DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/28/25 has been entered.
Receipt is acknowledged of Remarks filed on 04/28/25. No claims have been amended, canceled or added. Accordingly, claims 1 and 3-5 remain pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Horn (US 20100028266) in combination with Chapin et al (US 20100311688) and Mahadevan et al (US 20130203813).
Horn ‘266 teach compositions and methods for treating an allergic response with reduced rebound hyperemia, comprising highly selective alpha-2 adrenergic receptor agonists, at low concentrations, such as below 0.05% weight by volume, and histamine antagonists. The compositions preferably comprise brimonidine. The compositions preferably have pH between about 5.5 and about 6.5 (See abstract).
Horn disclose a composition for inducing vasoconstriction consisting essentially of brimonidine, wherein said brimonidine concentration is from between about 0.01% to about 0.02% weight by volume, wherein pH of said composition is between about 5.5 and about 6.5, and wherein said composition is formulated as an ocular drop (See [0047]-[0048] and [0086]). The disclosed methods induce preferential vasoconstriction of smaller blood vessels, such as capillaries and venules, relative to larger blood vessels, such as arteries and arterioles (See [0011], [0050], [0054] and [0058]-[0059]). In a preferred embodiment, the selective a-2 adrenergic receptor agonist is present at a concentration from between about 0.001% to about 0.035% weight by volume (See [0077]).
Ocular conditions include red eye, including chronic red eye; ocular vascular congestion; ocular itch, etc, (See [0110]).
Horn discloses a method of reducing redness in an eye, comprising administering to a patient in need thereof a topical composition comprising a selective a-2 adrenergic receptor agonist at a concentration below about 0.05% weight by volume. For the method of reducing redness in an eye, the preferred a-2 agonist is brimonidine at a concentration of from about 0.005% to about 0.015% (See [0125]-[0128]).
Horn teaches that phentolamine is a preferred pharmaceutical agent. Preferably, when used in combination, the highly selective a-2 agonists of the present invention are employed in ratios varying from about 0.02% to about 0.05% (See [0139]).
Horn further discuss a combination with antihistamines and state a composition formulated for treating and/or preventing an allergic response with reduced rebound hyperemia, comprising a selective a-2 adrenergic receptor agonist, and a histamine antagonist, wherein said selective a-2 adrenergic receptor agonist is present at a concentration below about 0.025% weight by volume (See [0140]-[0141] and Claims 6-7). In a preferred embodiment, the a-2 agonist is brimonidine at a concentration of from about 0.001% to about 0.025% weight by volume; and the preferred histamine antagonist is selected from the group consisting of loratadine, desloratadine, cetirizine, fexofenadine, acrivastine, ebastine, norastemizole, levocetirizine, and mizolastine (See [0142]).
Horn disclose a comparative tests between the disclosed formulations and prior art compositions comprising histamine antagonists such as tetrahydrozoline at 0.05%, oxymetazoline at 0.025%, and naphazoline at 0.033% (See [0018]-[0020] and [0182]-[0184]).
Horn further discloses that the said topical composition is formulated for treating an ocular condition. The topical compositions include ocular drops, ocular ointments, gels and creams. They may also include additional non-therapeutic components, which include preservatives, delivery vehicles, tonicity adjustors, buffers, pH adjustors, antioxidants, and water. Such components include polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers (non-ionic surfactants), saline, etc, (See [0147]-[0149]). The said buffers include citrate buffers, acetate buffers, etc, (See [0151]).
Horn’s teaching lacks a specific disclosure on the histamine antagonist being ketotifen fumarate, its amounts and the surfactant being polysorbate or its amounts. These are known in the art as disclosed by Chapin et al ‘688 and Mahadevan et al.
Chapin et al ‘688 teach compositions for treating signs and symptoms associated with dry eye and/or ocular irritation, and methods of use thereof. Such compositions are provided in novel ophthalmic formulations that are comfortable upon instillation in the eye (See abstract).
It is disclosed that dry eye can cause keratitis, conjunctival and corneal staining, redness, blurry vision, decreased tear production, increased conjunctival redness, ocular dryness, ocular burning, excess tearing, photophobia, ocular stinging, ocular sensitivity, and ocular irritation, ocular itching due to a combination of ocular allergy and dry eye symptoms (See [0004]).
Chapin et al disclose an aqueous ophthalmic solution containing viscosity enhancing agents, a tonicity agent and a buffer. The viscosity enhancing agent is preferably hydroxypropyl methylcellulose (also commonly referred to as hypromellose or HPMC), present in an amount of from 0.72% to 0.8% (See [0008] and [0040]). The formulations also comprise sorbate (See [0010]-[0012]). The said buffering components are present from 0.05% to 2.5% (w/v) or from 0.1% to 1.5% (w/v) and comprise citrate buffers, etc, (See [0047]-[0048]). The citrate buffer is used (in total) at a concentration of 0.004 to 0.2 M (Molar), preferably 0.04 to 0.1 M (See [0052]). The pH of the aqueous ophthalmic solution is at or near physiological pH, i.e. between about 6.8 to about 7.7 (See [0054]). The said viscosity enhancing agent may be polysorbate 80, HPMC, etc, or combinations thereof present at a concentration range from about 0.2% to about 10% w/v (See [0039]-[0040]). The said formulations may also comprise a solubilizer such as polysorbate 20 or polysorbate 80 (See [0070]).
Chapin et al disclose that the said aqueous ophthalmic formulations are suitable for use as artificial tear products to relieve symptoms of dry eye and as a vehicle for an ophthalmic drug. Ophthalmic drugs suitable for use in the said formulations include anti-glaucoma agents, such as brimonidine and anti-allergic or antihistamine agents such as ketotifen, norketotifen, loratedine, etc, and combinations thereof (See [0060]). The total concentration of drug will generally be about 5% or less (See [0064]).
Mahadevan et al teach an anionic, silicone hydrogel contact lens comprising contacted with 3 mL of an ophthalmic solution comprising 0.001 wt % polycationic component, 0.56% citrate dihydrate and 0.021% citric acid monohydrate (wt/wt) (See [0006]).
The said solution comprises pharmaceutical components or combinations thereof for treating dry and/or irritated eye, glaucoma, allergies, ocular inflammation, ocular redness, etc, including brimonidine and ketotifen (See [0111]-[0112]).
For example, if the anti-allergic agent is ketotifen fumarate, the minimum effective amount is between about 9 µg and about 20 µg (See [0114]).
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Chapin et al ‘688 and Mahadevan et al with that of Horn to arrive at the instant invention. One of ordinary skill in the art would have been motivated to do so because Horn teaches ophthalmic formulations comprising a combination of brimonidine at low doses and an antihistamine for treating an allergic response in the eye and reducing red eye of a human patient. While Horn list a number of suitable histamine antagonists for the said formulations, there is no specific disclosure on ketotifen fumarate being the histamine antagonist. Chapin et al teach ophthalmic formulations comprising multiple active agents including brimonidine and ketotifen to treat dry eye and ocular irritation and discloses guidance on suitable excipients. Mahadevan et al teach an ophthalmic formulation comprising drugs such as briminodine and ketotifen fumarate and disclose suitable amounts for ketotifen fumarate. As such one of ordinary skill in the art having possession of the said references would have been motivated to have selected ketotifen fumarate as the suitable histamine antagonist and take advantage of guidance provided on its suitable amounts as taught by Mahadevan et al with a reasonable expectation of success.
Thus, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Also, with regard to the concentration ranges the courts have held that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955).
Claims 1 and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Horn (US 20100028266) in combination with Chapin et al (US 20100240624) and Chapin et al (US 20100311688).
Horn ‘266’s teachings are delineated above and incorporated herein.
Horn lacks a specific disclosure on the addition of the histamine antagonist, ketotifen, its amounts and the surfactants being polysorbate or their amounts. These are known in the art as disclosed by Chapin et al ‘624 and Chapin et al ‘688.
Chapin et al ‘624 teach topical formulations of ketotifen that provide a comfortable formulation when instilled in the eye and are effective in the treatment and prevention of ocular allergy, particularly allergic conjunctivitis (See abstract).
Chapin et al teach ophthalmic formulations of ketotifen in combination with one or more additional active ingredients for mitigating the symptoms of ocular allergy, especially allergic conjunctivitis, such as redness, chemosis, lid swelling and nasal symptoms (See [0013]).
The said ophthalmic formulations comprise a tear substitute, such as hydroxypropylmethyl cellulose (Hypromellose or HPMC), which is present at ranges from about 0.5% to about 2% w/v (See [0014)).
The said ophthalmic formulation comprises ketotifen, or pharmaceutically acceptable salts thereof, wherein the concentration of ketotifen is from 0.01% to 0.20% (w/v), preferably 0.035% (w/v) and the pH of the formulation is between 5.5 and 7 or 5.5-6.5 (See [0021], [0024], [0030] and [0044)).
The said ketotifen, or a pharmaceutically acceptable salt thereof, is formulated at a concentration of 0.01% to 0.20% (w/v), (See [0043]-[0044]).
The said ketotifen formulations comprise ophthalmic demulcents and/or viscosity enhancing polymers selected from one or more of hydroxypropylmethyl cellulose or hypromellose (0.02% to 5%) and polysorbate 80 (0.02% to 3%) (See [0068]). The said formulations also comprise a buffering agent such as potassium citrate, citric acid or sodium citrate in amounts ranging from about 0.05 to 2.5 wt%, and preferably, from 0.1 to 1.5 wt% (See [0062]-[0063)).
Chapin et al ‘688’s teachings are delineated above and incorporated herein.
It would have been obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Chapin et al ‘624 and Chapin et al ‘688 with that of Horn to arrive at the instant invention. One of ordinary skill in the art would have been motivated to do so because Horn teaches ophthalmic formulations comprising a combination of brimonidine at low doses and an antihistamine for treating an allergic response and reducing redness in the eye of a human patient. While Horn list a number of suitable histamine antagonists for the said formulations, there is no specific disclosure on ketotifen being the histamine antagonist. Chapin et al ‘624 teach ophthalmic formulations comprising ketotifen to treat ocular allergy, particularly allergic conjunctivitis. Chapin et al’s formulations also comprise hydroxypropylmethyl cellulose, polysorbate and citrate buffers. Chapin et al also disclose that other suitable active agents may be added to the said formulations comprising ketotifen.
As such one of ordinary skill in the art having possession of the said references would have been motivated to have selected ketotifen as the suitable histamine antagonist and take advantage of guidance provided on its suitable amounts and suitable excipients as taught by Chapin et al with a reasonable expectation of success.
Chapin et al ‘688 also teach ophthalmic formulations comprising suitable active agents including ketotifen and brimonidine, hydroxypropyl methylcellulose, sorbate, polysorbate, citrate buffers, etc. It would have been obvious to one of ordinary skill in the art to take advantage of such teachings and incorporate suitable excipients into the ophthalmic formulations of Horn and Chapin et al with a reasonable expectation of success.
Thus, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-12 of copending Application No 17/405,773 (US 20210369706) in view of Gore et al (US 20130157963).
The Obviousness Double Patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims and would have been obvious over the reference claims in view of Gore et al.
Specifically, the examined claims are drawn to a liquid composition for the treatment of allergic conjunctivitis comprising: about 0.035% w/v ketotifen fumarate; about 0.025% w/v brimonidine; about 2.5% w/v polysorbate; from about 0.1% to about 1.2% w/v hydroxypropylmethyl cellulose; about 4 millimolar citrate buffer; and optionally, about 0.1% w/v sorbate, wherein the composition has a pH of about 6.5 and wherein w/v denotes weight by total volume of the composition.
The reference claims are drawn to an ophthalmological composition for the treatment of glaucoma comprising from about 0.01% to about 0.059% w/v brimonidine and from about 0.0015% to about 0.03% w/v latanoprost or a pharmaceutically acceptable salt thereof, wherein w/v denotes weight by total volume of the composition.
The difference between the two sets of claims is in the presence of a second active agent in the examined claims. The examined claims recite the presence of ketotifen while the reference claims recite the presence of latanoprost. However, as Gore et al states, it would have been obvious to have combined brimonidine with either ketotifen or latanoprost for their combined benefits.
Gore et al teach ophthalmic compositions for treating a disease of the eye comprising one or more therapeutically active agents such as an alpha-adrenergic antagonist, a prostaglandin, an alpha agonist, an anti-inflammatory, etc, or a combination thereof. The said therapeutically active agent comprises bimatoprost, latanoprost, brimonidine, ketorolac, etc, or a combination thereof. The said composition may be a solution (See [0012]-[0015] and [0046]).
Thus, it would have been obvious to one of ordinary skill in the art to have selected either ketotifen or latanoprost as the second active agent for combining with brimonidine and arrive at an effective ophthalmic composition.
In other words, the claims would have been obvious because the substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 04/28/25 have been fully considered but they are not persuasive.
Regarding the rejections of claims over Horn in combination with Chapin ‘688, Chapin ‘624 and Mahadevan, Applicant argues that “The present invention is limited to brimonidine at a concentration from 0.025% to about 0.035% w/v in combination with ketotifen. The Office Action asserts that Horn teaches below 0.05% brimonidine and histamine agonists. However, Horn teaches that compositions containing a histamine agonist and an alpha 2 adrenergic agonist should contain less than 0.025% of the alpha 2 adrenergic agonist. See, paragraph 140 of Horn. Thus, although Horn teaches brimonidine at other concentrations, Horn is specific as to the amount of alpha 2 adrenergic agonists to use when combining with histamine agonist, specifically less than 0.025%. In light of the cited prior art, a skilled artisan would not be motivated to use 0.025% or more when determining how much brimonidine to use when combining it with ketotifen. In fact, based on the teachings of Horn, the skilled artisan would understand NOT to use 0.025% or more brimonidine when combining with ketotifen. None of Chapin ‘688, Chapin ‘624 and Mahadevan cure this defect, because none of Chapin ‘688, Chapin ‘624 or Mahadevan teach the use of an alpha 2 adrenergic agonist at the claimed concentrations in combination with a histamine antagonist” (See Remarks, page 3).
The above arguments are not persuasive. Horn clearly teaches a method of treating an allergic response in the eye of a subject by administering a low dose of brimonidine and an antihistamine at given doses. Paragraphs 139 and 140 of Horn ‘266 are reproduced below in their entirety:
Phentolamine is a preferred pharmaceutical agent for such use. When combined with the present invention, its use is further optimized. Preferably, when used in combination, the highly selective a-2 agonists of the present invention are employed in ratios varying from about 0.02% to about 0.05%. Most preferably, the a-1 antagonist is phentolamine myrsalate, and its concentration is from about 0.01% to about 0.1%.
In another embodiment, the invention generally relates to a composition formulated for treating and/or preventing an allergic response with reduced rebound hyperemia, comprising a selective a-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for a-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, and a histamine antagonist, wherein said selective a-2 adrenergic receptor agonist is present at a concentration below about 0.025% weight by volume.
Horn teaches that the said brimonidine may be present in the combination from about 0.02% to about 0.05%. it is also noted that Phentolamine is a preferred pharmaceutical agent for the combination with brimonidine wherein the brimonidine is present from about 0.02% to about 0.05%. Furthermore, even if paragraph 140 was relevant, it discloses a range of below about 0.025%, wherein the term about 0.025% touches on the claimed 0.025% and meets the claimed range.
Thus, the only missing element from Horn’s teachings is that ketotifen is not recited as one of the histamines listed. Chapin ‘624 teach a method of treating ocular allergy in a subject by administering a composition comprising ketotifen at a dose of from about 0.01% to 0.20% (w/v) alone or combined with other antihistamines. One of ordinary skill in the art having possession of the two references would have been motivated to have combined the low dose of Horn with the dose of Chapin ‘624 to effectively treat an allergic response in the eye of a subject with a reasonable expectation of success as both active agents re disclosed for treating eye allergy.
In this regard the MPEP 2144.06 entitled Art Recognized Equivalence for the Same Purpose, states that “It would be prima facie obvious to combine two methods each of which is taught by the prior art to be useful for the same purpose in order to form a resultant method that is to be used for the very same purpose; the idea of combining them flows logically from their having been individually taught in prior art.” In re Kerkhoven, 205 USPQ 1069 (C.C.P.A. 1980).
In other words, even if Horn did not recite combining brimonidine with an antihistamine, one of ordinary skill in the art would have had reasons to combine brimonidine and ketotifen to increase the effectiveness of the combined formulation in reducing the symptoms of an allergic response in a subject.
Accordingly, the reduction in symptoms such as redness with low dose brimonidine alone was significant. One of ordinary skill in the art combining the said formulations with ketotifen would have expected even more reduction in redness and other symptoms of allergy.
Thus, we have clearly shown that there is no evidence of an inventive step.
Claims 1 and 3-5 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached on M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616