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 .
Priority
Acknowledgment is made of Applicant's claim for priority from U.S. Provisional Application No. 63/370,409, filed on 08/04/2022.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-15) drawn to an ophthalmic composition comprising: (a) ketotifen or a pharmaceutically acceptable salt thereof at a concentration from about 0.010% (w/v) to about 0.050% (w/v), (b) brimonidine or a pharmaceutically acceptable salt thereof at a concentration from about 0.010% (w/v) to about 0.050% (w/v), (c) two or more non-ionic tonicity agents in an amount such that the composition has an osmolality of about 275 mOsm/kg to about 385 mOsm/kg, (d) povidone at a concentration from about 0.15% (w/v) to about 0.45% (w/v), (e) an optional preservative, and (f) water, in the reply filed on March 2, 2026 is acknowledged.
Applicant's election with traverse of mannitol and glycerol as two or more non-ionic tonicity agents; benzalkonium chloride as an optional preservative; pH adjuster as an additional non-therapeutic component; and no additional therapeutic agent in the reply filed on March 2, 2026 is also acknowledged.
The traversal is on the ground(s) that the Office has not established that the inventions of Group I and Group II are indeed independent and distinct. Applicant argues that contrary to the Office's assertion that "the inventions as claimed do not encompass overlapping subject matter", the subject matter of Group II as recited in claim 16 falls squarely within subject matter of Group I as recited in claim 1. Thus, at least because the subject matter of Group I and Group II do not satisfy required element (A) above, the Office has not met its burden in establishing that said groups are indeed distinct.
Applicant’s traversal is not found persuasive because as detailed in the restriction requirement, invention I and invention II do not necessarily contain the same components since invention I contains any two or more non-ionic tonicity agents whereas invention II must contain glycerol and mannitol. In addition, invention I does not necessarily contain a salt of ketotifen and brimonidine, or a preservative, whereas invention II must contain a preservative and salts of ketotifen and brimonidine. Thus, the subject matter of the inventions do not necessarily overlap if the two or more non-ionic tonicity agents of invention I is anything other than glycerol and mannitol and the composition of Invention I excludes a preservative and does not contain salts of ketotifen and brimonidine. However, in view of Applicant’s species elections, Group II is hereby rejoined and examined herewith since Group II reads on Applicant’s elected species.
The requirement is still deemed proper and is therefore made FINAL.
Claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-8 and 10-17 are being examined as they read on the elected species.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Horn U.S. Publication No. 2022/0233524 A1 (provided on IDS dated 01/17/2024) in view of Chapin et al. U.S. Publication No. 2010/0240624 A1.
Claims 1-17 of the instant application claim an ophthalmic composition comprising: (a) ketotifen or a pharmaceutically acceptable salt thereof at a concentration from about 0.010% (w/v) to about 0.050% (w/v), (b) brimonidine or a pharmaceutically acceptable salt thereof at a concentration from about 0.010% (w/v) to about 0.050% (w/v), (c) two or more non-ionic tonicity agents in an amount such that the composition has an osmolality of about 275 mOsm/kg to about 385 mOsm/kg, (d) povidone at a concentration from about 0.15% (w/v) to about 0.45% (w/v), (e) an optional preservative, and (f) water.
Horn teaches compositions containing low-dose brimonidine and either a second glaucoma drug, an anti-histamine or non-steroidal anti-inflammatory drug (abstract and [0001]). Horn further teaches methods of treating glaucoma or allergies or reducing inflammation by administering compositions of the invention (abstract and [0001]). Horn teaches that many of the anti-histamines prescribed or administered to treat ocular allergies and or allergic rhinitis treat histamine induced itching and discomfort but do not fully alleviate the attendant symptoms including particularly swelling secondary to vascular leakage and hyperemia (eye redness) resulting in both remaining discomfort and an unhealthy appearance [0012]. Thus Horn teaches that there is a further need in the art for a combination allergy treatment that leads to a greater alleviation of attendant symptoms including eye redness [0012]. Horn teaches an ophthalmological composition for the treatment of allergies comprising brimonidine at a concentration from about 0.01% to about 0.050% w/v and a histamine antagonist [0018]. Horn further teaches a method of treating allergies comprising administering a composition comprising brimonidine at a concentration from about 0.005% to about 0.050% w/v and a histamine antagonist to a subject in need thereof [0019]. In addition, Horn teaches a method of treating allergies, wherein the method further provides eye whitening and or reduced inflammation [0020].
Horn teaches that postcapillary venular leakage may be reduced selectively by low dose brimonidine over alpha 1 vasoconstrictors because it is believed alpha 1 agonists constrict larger vessels such as arterioles to a much greater extent than low dose brimonidine and this constriction of the larger vessels creates ischemia, and with repeated use, inflammation and rebound hyperemia (eye redness) [0024]. Horn teaches that constriction of small vessels and particularly said postcapillary venules without ischemia by low dose brimonidine is surprisingly found to reduce such leakage without the ischemia of other alpha 1 agonist constrictors, and therefore alleviating redness and clinical sequelae of swelling and redness otherwise not as completely alleviated making the combination of low dose brimonidine with an anti-histamine particularly effective [0024].
Horn teaches that the term “brimonidine” encompasses, without limitation, brimonidine salts and other derivatives, and specifically includes, but is not limited to, brimonidine tartrate [0026].
Horn teaches that currently available anti-histamines (i.e. histamine antagonists) are not capable of fully alleviating all allergy symptoms including particularly the eye redness associated with cytokine induced vasodilation and it is a discovery of the invention that the use of extremely low dose brimonidine (“ELDB”) in combination with an anti-histamine leads to not only greater reduction of redness but greater alleviation of allergy symptoms such as conjunctival swelling than the use of the anti-histamine alone [0064]. Horn teaches an ophthalmological composition for the treatment of allergies comprising brimonidine at a concentration from about 0.005% to about 0.050% w/v and a histamine antagonist [0065]. Brimonidine may be at concentrations from about 0.005% to about 0.050% w/v, preferably from about 0.01% to about 0.050% w/v, more preferably from about 0.025% to about 0.035% w/v and about 0.025%, about 0.035% or about 0.04% w/v [0066] . Histamine antagonist useful include ketotifen, and pharmaceutically acceptable salts thereof [0067]. Histamine antagonist may be at concentrations from about 0.01% to about 1% w/v, preferably from about 0.025% to about 0.7% w/v [0068]. Histamine antagonists for ophthalmological administration are currently marketed under the following concentrations of active ingredients: 0.025% ketotifen [0068].
Horn teaches that compositions of the invention for the reduction of inflammation may be administered topically to the eye or nasal cavity via drops or spray [0075].
Horn teaches that compositions of the invention may have a pH from about 5.0 to about 8.0, more preferably from about 6.0 to about 7.5 [0059].
Horn teaches a combination of 0.005% to 0.050% w/v brimonidine and 0.025% to 0.035% w/v ketotifen fumarate [0080].
Claims 1-2 of Horn claim a method of treating an allergic response in an eye of a subject comprising administering to an eye of a subject in need thereof an ophthalmological liquid composition comprising from about 0.005% to about 0.050% w/v brimonidine and from about 0.01% to about 1% w/v ketotifen or a pharmaceutically acceptable salts thereof, wherein w/v denotes weight by total volume of the composition, wherein the ketotifen is at a concentration from about 0.025% to about 0.7% w/v. Claim 5 of Horn claims a liquid composition for the treatment of allergic conjunctivitis comprising: about 0.035% w/v ketotifen fumarate; about 0.035% w/v brimonidine.
Thus Horn teaches the combination of ketotifen and brimonidine for ophthalmic use in amounts as claimed in the instant claims.
Horn does not teach the carrier composition as claimed comprising (c) two or more non-ionic tonicity agents in an amount such that the composition has an osmolality of about 275 mOsm/kg to about 385 mOsm/kg, (d) povidone at a concentration from about 0.15% (w/v) to about 0.45% (w/v), (e) an optional preservative, and (f) water.
Chapin et al. teaches 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 as well as methods of treating and preventing ocular allergy by in a subject in need of such treatment by topical application of the ketotifen formulations of the invention to the eye of a subject in need thereof (abstract). Chapin et al. teaches comfortable topical ophthalmic formulations for the treatment and prevention of ocular allergy, particularly allergic conjunctivitis and products that contain a combination of ingredients which act synergistically to relieve the signs and symptoms of ocular allergy, particularly ocular itching, redness, swelling, and nasal symptoms [0011]. Chapin teaches the formulations described therein provide ketotifen, or a pharmaceutically acceptable salt thereof, suitable for ophthalmic use in a comfortable ophthalmic formulation when instilled in the eye and also methods for the treatment and prevention of ocular allergy, particularly allergic conjunctivitis, in a subject in need of such treatment, by topically administering a ketotifen formulation of the invention directly to the eye of the subject [0011].
Chapin et al. teaches preferably, the pharmaceutical compositions are formulated as solutions, suspensions, ointments, gels, emulsions, and other dosage forms for topical administration and aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes [0046].
Chapin et al. teaches the ophthalmic formulations of the invention comprise a polymeric, mucoadhesive vehicle including aqueous polymeric suspensions comprising one or more polymeric suspending agents including without limitation dextrans, polyethylene glycol, polyvinylpyrolidone, polysaccharide gels, Gelrite, cellulosic polymers, and carboxy-containing polymer systems [0016].
Chapin et al. teaches preferably, the ketotifen formulations of the invention are comprised of ketotifen fumarate [0019].
Chapin et al. teaches in a particular embodiment, the ketotifen formulations of the invention further comprises glycerol [0020]. Chapin et al. teaches glycerol may be used at 0.5% to 5% v/v ([0072]-0073]).
Chapin et al. teaches that optionally, the ketotifen formulations further comprise a preservative, preferably benzalkonium chloride wherein, the concentration of benzalkonium chloride in the formulation is from 0.005% to 0.02% (v/v), or any specific value within said range [0021]. Chapin et al. teaches the pH of the formulation is between 5.0 and 7, preferably between 5.0 and 6.5, and most preferably about 5.5 and the formulation is an aqueous formulation [0021].
Chapin teaches an ophthalmic formulation comprising ketotifen, or pharmaceutically acceptable salts thereof, wherein the pH of the formulation is greater than 5 such as between 5.5 and 7, and the osmolality is less than 400 mOsm such as between 225 to 390 mOsm and the concentration of ketotifen is from 0.01% to 0.20% (w/v) [0024].
Chapin teaches in particular embodiments, the ketotifen formulations comprise a preservative such as benzalkonium chloride, 0.001% to 0.05% [0065]. In another embodiment, the topical formulations do not include a preservative [0066].
In certain embodiments, viscosity enhancing agents may be added to the ketotifen formulations of the invention, such agents include polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers [0067]. In certain embodiments, the ketotifen formulations comprise ophthalmic demulcents and/or viscosity enhancing polymers selected from one or more of the following: cellulose derivatives such as carboxymethy cellulose (0.02 to 5%) hydroxyethylcellulose (0.02% to 5%), hydroxypropylmethyl cellulose or hypromellose (0.02% to 5%), and methylcelluose (0.02% to 5%); dextran 40/70 (0.01% to 1%); gelatin (0.01% to 0.1%); polyols such as glycerol (0.01% to 5%), polyethylene glycol 300 (0.02% to 5%), polyethylene glycol 400 (0.02% to 5%), polysorbate 80 (0.02% to 3%), propylene glycol (0.02% to 3%), polyvinyl alcohol (0.02% to 5%), and povidone (0.02% to 3%); hyaluronic acid (0.01% to 2%); and chondroitin sulfate (0.01% to 2%) [0068].
Tonicity is adjusted if needed typically by tonicity enhancing agents, such agents may, for example be of ionic and/or non-ionic type, wherein non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose [0070]. The aqueous solutions are typically adjusted with tonicity agents to approximate the osmotic pressure of normal lachrymal fluids which is equivalent to a 0.9% solution of sodium chloride or a 2.5% solution of glycerol [0070]. An osmolality of about 225 to 400 mOsm/kg is preferred, more preferably 280 to 320 mOsm [0070].
Thus Chapin et al. teaches ketotifen formulations that provide a comfortable formulation when instilled in the eye which may comprise an aqueous formulation containing glycerol at 0.5% to 5% v/v; a preservative such as benzalkonium chloride, 0.001% to 0.05%; an amount of a tonicity enhancing agents, such glycerol and mannitol, to reach an osmolality of about 225 to 400 mOsm/kg and more preferably 280 to 320 mOsm; viscosity enhancing agents such povidone (0.02% to 3%); wherein the pH of the formulation is greater than 5 such as between 5.5 and 7.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Horn et al. which teaches a combination of 0.005% to 0.050% w/v brimonidine and 0.025% to 0.035% w/v ketotifen fumarate wherein the compositions have a pH from about 5.0 to about 8.0, more preferably from about 6.0 to about 7.5; with the teachings of Chapin et al. which teaches formulations comprising ketotifen that provide a comfortable formulation when instilled in the eye which may comprise an aqueous formulation containing glycerol at 0.5% to 5% v/v; a preservative such as benzalkonium chloride, 0.001% to 0.05%; an amount of a tonicity enhancing agents, such glycerol and mannitol, to reach an osmolality of about 225 to 400 mOsm/kg and more preferably 280 to 320 mOsm; viscosity enhancing agents such povidone (0.02% to 3%); wherein the pH of the formulation is greater than 5 such as between 5.5 and 7.
Thus since the formulation of Chapin et al. provides the advantage of being comfortable to the eye upon instillation, an ordinary skilled artisan would have been motivated to formulate the combination taught in Horn which includes brimonidine and ketotifen according to the teachings of Chapin et al. with a reasonable expectation of improvements in comfort upon instillation of the formulation in the eye of the patient.
With respect to the amounts as claimed, the prior art teaches amounts of each component of the formulation that overlap with the claimed amounts. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.").
With respect the amount of mannitol as claimed in claim 16, although Chapin et al. does not specifically teach the amount of mannitol as claimed, as detailed above Chapin et al. specifically teaches that the tonicity is adjusted by tonicity enhancing agents, such as glycerol and mannitol to reach an osmolality of about 225 to 400 mOsm/kg and more preferably 280 to 320 mOsm/kg which overlaps with the osmolarity of about 275 to about 385 mOsm/kg as claimed in claim 16. Thus since Chapin et al. teaches using the same tonicity enhancing agents to reach the same osmolality, the amounts of the tonicity enhancing agents as claimed are rendered obvious in view of the cited prior art teachings because the same or similar amounts of the tonicity enhancing agents would be needed in order to arrive at the same or similar osmolality. Thus claim 16 is rendered obvious.
Claims 14, 15 and 17 of the instant application, which claims stability of the composition, are rendered obvious since the composition as claimed is rendered obvious and thus the properties of the composition as claimed are also rendered obvious. "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
In addition, Chapin et al. teaches that the formulations provide for the chemical stability of the formulated ketotifen and other optional active agents of the formulation, wherein "Stability" and "stable" in this context refers to the resistance of the ketotifen and other optional active agents to chemical degradation under given manufacturing, preparation, transportation and storage conditions [0082]. The "stable" formulations preferably retain at least 90%, 95%, 98%, 99%, or 99.5% of a starting or reference amount under given manufacturing, preparation, transportation, and/or storage conditions [0082]. Chapin et al. teaches that the ketotifen formulations are stable at temperatures ranging from about 20 to 30°C for at least 12 months [0083]. Since at least 12 months includes longer time periods, stable for at least two years as claimed is rendered obvious.
Claim 7 of the instant application is rendered obvious since Chapin et al. teaches that the pH of the composition is adjusted to 5.5 with Sodium hydroxide, 0.5N or Hydrochloric Acid, 0.5N (Table 3 page 13). Claims 10 and 11 are rendered obvious since Chapin et al. teaches that buffers such as borate buffers are optional and not required and are only suggested for the adjustment to physiological pH (pH 7.4) [0063]. However, since the preferred pH of the formulation is between 5.0 and 6.0 and not physiological pH, an ordinary skilled artisan would not have been motivated to include a buffer to the formulation.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-8 and 10-17 are rejected. Claim 9 is withdrawn. Claims 18-20 are canceled. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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