find that they typically address the parameters like (a) Dose approach (e.g. variable, fixed dosing), (b) Route of administration (e.g. oral, intravenous, intramuscular), (c) Dosing interval (e.g. daily, weekly, monthly, etc) (d) Dose amount (e.g. mg of compound administered with each dose) and (e) Adjustments for special populations (e.g. hepatic or renal impairment). The role of dosage patents in the protection of therapeutic antibodies is substantial.
Patent Eligibility of Dosage Regimen
This position of T0317/95 was reversed by the Enlarged Board of Appeal (EBA) of the European Patent Office (EPO) in its decision G2/08, issued on February 9, 2010, when it held that dosage regimen claims are principally admissible. EBA, in this case, ruled that.
“Where it is already known to use a medicament to treat an illness, Article 54(5) EPC does not exclude that this medicament be patented for use in a different treatment by therapy of the same illness. Such patenting is also not excluded where a dosage regime is the only feature claimed which is not comprised in the state of the art.”
The approach of EBA in the decision was cautious as in the decision, EBA admitted that they were aware that dosage regimen patents ran a risk of being applied in an abusive fashion and observed that:
“The EBA does not ignore the concerns with respect to undue prolongations of patent rights potentially resulting from patent protection for claims purporting to derive their novelty and inventive step only from a not hitherto so defined dosage regime (…).”
The EBA also clearly suggested that patent claims on dosage regimens need to be examined with the same scrutiny toward novelty and inventive steps as other patent claims and cautioned that:
“Therefore, it is important to stress that (…) for the assessment of novelty and inventive step of a claim in which the only novel feature would be the dosage regime, the whole body of jurisprudence relating to the assessment of novelty and inventive step generally also applies.”
Position in India
In India, two decisions of IPAB on this aspect of dosage patents are worth mentioning. The patent office in India is not averse to granting a patent for dosage regimens. We have seen that Patent No. 219504 for “Combination of Brimonidine and Timolol” for topical Ophthalmic use patent No. 212695, granted to Allergan Inc., for the invention “Hypotensive Lipid (prostaglandin derivatives) and Timolol composition and methods of using same” were granted by the Indian patent office to Allegan. Both of these patents were for the combination of two drugs in a unit dose instead of administering each drug separately after a short interval.
Ganfort is a patented fixed-dose combination of bimatoprost and timolol. It is used to reduce pressure inside the eye caused by a build-up of fluid. Combigan is a patented fixed-dose combination of brimonidine and timolol. It also reduces pressure inside the eye. These patented drugs were sold under the name Ganfort (for the treatment of a condition where the pressure inside the eye is higher than normal ocular hypertension) and Combigan (used for the treatment of glaucoma), respectively, by Allergan. It was the issue of enforcement that highlighted both patents. When Allegan acted against Ajanta Pharma for infringement of these patents, Ajanta Pharma filed an application for the revocation of IN 219504 and IN 212695 before the Intellectual Property Appellate Board.
In a well-argued case, the grant of patents in both patents was revoked by IPAB in two separate decisions. In both decisions, IPAB found the claimed inventions to be obvious and in violation of section 8, which relates to the mandatory filing of information related to foreign filings. The former trend clearly matches the trends in EPO, where, in decision G2/08 (February 9, 2010), the Enlarged Board of Appeal (EBA) held that dosage regimen claims to be principally admissible. However, such combination/dosage regimen patents should pass the test of obviousness as well for seeking a favourable grant of a patent.
From the above decisions in India and EPO, one can safely state that one will not receive a patent on a dosage regimen, which is obvious in view of the existing prior art. If it passes the novelty and inventive step test, patents are allowed in India as well. For example, two patents, 202297 and 206098, were granted for ‘Dosage Regimen and Pharmaceutical Composition for Emergency Contraception” and “Dosage Regimen and Pharmaceutical Composition for Emergency Contraception”, respectively. Later, in post-grant opposition by CIPLA, patent no 202297 was revoked by the patent office by order dated May 3 2010. The main ground of revocation was lack of novelty/inventive step. In the second patent, 206098, the granted claim 1 read as:
“1. Pharmaceutical composition as single application dose for emergency contraception administered up to 72 hours of the coitus, characterised by containing 1.5 ± 0.2 mg of levonorgestrel as an active ingredient in admixture with known excipients, diluents, flavouring or aromatising, stabilisers, as well as formulation-promoting or formulation-providing additives, commonly used in the pharmaceutical practice.”
This patent was also opposed by CIPLA. However, patent no 206098 was allowed to be ceased by the applicant due to nonpayment of renewal fee. Both patents were owned by Richter Gedeon Vegyeszeti Gyar RT.
Conclusion
For the purpose of Indian patent law, the ‘Dose’, ‘Dosage’, ‘Dosage Form’ and ‘Dosage Regimens’ or combinations/dosage can qualify for patents. In fact, many such combination patents were granted if the examiner is satisfied that the claimed combination shows an enhanced/synergistic effect. We may note that both Allergan patents discussed above were found to be patentable by the patent office.
It is another thing that these patents were challenged and revoked based on the basis of evidence submitted by the opponent and found clinching by IPAB, which showed that the claimed inventions were lacking inventive steps in view of cited prior art and expert evidence. Similarly, two Richter patents on dosage regimens were also granted by the patent office.
However, IN 202297 was later revoked on the opposition by CIPLA on the grounds of novelty/obviousness.
Simply said, one may not receive a patent on a dosage regimen that is obvious in view of the existing prior art. However, there is no bar on the patentability of inventive ‘Dose’, ‘Dosage’, ‘Dosage Form’ and ‘Dosage Regimens’ or combinations/dosages in India. They can be patent eligible under section 3(d) as well if the applicant is able to prove the enhanced therapeutic efficacy as required by its interpretation given by the Supreme Court in the Novartis case.
With personalised medicines gaining importance in medical treatment for specific patient classes, the need for tailor-made dosage regimens is being developed through subject-specific research in drug dosage regimens. An expert aid can be useful to dispel any doubt about the patentability of ‘Dose’, ‘Dosage’, ‘Dosage Form’, and ‘Dosage regimens’ in India.
