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
This application is a national stage entry of PCT/IB2021/052237 filed on 03/17/2021 which claims priority to U.S, Provisional Application No. 62/991,611 filed on 03/19/2020.
Response to Amendment
Applicant’s amendment filed on October 6, 2025 amending claims 1, 2, 5, 6, 8, 9, 16, 19 and 30; and adding new claims 45-47 has been entered. Claims 3, 4, 7, 10-15, 17, 18, 27-29, 31-43 were previously canceled.
Response to Arguments
Due to Applicant’s amendment to claim 30, the previous rejection of claim 30 under 35 U.S.C. 112(b) is hereby withdrawn.
Due to the abandonment of copending Application No. 18/406,539, the previous double patenting rejection over U.S. Application No. 18/406,539 is hereby withdrawn.
Applicant's arguments filed October 6, 2025 with respect to the remaining rejection have been fully considered but they are not persuasive.
Applicant argues that they have unexpectedly discovered that the use of HEC having a particular, narrow average molecular weight range in the formulation provides for a formulation with improved properties as discussed on pages 6-8 of Applicant’s remarks. Applicant argues that it has been experimentally determined that HEC having a molecular weight of about 1,300,000 Daltons will produce a HEC matrix having a viscosity greater than 25,000 cP after thermal sterilization, and that these viscosities will result in a viscosity of the final gel of from 1000 to 2000 cP at 25 °C after mixing with the aqueous acidic solution. Applicant argues that they have determined that heat sterilization does not significantly affect the viscosity of the HEC matrix prior to mixing with the aqueous acidic solution, as well as identified a suitable concentration range for the wherein, a particularly advantageous concentration of about 1.04% to 1.14% is indicated.
Applicant argues that none of the cited references teach the desirability of HEC having an average molecular as currently claimed. Applicant argues that the double patenting references simply states that "hydroxyethyl cellulose can be added in an amount (q.s.) needed to achieve any of the foregoing viscosities," and does not disclose what molecular weight is needed to achieve non-Newtonian flow, particularly after being subjected to heat sterilization and mixing with an acidic solution of chloroprocaine.
Applicant argues that King cites HEC in a laundry list of water-soluble gums and resins but does not provide any examples with HEC or provide any teaching of the molecular weight necessary to produce the elegant drops of the present invention exhibiting non-Newtonian flow behavior.
Applicant argues that Chynn also cites HEC in a laundry list of wetting agents but does also not provide any examples with HEC or provide any teaching of the molecular weight necessary to produce the drops of the present invention exhibiting non-Newtonian flow behavior.
Applicant argues that Sawaya does not disclose eye drops containing HEC or chloroprocaine and does not cure the deficiencies in Chynn.
With respect to Applicant’s arguments regarding unexpected results, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected results must be established by factual evidence.” “[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument.”). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
In the instant case, Applicant has not provided any data to support their arguments of unexpected results. Applicant has not provided any data to support the criticality of HEC in the formulation or to support the amount of HEC in the formulation. In addition, based on the prior art cited, Applicant’s findings would not be considered surprising or unexpected in view of the teachings of Sawaya.
Sawaya specifically provides motivation to use a high viscosity (high molecular weight) cellulose derivative such as HEC in the formulation of Chynn and to the formulations claimed in the claims of the double patenting references. Sawaya specifically teaches preparing high viscosity ophthalmic gel using a gelling agent consisting essentially of cellulose or a water soluble cellulose derivative (abstract). Sawaya specifically teaches the need for a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer, and that is capable of controlled release of a pharmaceutically active substance, which is solved by a formulation adapted for ophthalmic use containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel wherein the gel has a viscosity of from 75,000 to 3,000,000 centipoise at a temperature of 22° to 30°C., preferably 25°C., and is substantially free of an oil phase and the gelling agent consists essentially of cellulose or a water soluble cellulose derivative (column 2 lines 8-27).
Sawaya further teaches other advantages including: upon administration, aqueous eye fluids mix with the gel, resulting in immediate release of the active agent; a predetermined dose reaches the site being treated; a much higher percentage of the dose is maintained in the eye than with a conventional ophthalmic ointment or solution; the formulation also allows an amount of active to be applied that slowly spreads over the eye; and the gel of the invention can be formulated to be substantially clear, thereby avoiding or decreasing blurring associated with conventional ophthalmic products (column 2 lines 45-59). Sawaya further teaches the formulation of the invention provides a safe means for time release of actives into the eye, wherein the release rate depends on the viscosity of the gel, i.e., higher viscosity results in slower release (column 3 lines 1-6).
Sawaya further teaches the newly added properties of the formulation as currently claimed since Sawaya teaches that the formulation of the invention can be placed in any desired dispensing device suitable for an ophthalmic formulation, wherein the device can be an ophthalmic delivery system, such as a sterile ophthalmic tube, e.g., a conventional 3.5 g tube having an ophthalmic tip and containing the ophthalmic formulation of the invention, or a sterile single use container containing 0.2-0.5 g of the formulation which would result in a drop containing the amount as claimed (column 3 lines 38-44).
Sawaya specifically teaches the use of high viscosity cellulose based agents are preferred, wherein such agents have a higher number of substituents, such as methoxy, ethoxy, hydroxy propyl and carboxy substituents, attached to the cellulose backbone than low viscosity cellulose based agents, specifically hydroxyethyl cellulose (column 3 line 45-column 4 line 5).
Thus the teachings of Sawaya specifically teach and suggest the use of high viscosity cellulose derivatives in ophthalmic formulations to produce formulations having improved properties including a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer.
Prior to the effective filing date of the claimed invention, high viscosity hydroxyethylcellulose gelling agents were known in the art. Natrosol ™250 Pharm hydroxyethyl cellulose (HEC) was available in several grades which differ in their weight average molecular weight and thus in their viscosities measured in aqueous solutions. HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% was known in the art (Ashland 2018, table 1 page 5).
Accordingly, based on the teachings of Sawaya, a person of ordinary skill in the art would have been motivated to use high molecular weight HEC products available including HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% in the formulation of Chynn and the formulations claimed in the double patenting references with a reasonable expectation of success to arrive at the instant invention.
In addition, with respect to Applicant’s argument that Chynn discloses a laundry list of wetting agents, Chynn specifically suggests, teaches and claims a limited number of gelling/wetting agents, wherein examples of useful wetting agents are carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol (PVA), or hydroxyethylcellulose (column 4 lines 9-12 and claim 11). Moreover, although Chynn includes hydroxyethylcellulose on a list that includes other gelling agents, a prima facie case of obviousness can still be established since picking one of a finite number of known solutions to a known problem is prima facie obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). Furthermore, since Applicant has not presented any data demonstrating the criticality for HEC over other cellulose derivatives taught in the prior art, Applicant’s argument is found not persuasive.
Thus Applicant’s arguments are found not persuasive.
Furthermore, King et al. teaches that optimal properties of the composition include, the finished gel being clear, the gel having a consistency that allowed it to remain at a vertical surface when applied to the surface, the viscosity of the finished gel also allowing it to remain, and not flow or drop, when it is applied to an underside of a surface, the finished gel also retained its integrity in that it maintained its characteristics when stored at room temperature for days or when place on body surfaces, resisting drying and maintaining its gel properties (column 6 lines 55-65). Thus the teachings of King et al. suggest the use of a high viscosity gelling agent in order to achieve the properties of the composition as described. Thus, as detailed above a person of ordinary skill in the art would have been motivated to use high molecular weight HEC products available including HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% in the formulation of King with a reasonable expectation of success to arrive at the instant invention.
In addition, with respect to Applicant’s argument that King discloses a laundry list of gelling agents, although King includes hydroxyethylcellulose on a list that includes other gelling agents, a prima facie case of obviousness can still be established since picking one of a finite number of known solutions to a known problem is prima facie obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). Moreover, since Applicant has not presented any data demonstrating the criticality for HEC over other cellulose derivatives taught in the prior art, Applicant’s argument is found not persuasive.
Thus Applicant’s arguments are found not persuasive.
However, in view of Applicant’s amendments to the claims, the previous rejections are being modified to address Applicant’s newly added limitations. Accordingly, this action is FINAL.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Misnumbered claims 45-47 have been renumbered 44-46.
Claims 1, 2, 5, 6, 8, 9, 16, 19-26, 30 and 44-46 are currently pending and presented for examination.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-6, 8-9, 16 and 44-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,969,403 B2 in view of Sawaya U.S. Patent No. 5,888,493 (Provided on IDS) and Ashland (2018 Natrosol ™250 Pharm hydroxyethyl cellulose (HEC), formulating elegant liquid and semisolid drug products). Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of ‘403 are drawn to a topical gel formulation comprising 3% by weight of chloroprocaine hydrochloride, hydroxyethyl cellulose, and water, at a pH of from 2.8 to 3.8.
Although ‘403 does not claim the steps as claimed in claim 1 of the instant application of preparing the composition, please note that even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113.
Although the patent does not teach the use of the hydroxyethyl cellulose having an average molecular weight of from 1,000,000 to 1,500,000 Daltons to form a drop comprising from 0.03 to 0.1 g of the topical gel, prior to the effective filing date of the claimed invention, the use of high molecular weight (high viscosity) cellulose derivative in topical formulations were known in the art.
Sawaya specifically provides motivation to use a high viscosity (high molecular weight) cellulose derivative such as HEC in the formulation of the claims of the patent. Sawaya specifically teaches preparing high viscosity ophthalmic gels using a gelling agent consisting essentially of cellulose or a water soluble cellulose derivative (abstract). Sawaya specifically teaches the need for a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer, and that is capable of controlled release of a pharmaceutically active substance, which is solved by a formulation adapted for ophthalmic use containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel wherein the gel has a viscosity of from 75,000 to 3,000,000 centipoise at a temperature of 22° to 30°C., preferably 25°C., and is substantially free of an oil phase and the gelling agent consists essentially of cellulose or a water soluble cellulose derivative (column 2 lines 8-27).
Sawaya further teaches other advantages including: upon administration, aqueous eye fluids mix with the gel, resulting in immediate release of the active agent; a predetermined dose reaches the site being treated; a much higher percentage of the dose is maintained in the eye than with a conventional ophthalmic ointment or solution; the formulation also allows an amount of active to be applied that slowly spreads over the eye; and the gel of the invention can be formulated to be substantially clear, thereby avoiding or decreasing blurring associated with conventional ophthalmic products (column 2 lines 45-59). Sawaya further teaches the formulation of the invention provides a safe means for time release of actives into the eye, wherein the release rate depends on the viscosity of the gel, i.e., higher viscosity results in slower release (column 3 lines 1-6).
Sawaya further teaches the newly added properties of the formulation as currently claimed since Sawaya teaches that the formulation of the invention can be placed in any desired dispensing device suitable for an ophthalmic formulation, wherein the device can be an ophthalmic delivery system, such as a sterile ophthalmic tube, e.g., a conventional 3.5 g tube having an ophthalmic tip and containing the ophthalmic formulation of the invention, or a sterile single use container containing 0.2-0.5 g of the formulation which would result in a drop containing the amount as claimed (column 3 lines 38-44).
Sawaya specifically teaches the use of high viscosity cellulose based agents are preferred, wherein such agents have a higher number of substituents, such as methoxy, ethoxy, hydroxy propyl and carboxy substituents, attached to the cellulose backbone than low viscosity cellulose based agents, specifically hydroxyethyl cellulose (column 3 line 45-column 4 line 5).
Thus the teachings of Sawaya specifically teach and suggest the use of high viscosity cellulose derivatives in ophthalmic formulations to produce formulations having improved properties including a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer.
Prior to the effective filing date of the claimed invention, high viscosity hydroxyethylcellulose gelling agents were known in the art. Natrosol ™250 Pharm hydroxyethyl cellulose (HEC) was available in several grades which differ in their weight average molecular weight and thus in their viscosities measured in aqueous solutions (page 5). HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% was known in the art (Ashland 2018, table 1 page 5).
Accordingly, based on the teachings of Sawaya, a person of ordinary skill in the art would have been motivated to use high molecular weight HEC products available including HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% as taught by Ashland, in the formulation claimed in the patent with a reasonable expectation of success and thus arriving at the instant invention.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 1-2, 5-6, 8-9, 16 and 44-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,792,271 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of ‘271 are drawn to a topical gel formulation comprising 3% by weight of chloroprocaine hydrochloride, hydroxyethyl cellulose, and water, at a pH of from 2.8 to 3.8 such as 3.0-3.4.
Although ‘271 does not claim the steps as claimed in claim 1 of the instant application of preparing the composition, please note that even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113.
Although the patent does not teach the use of the hydroxyethyl cellulose having an average molecular weight of from 1,000,000 to 1,500,000 Daltons to form a drop comprising from 0.03 to 0.1 g of the topical gel, prior to the effective filing date of the claimed invention, the use of high molecular weight (high viscosity) cellulose derivative in topical formulations were known in the art.
Sawaya specifically provides motivation to use a high viscosity (high molecular weight) cellulose derivative such as HEC in the formulation of the claims of the patent. Sawaya specifically teaches preparing high viscosity ophthalmic gels using a gelling agent consisting essentially of cellulose or a water soluble cellulose derivative (abstract). Sawaya specifically teaches the need for a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer, and that is capable of controlled release of a pharmaceutically active substance, which is solved by a formulation adapted for ophthalmic use containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel wherein the gel has a viscosity of from 75,000 to 3,000,000 centipoise at a temperature of 22° to 30°C., preferably 25°C., and is substantially free of an oil phase and the gelling agent consists essentially of cellulose or a water soluble cellulose derivative (column 2 lines 8-27).
Sawaya further teaches other advantages including: upon administration, aqueous eye fluids mix with the gel, resulting in immediate release of the active agent; a predetermined dose reaches the site being treated; a much higher percentage of the dose is maintained in the eye than with a conventional ophthalmic ointment or solution; the formulation also allows an amount of active to be applied that slowly spreads over the eye; and the gel of the invention can be formulated to be substantially clear, thereby avoiding or decreasing blurring associated with conventional ophthalmic products (column 2 lines 45-59). Sawaya further teaches the formulation of the invention provides a safe means for time release of actives into the eye, wherein the release rate depends on the viscosity of the gel, i.e., higher viscosity results in slower release (column 3 lines 1-6).
Sawaya further teaches the newly added properties of the formulation as currently claimed since Sawaya teaches that the formulation of the invention can be placed in any desired dispensing device suitable for an ophthalmic formulation, wherein the device can be an ophthalmic delivery system, such as a sterile ophthalmic tube, e.g., a conventional 3.5 g tube having an ophthalmic tip and containing the ophthalmic formulation of the invention, or a sterile single use container containing 0.2-0.5 g of the formulation which would result in a drop containing the amount as claimed (column 3 lines 38-44).
Sawaya specifically teaches the use of high viscosity cellulose based agents are preferred, wherein such agents have a higher number of substituents, such as methoxy, ethoxy, hydroxy propyl and carboxy substituents, attached to the cellulose backbone than low viscosity cellulose based agents, specifically hydroxyethyl cellulose (column 3 line 45-column 4 line 5).
Thus the teachings of Sawaya specifically teach and suggest the use of high viscosity cellulose derivatives in topical ophthalmic formulations to produce formulations having improved properties including a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer.
Prior to the effective filing date of the claimed invention, high viscosity hydroxyethylcellulose gelling agents were known in the art. Ashland teaches that Natrosol ™250 Pharm hydroxyethyl cellulose (HEC) was available in several grades which differ in their weight average molecular weight and thus in their viscosities measured in aqueous solutions (page 5). HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% was known in the art (Ashland 2018, table 1 page 5).
Accordingly, based on the teachings of Sawaya, a person of ordinary skill in the art would have been motivated to use high molecular weight HEC products available including HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% as taught by Ashland, in the formulation claimed in the patent with a reasonable expectation of success and thus arriving at the instant invention.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
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 1-2, 5-6, 8-9, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over King et al. U.S. Patent No. 5,276,032 in view of Ashland (2018 Natrosol ™250 Pharm hydroxyethyl cellulose (HEC), formulating elegant liquid and semisolid drug products).
Claims 1-2, 5-6, 8-9 and 16 of the instant application claim a drop comprising from 0.03 to 0.1 g of a topical gel comprising an acidic aqueous solution of chloroprocaine hydrochloride at a pH of 2.4 to 3.2 admixed with an aqueous matrix of hydroxyethyl cellulose having a viscosity greater than 25,000 cP at 25 °C and a pH optionally greater than 6, wherein: a) the gel comprises 3% chloroprocaine hydrochloride; b) the gel has a pH of 2.8-3.8; c) the matrix viscosity is measured by a BrookField DV III+Pro Spindle 3 at 20 rpm, as described in section 2.2.10 of the European Pharmacopeia 2016 edition; and d) the hydroxyethyl cellulose has an average molecular weight of from 1,000,000 to 1,500,000 Daltons.
With respect to the claimed limitations of claim 1 reciting the preparation of the formulation, please note that even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113.
King et al. teaches a new visualizing and anesthetic composition and the process for the preparation thereof, wherein the composition, generally as a gel, contains an effective amount of a topical anesthetic, an effective amount of a visualizing agent and a pharmaceutically acceptable gelling reservoir as a heat exchanger and/or a light transmitter (abstract).
King et al. teaches a composition for topical application to a region of mammalian skin to supply visualization to a lesion therein and to anesthetize the region for a subsequent destructive therapy (column 2 lines 65-68). King et al. teaches that broadly, the composition contains: an effective amount of a topical anesthetic to impart local anesthesia around the region; an effective amount of a visualizing agent to visualize and recognize the lesion; and a pharmaceutically acceptable gelling reservoir to give the desired consistency and to provide the necessary heat exchange interface and/or light transmitter (column 3 lines 1-7). King et al. teaches that it is, therefore, an object of the present invention to provide a new water base gel containing an effective amount of topical anesthetic and an effective amount of visualizing agent (column 3 lines 8-11).
King et al. teaches that topical anesthetics are compounds which block nerve conduction when applied topically to nerve tissue in appropriate concentrations and they produce reversible loss of sensation by preventing or diminishing the conduction of sensory nerve impulses near the site of their application or action (column 3 lines 46-51). King et al. teaches that local anesthetics could also be described as local analgesics as they are most often used to produce loss of pain without loss of nervous control (column 3 lines 52-54). King et al. teaches that a preferred local anesthetic should not be irritating to the tissue to which it is applied, nor should it cause any permanent damage to nerve structure, it should have low systemic toxicity because it is eventually absorbed from its site of application, and the time required for the onset of anesthesia should be as short as possible (column 3 lines 54-63). King et al. teaches that local anesthetics, and their acid addition salts, include: chloroprocaine hydrochloride (column 4 lines 10-18).
King et al. teaches that the effective amount of the local anesthetic ranges from about 0.5% to about 30% by weight based on the total weight of the final composition (column 4 lines 55-58).
King et al. teaches that visualizing agents that are useful include acetic acid and hydrochloric acid (column 5 lines 16-18). A suitable range of the visualizing agent is from about 0.1% to about 15% by weight based on the total weight of the final composition (column 5 lines 19-21). King et al. teaches the pH of the composition is reduced by the use of the acidic visualizing agent, wherein a suitable and effective range of the pH is from about 2 to 5, and preferably around 3 (column 5 lines 21-24). King et al. specifically teaches the use of a sufficient amount of 0.1% hydrochloric acid to reach a pH of about 3.0 (column 7 lines 1-5).
King et al. teaches among other functions, the gelling reservoir aids in providing the final composition with a desired consistency. King et al. teaches generally, this gelling reservoir is in the form of gel, ointment, lotion, paste, jelly, spray, solution, cream, or aerosol and is preferably made up of a water-soluble gum or resin, which may have to be dissolved in water if necessary. Water-soluble resins are polymeric materials whose composition enables them either to dissolve or to swell in water and a wide variety of these polymeric compositions are known. Representative of these water-soluble gums and resins include: hydroxyethylcellulose. Suitable ranges of gelling reservoir vary from about 0.5% to about 10% by weight based on the total weight of the final composition. See column 5 lines 25-67.
King et al. further teaches that the preferred range for cellulose derivatives is 0.5-5% (column 6 lines 1-10). King et al. teaches that optimal properties of the composition include, the finished gel being clear, the gel having a consistency that allowed it to remain at a vertical surface when applied to the surface, the viscosity of the finished gel also allowing it to remain, and not flow or drop, when it is applied to an underside of a surface, the finished gel also retained its integrity in that it maintained its characteristics when stored at room temperature for days or when place on body surfaces, resisting drying and maintaining its gel properties (column 6 lines 55-65).
King et al. teaches that other agents can be added to the composition to impart additional desirable properties including for example, a vehicle such as water (column 6 lines 12-15).
King et al. does not specifically exemplify a gel formulation containing 3% of chloroprocaine hydrochloride. King et al. does not specifically exemplify a gel formulation containing hydroxyethyl cellulose in an amount of from 1.0% to 1.25%. King does not teach the average molecular weight of hydroxyethyl cellulose and that the composition forms a drop comprising 0.03 to 0.1 g of the gel.
However, it would have been obvious to a person of ordinary skill in the art to prepare a gel formulation comprising any of the local anesthetics disclosed in King et al. including chloroprocaine hydrochloride with a reasonable expectation of similar success. Likewise, it would have been obvious to a person of ordinary skill in the art to prepare a gel local anesthetic formulation comprising any of the suitable gelling agents including hydroxyethylcellulose with a reasonable expectation of similar success.
Thus although King et al. includes chloroprocaine hydrochloride and hydroxyethylcellulose on lists that include other suitable local anesthetics and other suitable gelling agents, respectively, a prima facie case of obviousness can still be established since picking one of a finite number of known solutions to a known problem is prima facie obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
With respect to the amount of chloroprocaine hydrochloride as claimed, King et al. teaches that the effective amount of the local anesthetic ranges from about 0.5% to about 30% by weight based on the total weight of the final composition.
With respect to the amount of hydroxyethylcellulose as claimed, King et al. teaches suitable ranges of gelling reservoir vary from about 0.5% to about 10% by weight based on the total weight of the final composition, wherein the preferred range for cellulose derivatives is 0.5-5% (column 6 lines 1-10).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
In addition, 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.").
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Waite, 168 F.2d 104, 108 (CCPA 1948); In re Scherl, 156 F.2d 72, 74-75 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Swenson, 132 F.2d 1020, 1022 (CCPA 1942); In re Bergen, 120 F.2d 329, 332 (CCPA 1941); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934 (CCPA 1934); In re Lilienfeld, 67 F.2d 920, 924 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); Gentiluomo v. Brunswick Bowling and Billiards Corp., 36 Fed. App'x 433 (Fed. Cir. 2002)(non-precedential)(disagreeing with argument that overlapping ranges were required to find a claim prima facie obvious); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
With respect to the claimed pH range of 2.8 to 3.8 and 3.0 to 3.4, King et al. teaches the pH of the composition is reduced by the use of the acidic visualizing agent, wherein a suitable and effective range of the pH is from about 2 to 5, and preferably around 3, and thus the claimed pH range of the composition is rendered obvious in view of King et al.
Although King does not teach the average molecular weight of hydroxyethyl cellulose and that the composition forms a drop comprising 0.03 to 0.1 g, King et al. teaches that optimal properties of the composition include, the finished gel being clear, the gel having a consistency that allowed it to remain at a vertical surface when applied to the surface, the viscosity of the finished gel also allowing it to remain, and not flow or drop, when it is applied to an underside of a surface, the finished gel also retained its integrity in that it maintained its characteristics when stored at room temperature for days or when place on body surfaces, resisting drying and maintaining its gel properties (column 6 lines 55-65). Thus the teachings of King et al. suggest the use of a high viscosity gelling agent in order to achieve the properties of the composition as described therein.
Ashland teaches Natrosol ™250 Pharm hydroxyethyl cellulose (HEC) available in several grades which differ in their weight average molecular weight and thus in their viscosities measured in aqueous solutions (page 5). HEC products having an average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% is known in the art (Ashland 2018, table 1 page 5). Ashland specifically teaches that higher molecular weight grades of Natrosol ™250 including HX an HHX having an average molecular weight of 1,000,000 and 1,300,000 Da, respectively, are the preferred pharmaceutical gel formers for topical gels (page 25).
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 King et al. which teaches that optimal properties of the composition include, the finished gel being clear, the gel having a consistency that allowed it to remain at a vertical surface when applied to the surface, the viscosity of the finished gel also allowing it to remain, and not flow or drop, when it is applied to an underside of a surface, the finished gel also retained its integrity in that it maintained its characteristics when stored at room temperature for days or when place on body surfaces, resisting drying and maintaining its gel properties; with the teachings of Ashland which teaches that higher molecular weight grades of Natrosol ™250 including HX an HHX having an average molecular weight of 1,000,000 and 1,300,000 Da, respectively, are the preferred pharmaceutical gel formers for topical gels. Thus an ordinary skilled artisan would have been motivated to use high molecular weight HEC products available including HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% in the formulation of King with a reasonable expectation of success to arrive at the instant invention.
With respect to the viscosity of the composition as claimed, since the teachings of King et al. and Ashland render obvious a gel composition comprising the same components as claimed in overlapping amounts, including HEC products having an average molecular weight of 1,000,000 and 1,300,000 Da, 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).
Thus the composition rendered obvious over the prior art teachings will necessarily form a drop comprising from 0.03 to 0.1 g of the topical gel as claimed.
Furthermore, with respect to claims 2 and 30 which claim the drop and the HEC exhibit non-Newtonian pseudo-plastic behavior, said property of the drop and the HEC is rendered obvious since King and Ashland render obvious the use of hydroxyethyl cellulose having the average molecular weight as claimed as the thickening/viscosity agent and thus the composition and HEC rendered obvious over the prior art teachings will necessarily have the same properties as claimed.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 1-2, 5-6, 8-9, 16, 19-26, 30 and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Chynn U.S. Patent No. 6,218,428 B1 (provided on IDS 11/30/2020) in view of Sawaya U.S. Patent No. 5,888,493 (Provided on IDS) and Ashland (2018 Natrosol ™250 Pharm hydroxyethyl cellulose (HEC), formulating elegant liquid and semisolid drug products).
Claims 1-2, 5-6, 8-9,16 and 44-46 of the instant application claim a drop comprising from 0.03 to 0.1 g of a topical gel comprising an acidic aqueous solution of chloroprocaine hydrochloride at a pH of 2.4 to 3.2 admixed with an aqueous matrix of hydroxyethyl cellulose having a viscosity greater than 25,000 cP at 25 °C and a pH optionally greater than 6, wherein: a) the gel comprises 3% chloroprocaine hydrochloride; b) the gel has a pH of 2.8-3.8; c) the matrix viscosity is measured by a BrookField DV III+Pro Spindle 3 at 20 rpm, as described in section 2.2.10 of the European Pharmacopeia 2016 edition; and d) the hydroxyethyl cellulose has an average molecular weight of from 1,000,000 to 1,500,000 Daltons.
Claims 19-26 and 30 of the instant application claim a method of manufacturing a 3% chloroprocaine hydrochloride topical gel forming a drop comprising from 0.03 to 0.1 g of the gel comprising: a) admixing hydroxyethyl cellulose having a weight average molecular weight of from 1,000,000 to 1,500,000 Daltons and water to make an aqueous matrix having an initial viscosity greater than 40,000 cP at 25 °C measured by a BrookField DV III+Pro Spindle 3 at 20 rpm, as described in section 2.2.10 of the European Pharmacopeia 2016 edition; b) thermally sterilizing the aqueous matrix at a temperature of greater than 35 or 40 °C, reducing the viscosity of the aqueous matrix by no more than 40%; c) admixing chloroprocaine hydrochloride with water and hydrochloric acid to prepare an aqueous acidic solution at a temperature of 35 or 40 °C or greater, having a pH of from 2.4 to 3.2;d) filter sterilizing the aqueous acidic solution at a temperature of 35 or 40 °C or greater; e) mixing the aqueous matrix and the aqueous acidic solution to make the gel; and f) filling the gel into containers.
Chynn teaches an ophthalmic composition that combines multiple agents necessary to perform a routine eye examination including a topical local anesthetic, a pupillary dilating agent, and a dye, all in solution which may also include a preservative, a wetting agent, a diluting agent and/or a buffer (abstract). Chynn further teaches that one function of the composition is to anesthetize the cornea to allow for pain relief and that the composition may be used pre-operatively before ophthalmic surgery such as cataract surgery (abstract and column 2 lines 53-55).
Chynn teaches that the local anesthetic is used to anesthetize the front structures of the eye, allowing for their examination and manipulation without discomfort to the patient (column 3 lines 23-25). Examples of useful anesthetics include proparacaine, tetracaine, lidocaine, procaine, hexylcaine, cocaine, bupivacaine, benoxinate, mepivacaine, prilocaine, etidocaine, benzocaine, chloroprocaine, propoxycaine, dyclonine, dibucaine, pramoxine, oxybuprocaine or other anesthetics useful for eye examinations (column 3 lines 25-31). Preferably, the anesthetic should be in an amount between about 0.01% (or 0.01 mg/ml if in solution) and about 10% (or 10 mg/ml if in solution), and more preferably, the anesthetic should be present in an amount between about 0.1% and about 5% (column 3 lines 31-35).
Chynn further teaches that the formulation may further comprise a wetting agent selected from carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol (PVA), hydroxyethylcellulose or other wetting agents as understood by those skilled in the art (column 4 lines 9-13). Preferably, the wetting agent should be in an amount between 0.001% and 10%, more preferably between 0.01% and 5%, and most preferably between 0.1% and 1% of the solution (column 4 lines 13-17).
Chynn further teaches that the formulation may comprise a diluting agent selected from water, distilled water, sterile water, artificial tears or other diluting agents as understood by those skilled in the art (column 4 lines 18-20). Preferably, the diluting agent provides a substantial majority of the volume of the solution (column 4 lines 20-22).
Chynn further teaches that the formulation may comprise additional excipients, additives, and/or buffers (column 4 lines 23-24). Chynn teaches that buffers and other excipients are typically added to adjust the pH of the composition to make it acceptable to the eye and to maximize the efficiency of the components (column 4 lines 24-27). Preferably, the pH of a composition instilled into the eye should be between about 4.0 to about 7.5 (column 4 lines 27-29). Excipients that are suitable to adjust the pH of the composition include hydrochloric acid (column 5 lines 1-17).
Chynn further teaches that it may also be desired to provide an ophthalmic composition that combines some, but not all, of the aforementioned components, for example, diagnostically acceptable amounts of the anesthetic and dilating agent(s) can be combined (without the dye) or diagnostically acceptable amounts of the dye and the dilating agent(s) (without the anesthetic) can also be combined (column 4 lines 37-43). Chynn further teaches that the compositions may be formulated as a solution, ointment, cream, suspension, gel, or sustained release vehicle (column 4 lines 47-49).
Chynn further teaches that the inventive composition can have applications other than in the routine eye exam, for example, the inventive composition may be used before ophthalmic surgery (column 7 lines 13-16). In this application, the inventive composition would both anesthetize the eye and dilate the pupil, thereby permitting many types of ophthalmic surgery, including cataract and retinal surgery (column 7 lines 16-19). The dye component of the inventive composition would be useful to mark the operative eye, and prevent inadvertent operation on the fellow eye (column 7 lines 19-21).
Claims 1-3 and 10-12 of Chynn claim an ophthalmic composition comprising a solution mixture of diagnostically acceptable amounts of a local topical anesthetic and a pupillary dilating agent, wherein the anesthetic is proparacaine, tetracaine, lidocaine, procaine, hexylcaine, cocaine, bupivacaine, benoxinate, mepivacaine, prilocaine, etidocaine, benzocaine, chloroprocaine, propoxycaine, dyclonine, dibucaine, pramoxine, or oxybuprocaine, in an amount of about 0.01% to about 10%, further including a diagnostically acceptable amount of a wetting agent and a diluting agent, wherein the wetting agent is carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol or hydroxyethylcellulose and the diluting agent is water, distilled water, sterile water, or artificial tears, wherein the wetting agent is present in an amount of about 0.001% to about 10%, further including a diagnostically acceptable amount of a buffer to adjust the pH of the solution between about 4.0 to about 7.5. Claim 13 of Chynn claims an ophthalmic composition comprising a diagnostically acceptable amount of a topical local anesthetic, and a pupillary dilating agent, wherein the composition is an ointment, cream, or gel. Claim 28 of Chynn claims a method of treating an eye prior to surgery, comprising the step of applying a topical local anesthetic and a dilating agent to the eye, wherein the anesthetic and the dilating agent are applied together from a single solution mixture.
Thus, Chynn teaches an ophthalmic composition comprising between about 0.1% and about 5% of an anesthetic agent such as chloroprocaine and a wetting agent such as preferably between 0.1% and 1% of hydroxyethylcellulose and water, wherein the pH is about 4.0.
Chynn does not specifically exemplify a formulation comprising chloroprocaine, hydroxyethylcellulose and water. Chynn does not specifically teach a pH of the composition from 2.8-3.8. Chynn does not teach the molecular weight of the HEC to form a drop comprising from 0.03 to 0.1 g of the gel. Chynn does not teach a method of preparing the formulation.
However, it would have been obvious to a person of ordinary skill in the art to select any of the anesthetic agents including chloroprocaine or any of the wetting agents including hydroxyethylcellulose from the lists disclosed in Chynn with a reasonable expectation of similar success.
Thus, although Chynn includes chloroprocaine and hydroxyethylcellulose on lists that include other anesthetic agents and wetting agents, respectively, a prima facie case of obviousness can still be established since picking one of a finite number of known solutions to a known problem is prima facie obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
With respect to the amount of chloroprocaine hydrochloride as claimed, Chynn teaches an amount of the anesthetic agent that overlaps with the amount as claimed
With respect to the amount of hydroxyethylcellulose as claimed, Chynn teaches an amount of the thickening agent that overlaps with the amount of thickening agent as claimed.
With respect to the pH as claimed, Chynn teaches that buffers and other excipients are typically added to adjust the pH of the composition to make it acceptable to the eye and to maximize the efficiency of the components, which is preferably between about 4.0 to about 7.5 (column 4 lines 24-29). A pH of about 4 as taught in Chynn includes amounts less than 4 and thus said pH is very close to the pH of 3.8 and 3.4 as claimed in the instant claims because pH amounts of about 4 as taught in Chynn allows for amounts less than 4 which overlaps with a pH of 3.8 and 3.4 as claimed in the instant claims.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
In addition, 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.").
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Waite, 168 F.2d 104, 108 (CCPA 1948); In re Scherl, 156 F.2d 72, 74-75 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Swenson, 132 F.2d 1020, 1022 (CCPA 1942); In re Bergen, 120 F.2d 329, 332 (CCPA 1941); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934 (CCPA 1934); In re Lilienfeld, 67 F.2d 920, 924 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); Gentiluomo v. Brunswick Bowling and Billiards Corp., 36 Fed. App'x 433 (Fed. Cir. 2002)(non-precedential)(disagreeing with argument that overlapping ranges were required to find a claim prima facie obvious); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
With regard to the molecular weight of the HEC to form a drop comprising from 0.03 to 0.1 g of the gel, Sawaya specifically provides motivation to use a high viscosity (high molecular weight) cellulose derivative such as HEC in the formulation of the Chynn et al. Sawaya specifically teaches preparing high viscosity ophthalmic gels using a gelling agent consisting essentially of cellulose or a water soluble cellulose derivative (abstract). Sawaya specifically teaches the need for a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer, and that is capable of controlled release of a pharmaceutically active substance, which is solved by a formulation adapted for ophthalmic use containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel wherein the gel has a viscosity of from 75,000 to 3,000,000 centipoise at a temperature of 22° to 30°C., preferably 25°C., and is substantially free of an oil phase and the gelling agent consists essentially of cellulose or a water soluble cellulose derivative (column 2 lines 8-27).
Sawaya further teaches other advantages including: upon administration, aqueous eye fluids mix with the gel, resulting in immediate release of the active agent; a predetermined dose reaches the site being treated; a much higher percentage of the dose is maintained in the eye than with a conventional ophthalmic ointment or solution; the formulation also allows an amount of active to be applied that slowly spreads over the eye; and the gel of the invention can be formulated to be substantially clear, thereby avoiding or decreasing blurring associated with conventional ophthalmic products (column 2 lines 45-59). Sawaya further teaches the formulation of the invention provides a safe means for time release of actives into the eye, wherein the release rate depends on the viscosity of the gel, i.e., higher viscosity results in slower release (column 3 lines 1-6).
Sawaya further teaches the newly added properties of the formulation as currently claimed since Sawaya teaches that the formulation of the invention can be placed in any desired dispensing device suitable for an ophthalmic formulation, wherein the device can be an ophthalmic delivery system, such as a sterile ophthalmic tube, e.g., a conventional 3.5 g tube having an ophthalmic tip and containing the ophthalmic formulation of the invention, or a sterile single use container containing 0.2-0.5 g of the formulation which would result in a drop containing the amount as claimed (column 3 lines 38-44).
Sawaya specifically teaches the use of high viscosity cellulose based agents are preferred, wherein such agents have a higher number of substituents, such as methoxy, ethoxy, hydroxy propyl and carboxy substituents, attached to the cellulose backbone than low viscosity cellulose based agents, specifically hydroxyethyl cellulose (column 3 line 45-column 4 line 5).
Thus the teachings of Sawaya specifically teach and suggest the use of high viscosity cellulose derivatives in topical ophthalmic formulations to produce formulations having improved properties including a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer.
Prior to the effective filing date of the claimed invention, high viscosity hydroxyethylcellulose gelling agents were known in the art. Ashland teaches that Natrosol ™250 Pharm hydroxyethyl cellulose (HEC) was available in several grades which differ in their weight average molecular weight and thus in their viscosities measured in aqueous solutions (page 5). HEC products having weight average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% was known in the art (Ashland 2018, table 1 page 5).
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 Chynn et al. which teaches an ophthalmic composition comprising between about 0.1% and about 5% of an anesthetic agent such as chloroprocaine and a wetting agent such as preferably between 0.1% and 1% of hydroxyethylcellulose and water, wherein the formulation may be in the form of a topical ophthalmic gel; with the teachings of Sawaya which teaches the need for a safe ophthalmic formulation that is not easily expelled from the eye after administration, that delivers a precise dosage, that is easy to administer, and that is capable of controlled release of a pharmaceutically active substance, which is solved by a formulation adapted for ophthalmic use containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel wherein high viscosity cellulose based agents are preferred, wherein such agents have a higher number of substituents, such as methoxy, ethoxy, hydroxy propyl and carboxy substituents, attached to the cellulose backbone than low viscosity cellulose based agents, specifically hydroxyethyl cellulose; and the teachings of Ashland which teaches high molecular weight HEC products available having high viscosity, including HEC products having an average molecular weight of 1,000,000 and 1,300,000 Da. Thus, based on the teachings of Sawaya, a person of ordinary skill in the art would have been motivated to use high molecular weight HEC products available including HEC products having an average molecular weight of 1,000,000 and 1,300,000 Da at a recommended concentration of 1% as taught by Ashland, in the formulation of Chynn with a reasonable expectation of success and thus arriving at the instant invention.
With respect to the method of preparing the formulation Sawaya teaches an ophthalmic formulation containing at least one pharmaceutically active substance, purified water, and an amount of gelling agent effective to form an aqueous gel, wherein the gel has a viscosity of from 75,000 to 3,000,000 centipoise, does not contain an oil phase, the pharmaceutically active substance is solubilized in the formulation, and the gelling agent consists essentially of cellulose or a water soluble cellulose derivative (abstract and column 2 lines 15-27). Sawaya teaches that the ophthalmic formulation improves over existing oil based formulations and solutions because upon administration, aqueous eye fluids mix with the gel, resulting in immediate release of the active agent, and a predetermined dose reaches the site being treated, and a much higher percentage of the dose is maintained in the eye than with a conventional ophthalmic ointment or solution (column 2 lines 46-53). The formulation also allows an amount of active to be applied that slowly spreads over the eye, it has been determined that the gel can be formulated to be substantially clear, thereby avoiding or decreasing blurring associated with conventional ophthalmic products (column 2 lines 54-59).
Sawaya teaches that the procedure for viscosity measurement utilizes a Brookfield Digital Viscometer (Model DV-l (DVM)), equipped with a helipath stand and an LV attachment (column 9 lines 30-43). Sawaya teaches the use of cellulose derivatives including hydroxyethyl cellulose (column 3 lines 45-65).
Sawaya teaches a method of preparing an ophthalmic gel comprising an active ingredient by combining the active ingredient and pH adjusting agents in water and mixing and dissolving until a clear solution was obtained. The solution was then sterilized by membrane filtration (0.2 microns). Sawaya further teaches that purified water was heated to 90° C and the cellulose derivative was added and mixed until it was uniformly dispersed. While mixing in a pressure vessel, the mixture was sterilized at 121° C for 30-45 minutes. The temperature was brought down to 50°-55°C. The active agent solution was then aseptically added to the cellulose solution and mixing was continued, and the temperature lowered to 25°-30°C wherein the gel resulted that was used to aseptically fill pre-sterilized 3.5 gram ophthalmic tubes. See column 6 Example 2. Sawaya further teaches that the pH of the cellulose solution was 7.4 and the viscosity was measured (column 8 lines 63-64).
Thus Sawaya teaches the same procedure as claimed for preparing an ophthalmic topical gel formulation.
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 prepare the formulation of Chynn according to procedures well-known in the art such as the procedures of Sawaya to arrive at the instant invention. Since Sawaya et al. teaches the benefits of this procedure as detailed above, a person of ordinary skill in the art would have been motivated to use the procedure of Sawaya et al. in preparing the ophthalmic formulation comprising chloroprocaine rendered obvious in view of the teachings of Chynn with a reasonable expectation of success to arrive at the instant invention.
With respect to the viscosity of the composition as claimed, since Chynn, Sawaya and Ashland renders obvious a gel composition comprising the same components in overlapping amounts, including HEC products having an average molecular weight of 1,000,000 and 1,300,000 Da, 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).
Thus the composition rendered obvious over the prior art teachings will necessarily form a drop comprising from 0.03 to 0.1 g of the topical gel as claimed.
Furthermore, with respect to claims 2 and 30 which claim the drop and the HEC exhibits non-Newtonian pseudo-plastic behavior, said property of the drop and HEC is rendered obvious since Chynn, Sawaya and Ashland render obvious the use of hydroxyethyl cellulose having the average molecular weight as claimed as the thickening/viscosity agent and thus the composition and HEC rendered obvious over the prior art teachings will necessarily have the same properties as claimed.
With respect to new claims 45-47 Chynn specifically teaches ophthalmic formulations which must be sterile in order to administer to the eye. Furthermore, the process of preparing the formulation rendered obvious over the teachings of Sawaya specifically teaches preparing a sterile topical ophthalmic formulation and placing the formulation in a sterile ophthalmic tube as detailed above and claims 6, 18 and 26 of Sawaya.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 3, 4, 7, 10-15, 17, 18, 27-29, 31-43 are canceled. Claims 1, 2, 5, 6, 8, 9, 16, 19-26, 30 and 44-46 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM