Details for Patent: 6,248,735
Summary for Patent: 6,248,735
| Title: | Ophthalmic compositions comprising combinations of a carbonic anhydrase inhibitor and a β-adrenergic antagonist | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | Combinations of a beta-adrenergic antagonist and a topical carbonic anhydrase inhibitor are particularly useful in the treatment of ocular hypertension, especially in patients insufficiently responsive to treatment with beta-adrenergic antagonists. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | John J. Baldwin | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Merck and Co Inc | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US08/833,067 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; Formulation; Dosage form; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | US Patent 6,248,735: Scope, Claims, Expiration, Orange Book Status, and Generic RiskUS Patent 6,248,735 covers topical ophthalmic formulations combining dorzolamide, a carbonic anhydrase inhibitor, with timolol, a beta-adrenergic blocker, for treating ocular hypertension or glaucoma. The patent protects the combination formulation, selected salt forms, concentration ranges, gellan-gum formulations, dosage forms, and methods of treatment. The patent issued on June 19, 2001, from an application claiming priority to December 19, 1996. Its ordinary 20-year patent term therefore ended on December 19, 2017, subject to any applicable patent-term adjustment or extension. The patent is expired and does not presently block manufacture, sale, or use of a qualifying dorzolamide/timolol product in the United States. The covered product was commercialized by Merck & Co. as Cosopt. What drug combination does US Patent 6,248,735 cover?The patent covers a fixed-dose topical ophthalmic combination of:
Dorzolamide is generally used as the hydrochloride salt. Timolol is generally used as the maleate salt. The patent expressly identifies both salt forms in dependent claims 2, 3, 12, 16, and 26. The principal commercial embodiment was a twice-daily ophthalmic solution containing dorzolamide hydrochloride equivalent to 2% dorzolamide and timolol maleate equivalent to 0.5% timolol. The formulation was marketed as Cosopt ophthalmic solution for reduction of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. [1] What are the main claim categories in US Patent 6,248,735?The 27 claims divide into two groups:
The composition claims are commercially more direct because they can read on the product itself. The method claims focus on administration to a patient and would generally be asserted against activities involving use or inducement of use rather than against the formulation alone. How broad is independent claim 1?Claim 1 is the principal formulation claim. It requires all of the following:
The use of “comprising” makes the claim open-ended. A formulation can contain additional excipients, preservatives, tonicity agents, buffers, surfactants, viscosity modifiers, or other ingredients without falling outside the claim, provided it includes the required dorzolamide and timolol components in the specified ranges. The claim is narrower than a claim to either active ingredient alone. It requires the combination in a single topical ophthalmic formulation. A product containing only dorzolamide or only timolol would not meet claim 1. What concentration ranges does claim 1 cover?The ranges are broad:
The commercial 2%/0.5% combination falls squarely within those ranges. The claim also covers substantially lower or higher concentrations, subject to the boundaries and other claim limitations. A formulation containing 2% dorzolamide and 0.25% timolol would potentially fall within claim 1. A formulation containing 0.05% dorzolamide and 1.0% timolol would also fall within the literal concentration ranges. A formulation containing 6% dorzolamide would not satisfy claim 1 based on concentration alone. What do the dependent formulation claims add?Claims 2 through 13 impose narrower limitations.
Claim 12 is the clearest product-specific claim directed to the commercial Cosopt-type formulation. Claim 13 adds gellan gum, a viscosity-enhancing and delivery-modifying excipient. What is the importance of claim 12?Claim 12 recites:
It does not expressly require gellan gum. Claim 13 adds the gellan-gum limitation. A generic product with the same active ingredients and concentrations but a different viscosity agent could potentially fall within claim 12 while avoiding claim 13, subject to the patent’s expiration and any other relevant patents. What do the method claims cover?Claims 14 through 27 mirror the formulation claims but require administration to a patient for treating ocular hypertension or glaucoma. Independent claim 14 covers administration of a formulation containing:
Independent claim 26 covers the specific 2%/0.5% combination:
Claim 23 narrows the dosage form to a solution adapted for topical administration. Claims 20 and 21 address gum and gellan-gum formulations. Claims 24 and 25 address the dorzolamide-to-timolol ratio and the 2%/0.5% embodiment. The method claims could have been relevant to physicians, manufacturers, distributors, or parties promoting the combination before expiration. Their practical enforcement value was limited by the requirement to establish treatment activity or inducement, rather than merely showing possession or sale of the formulation. How does the patent define the protected dosage forms?Claim 9 identifies five dosage-form categories:
The claim language is broad enough to cover more than the commercial aqueous solution. A non-solution dosage form could fall within the patent if it contains both active ingredients in the required concentrations and is suitable for topical ophthalmic administration. The breadth is reduced by the requirement that the formulation contain both actives. A sustained-release ocular insert containing dorzolamide alone, timolol alone, or a different glaucoma drug combination would not meet the claims as written. What is the scope of the gellan-gum claims?Claims 7, 8, 13, 20, 21, and 27 address gum-containing formulations. Claim 8 specifically identifies gellan gum at 0.1% to 2%. Gellan gum can increase viscosity and support retention of an ophthalmic formulation on the ocular surface. The patent therefore reaches beyond the active-ingredient combination into formulation engineering. The gellan-gum claims are narrower than claim 1 and may be avoided by using a different viscosity modifier. That design-around would not necessarily avoid claim 1, claim 12, or corresponding method claims if the active ingredients and concentration requirements remain satisfied. How does the patent’s stereochemical language affect claim scope?The claims identify the specific stereochemical forms associated with dorzolamide and timolol, but also use language covering:
This language increases the potential chemical scope beyond one specific salt or physical form. The claims are not limited solely to dorzolamide hydrochloride and timolol maleate, except where those salts are expressly required by dependent claims. A formulation containing a different ophthalmologically acceptable salt could potentially fall within claim 1 or claim 14. It would not meet claims 2, 3, 12, or 26 unless it used the specified maleate and monohydrochloride forms. The stereochemical wording also creates potential claim-construction issues. The chemical identity of the claimed compound, the meaning of “individual diastereomers,” and the relationship between the named stereoisomer and the broader alternative language would have been relevant in any infringement or validity dispute. What patent protected the underlying active ingredients?US Patent 6,248,735 is a combination and formulation patent. It did not originate the underlying dorzolamide or timolol molecules. The relevant patent landscape historically included:
The compound patent terms for dorzolamide and timolol were earlier than the combination patent term. By the time US Patent 6,248,735 expired, the principal US barrier was the combination and formulation estate rather than basic molecule exclusivity. When did US Patent 6,248,735 lose exclusivity?The patent’s ordinary expiration date was December 19, 2017, calculated from the claimed December 19, 1997 US nonprovisional filing date under the post-1995 20-year patent-term rule. [2]
A patent’s expiration date must be distinguished from FDA approval exclusivity. Patent expiration is governed by Title 35, while FDA regulatory exclusivity is governed by the Federal Food, Drug, and Cosmetic Act. Neither mechanism extends automatically because the product remains commercially important. [2, 3] What was the Orange Book status of US Patent 6,248,735?The patent was associated with the Cosopt NDA and was relevant to the FDA’s patent-certification framework for abbreviated new drug applications. The Orange Book identifies patents submitted by NDA sponsors for approved drug products, but an Orange Book listing does not itself determine patent validity or infringement. [3] For a generic applicant, the relevant certification options historically included:
Before December 19, 2017, a generic applicant seeking approval before expiration could have used a Paragraph IV certification against the listed patent. After expiration, a Paragraph II certification would generally address the expired patent. The practical significance of any Paragraph IV challenge depended on whether the generic applicant faced a 30-month stay, litigation, settlement, or potential 180-day exclusivity consequences under the Hatch-Waxman framework. [4] Current Orange Book status should be assessed against the FDA’s active patent listing rather than historical litigation records. An expired patent cannot support a continuing injunction against new US generic entry. Which companies challenged the Cosopt patent estate?The principal competitive challenge came from ANDA applicants seeking approval for generic dorzolamide hydrochloride/timolol maleate ophthalmic solution. Generic entrants typically addressed the listed patent through patent certifications and, where necessary, federal district court litigation. The patent record and FDA approval history should be separated from later commercial competition. An ANDA may be approved after patent expiration without a successful Paragraph IV judgment. Approval timing can reflect:
The information supplied identifies the patent and claims but does not establish a complete, verified list of all ANDA filers, litigation docket numbers, or settlement parties. A definitive company-by-company litigation chronology cannot be stated accurately from the claim text alone. Were there biosimilar risks for Cosopt?No. Cosopt is a small-molecule ophthalmic drug, not a biologic. Biosimilar pathways under the Public Health Service Act do not apply. The relevant competitive pathway was an ANDA for a generic drug under section 505(j) of the Federal Food, Drug, and Cosmetic Act. Generic applicants needed to demonstrate pharmaceutical equivalence and bioequivalence or otherwise satisfy FDA requirements for the ophthalmic product. [3, 5] The principal commercial risks were therefore:
What manufacturing and formulation barriers remain after patent expiration?Patent expiration removes the legal exclusion right for this patent but does not remove technical and regulatory barriers. A generic manufacturer still must address:
These barriers may delay entry or limit the number of commercially viable suppliers, but they are not substitutes for patent exclusivity. How strong was the patent estate?StrengthsThe patent had meaningful commercial scope before expiration because it:
WeaknessesThe patent also had structural limitations:
The patent’s strongest pre-expiration claims were claims 1, 12, 14, and 26. Claims 12 and 26 directly targeted the 2% dorzolamide/0.5% timolol product. Claims 13 and 27 added gellan gum but were narrower and more vulnerable to formulation design-around. What was the commercial impact of generic entry?The covered product was historically important in the glaucoma market because it combined two commonly used mechanisms in one bottle. Fixed-dose combination products can reduce dosing frequency and improve treatment convenience compared with separate dorzolamide and timolol products. After patent expiration, commercial exposure shifted from patent protection to:
No reliable revenue figure can be assigned to US Patent 6,248,735 itself because patent-level revenue is not separately reported. The relevant exposure was the US sales of Cosopt and authorized or branded generic versions during the protected period. What is the current litigation and licensing position?US Patent 6,248,735 is expired. Its expired status means it cannot support a new US infringement action based on post-expiration commercial activity. Historical licenses, settlements, or authorized-generic arrangements may have governed entry before expiration, but the claim text does not establish their terms. Any current commercial agreement would likely concern trademarks, supply, manufacturing, regulatory rights, or other unexpired intellectual property rather than enforceability of this patent. How does US Patent 6,248,735 compare with competing glaucoma patents?
The patent was strongest against a product reproducing the commercial fixed-dose combination. It was less relevant to competing products using a prostaglandin analog, brimonidine, brinzolamide, or a different therapeutic combination. Key Takeaways
FAQsDoes US Patent 6,248,735 cover Cosopt?Yes. The patent’s claims cover the core fixed-dose combination of dorzolamide and timolol, including the 2%/0.5% formulation corresponding to Cosopt. Can a generic use 2% dorzolamide and 0.5% timolol today?Yes, the patent is expired. A manufacturer must still satisfy FDA requirements and assess any other unexpired patents, trademarks, or regulatory obligations. Does changing gellan gum avoid all claims?No. Removing gellan gum may avoid claims specifically requiring gellan gum, but it would not necessarily avoid broader claims directed to the active-ingredient combination. Is a dorzolamide/timolol product subject to biosimilar approval?No. Dorzolamide/timolol is a small-molecule drug combination and is generally pursued through the ANDA pathway rather than the biosimilar pathway. Did the patent protect separate dorzolamide and timolol products?No. The claims require both active ingredients in the claimed formulation or treatment method. Separate dorzolamide-only and timolol-only products fall outside the combination claims. References
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Drugs Protected by US Patent 6,248,735
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| >Applicant | >Tradename | >Generic Name | >Dosage | >NDA | >Approval Date | >TE | >Type | >RLD | >RS | >Patent No. | >Patent Expiration | >Product | >Substance | >Delist Req. | >Patented / Exclusive Use | >Submissiondate |
International Family Members for US Patent 6,248,735
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| European Patent Office | 0509752 | ⤷ Start Trial | CA 2000 00002 | Denmark | ⤷ Start Trial |
| European Patent Office | 0509752 | ⤷ Start Trial | C990041 | Netherlands | ⤷ Start Trial |
| European Patent Office | 0509752 | ⤷ Start Trial | SPC/GB99/043 | United Kingdom | ⤷ Start Trial |
| European Patent Office | 0509752 | ⤷ Start Trial | 2000C/001 | Belgium | ⤷ Start Trial |
| European Patent Office | 0509752 | ⤷ Start Trial | 49/1999 | Austria | ⤷ Start Trial |
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
