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 . 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.
Claims Status
Claims 1-6, and 9-16 are pending.
Claim 1 has been amended.
Claim 16 is new.
Withdrawn Rejections
The provisional rejection of claims 1-4 and 6-14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, and 6-8 of copending Application No. 17/924,651 (US 20230181460) in view of Forman et al (US 20180049981) is hereby withdrawn due to amendment.
The rejection of claims 1-6 and 9-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph due to the addition of new matter is hereby withdrawn due to argument.
The rejection of claim(s) 1-6, 9, and 12-15 under 35 U.S.C. 103 as being unpatentable over Forman et al (US 20180049981, cited by applicants) in view of Kreitmeier et al (EP 1275376, cited by applicants), Ames et al (Clin Investig (Lond) 2015) 5(3) p267-285, previously cited), and Alvarez-Nunez et al (Int. J. Pharmeceut. (2000) 200 p217-222) is hereby withdrawn due to amendment.
The rejection of claim(s) 1-6 and 9-15 under 35 U.S.C. 103 as being unpatentable over Forman et al (US 20180049981, cited by applicants) in view of Kreitmeier et al (EP 1275376, cited by applicants), Ames et al (Clin Investig (Lond) 2015) 5(3) p267-285), ABAK sales literature (2015), and Alvarez-Nunez et al (Int. J. Pharmeceut. (2000) 200 p217-222) is hereby withdrawn due to amendment.
New Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6 and 9-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, and claims dependent on it, has a limitation of droplet size in an emulsion. However, emulsions are thermodynamically unstable, and so the particle size will change with time (Akbari et al, Int. J. Innov. Res. Sci. Studies (2018) 1(1) p11-17, p13, 6th paragraph). This means that, if the particle size is measured at different times, it will not necessarily be the same. But applicants have not defined when the particle size is measured. If the emulsion meets the claim limitations at one time, but not another, it is not clear if the limitation is met.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
first rejection
Claim(s) 1-6, 9, and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Forman et al (US 20180049981, cited by applicants) in view of Kreitmeier et al (EP 1275376, cited by applicants), Ames et al (Clin Investig (Lond) 2015) 5(3) p267-285, previously cited), Alvarez-Nunez et al (Int. J. Pharmeceut. (2000) 200 p217-222), and Masucci et al (Processing (2017)) with evidentiary support from Lubrizol sales literature (2024, previously cited). Note that Kreitmeier et al is in German. A machine translation was relied upon for this rejection; all citations to locations in the document refer to the machine translation.
Foreman discusses O/W emulsions for pharmaceutical formulations (title). Among the drugs that can be used is cyclosporine (paragraph 20). An aqueous mixture containing a polyol, a non-ionic surfactant, and water is mixed with an oil phase comprising the pharmaceutical ingredient and a long chain triglyceride, which is homogenized with a homogenizer and a microfluidizer (paragraph 42). Among the polyols that can be used is glycerol (paragraph 53), and the surfactant can be polysorbate 80 (paragraph 56). Suitable long chain triglycerides include castor oil (paragraph 68). This leads to a concentrated formulation, which is diluted with a solution to adjust the viscosity, pH, concentration, and osmolarity (paragraph 86), which could include a polymeric stabilizer (paragraph 87). The polymer is very general (paragraph 95). The microemulsion can be sterile filtered prior to combining it with the sterilized polymer solution (paragraph 92). Droplet size is preferably between 50 and 120 nm (paragraph 27). Note that there is no mention of a preservative in the formulation.
The difference between this reference and the instant claims is that this reference does not discuss aseptically filling an appropriate ophthalmic container, does not discuss carbomer copolymer type A, heat sterilization, multiuse containers, or drop volume, nor does it give the claimed concentrations or particle sizes.
Kreitmeier et al also discusses ocular formulations (paragraph 1). Viscosity is modulated using a gel emulsion (paragraph 18), using a carbomer type polymer, such as 971P and 981 (paragraph 20), which, as evidence by the Lubrizol sales literature, are carbomer homopolymer type a polymers (table 3, p6). The carbomer is dissolved in water, along with ingredients to render the final solution isotonic (solution A). Oil phase is homogenized to make solution B (paragraph 35), along with a pH modulating solution (solution C) (paragraph 34). These solutions can be sterilized by either autoclaving or membrane filtration, as is suitable (paragraph 36). These solutions are then mixed together (paragraph 35). Sodium hydroxide is typically used for adjusting the pH of such formulations (paragraph 29), and the examples all have a pH of around 7 (tables 1-4). This reference discusses a very similar process to that of Forman et al, with emphasis on different details.
Ames et al discuss cyclosporine formulations for treatment of dry eye (title). Only one medication has been approved by the FDA for this condition (abstract). This material, Restasis, is 0.05% CsA in an emulsion with glycerine (2.2%), castor oil (1.25%), polysorbate 80 (1.00%), carbomer copolymer type A (0.05%), and purified water, with pH adusted with sodium hydroxide (3d page, 5th paragraph). This reference discusses an FDA approved cyclosporine formulation for treatment of an eye disorder.
Alvarez-Nunez et al discusses the ability of polysorbate 80 to solubilize drugs and the relationship between that and other solubility parameters (title). In general, there is a linear relationship between the concentration of surfactant and the total amount of material that can be solubilized (p217, 2nd column, 1st paragraph, continues to p218, 1st column, 1st paragraph). This relationship was demonstrated for a large number of different drugs (table 1, p230). This reference shows that the effects of changing the concentration of surfactant.
Masucci et al discusses emulsions (title). Oil droplet size must be reduced to a point where the condensed phase droplets do not travel due to gravity/buoyancy (5th page, 3d paragraph). Lower limit is based on the concentration of the emulsifier; as particles get smaller, there is more surface area for the emulsifier to stabilize. If there is not enough emulsifier for the surface area, the emulsion will be unstable (7th page, 3d paragraph). The actual droplet size is dependent on mixing (7th page, 4th paragraph). This reference discusses the relationship between droplet size and stability in emulsions.
Therefore, it would be obvious to use the methodology of Kreitmeier et al, to fill in the gaps of the process of Forman et al, such as the polymer, the pH modulation agent, sterilization method, and other odds and ends. This is a simple substitution of one known element (the unmentioned elements of Forman et al) for another (the elements of Kreitmeier et al) yielding expected results (cyclosporine formulations). As both references discuss very similar multisolution methods to make ocular emulsions, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use the concentrations of the FDA approved formulation for at least a starting point in optimization, as these concentrations were successful enough to be used in a composition for the same purpose. As this is an FDA approved formulation, meaning it has been tested for safety and efficacy, an artisan in this field would use these concentrations with a reasonable expectation of success. Note that differences in concentration are not a patentable distinction absent secondary considerations (MPEP2144.05.II). and Alvarez-Nunez et al demonstrates that a person of skill in the art would know how to change the concentration of the surfactant while maintaining emulsion stability.
Finally, it would be obvious to optimize the mixing of the emulsion of step a to optimize the particle size for maximum stability, as discussed by Masucci et al. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.”) (MPEP2144.05.II). Alternatively, as step c involves further mixing, which will affect the droplet size, any droplet size at step a will be equivalent, because it will not change the final droplet size, which is set by the mixing at step c.
Forman et al discuss a process where cyclosporine in an oil phase is mixed with water to form an emulsion and sterilized, and a sterile polymer (viscosity modifying agent) solution is mixed with the cyclosporine emulsion. The ABAK sales literature renders obvious placing this formulation in their bottles (an appropriate ophthalmic container). Ames et al discuss an approved formulation with concentrations that are similar to those claimed by applicants. Masucci et al renders obvious the particle size at step a. Thus, the combination of references renders obvious claim.
Both Forman et al and Kreitmeier et al discuss a high pressure homogenizer, rendering obvious claims 2 and 6.
Forman et al discusses filtering the emulsion. Kreitmeier et al discusses either filtering or autoclaving the solutions that make up their formulation. Thus, the combination of references renders obvious claims 3 and 5.
Kreitmeier et al discuss using one of a handful of polymers, including two that are carbomer copolymer type A, and Ames et al discusses a formulation with this polymer, rendering obvious claim 4.
Kreitmeier et al mention adjusting the pH with sodium hydroxide, and have formulations with pH values around pH 7, rendering obvious claim 9.
Forman et al discuss droplet sizes in the same range of sizes as applicants, rendering obvious claim 12.
The droplet size is required to give an appropriate dose of cyclosporine for whatever disorder is to be treated. It is thus a function of the cyclosporine concentration and the patient population, and so is subject to optimization. A person of skill in the art would reasonably optimize the droplet size to give an appropriate dosage. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.”) (MPEP2144.05.II). Thus, the combination of references renders obvious claims 13 and 14.
Alvarez-Nunez et al demonstrate that a person of skill in the art would know how to modify the surfactant concentration without compromising stability, allowing different surfactant concentrations, and rendering obvious claim 16.
second rejection
Claim(s) 1-6 and 9-16 are rejected under 35 U.S.C. 103 as being unpatentable over Forman et al (US 20180049981, cited by applicants) in view of Kreitmeier et al (EP 1275376, cited by applicants), Ames et al (Clin Investig (Lond) 2015) 5(3) p267-285), Masucci et al (Processing (2017)), ABAK sales literature (2015), and Alvarez-Nunez et al (Int. J. Pharmeceut. (2000) 200 p217-222), with evidentiary support from Lubrizol sales literature (2024). Note that Kreitmeier et al is in German. A machine translation was relied upon for this rejection; all citations to locations in the document refer to the machine translation.
The teachings of Forman et al, Kreitmeier et al, Ames et al, Alvarez-Nunez et al, and Masucci et al were given above, and will not be repeated here. Please note that these references render obvious claims 1-6, 9, and 12-16.
The ABAK sales literature discusses a preservative free multidose bottle (5th page, 4th paragraph) for use in eye drop formulations (5th page, 1st paragraph). This avoids the high cost of single dose container formulations used to avoid preservatives (12th page, 2nd column, 3d and 4th paragraphs). The ABAK device has a filter to prevent contamination of the bulk solution (p20, 1st column, 2nd paragraph). This reference discusses a multi use ocular device with an integral bacterial protection system (the filter).
Therefore, it would be obvious to use the ABAK bottles from the ABAK sales literature, to provide a multiuse sterile protected formulation and avoid the cost of single use devices, as discussed by the ABAK sales literature. As this device is intended for eye drops, an artisan in this field would attempt this process with a reasonable expectation of success.
the ABAK sales literature renders obvious preservative free ocular formulations in multidose bottles, rendering obvious claims 10 and 11.
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 1-4 and 6-14 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, and 6-8 of copending Application No. 17/924,651 (US 20230181460) in view of Forman et al (US 20180049981, cited by applicants) and Masucci et al (Processing (2017)).
Competing claim 1 claims preservative free emulsions of cyclosporine. Competing claims 3 and 4 specify that the formulation comprises glycerin, castor oil, polysorbate 80, and carbomer copolymer type A, with the pH adjusted with sodium hydroxide. Competing claims 2 and 5 specify concentration ranges of the components that overlap those of the examined claims. Competing claim 6 specifies the same pH as examined claim 9. Competing claim 7 specifies an eye drop formulation, while competing claim 8 specifies a multi-use container with an integral bacterial protection system, identically with examined claim 11.
The difference between the competing claims and the examined claims is that the competing claims do not specify how the material is made, or the particle size at step a.
Foreman et al discuss O/W emulsions for pharmaceutical formulations (title). Among the drugs that can be used is cyclosporine (paragraph 20). An aqueous mixture containing a polyol, a non-ionic surfactant, and water is mixed with an oil phase comprising the pharmaceutical ingredient and a long chain triglyceride, which is homogenized with a homogenizer and a microfluidizer (paragraph 42). Among the polyols that can be used is glycerol (paragraph 53), and the surfactant can be polysorbate 80 (paragraph 56). Suitable long chain triglycerides include castor oil (paragraph 68). This leads to a concentrated formulation, which is diluted with a solution to adjust the viscosity, pH, concentration, and osmolarity (paragraph 86), which could include a polymeric stabilizer (paragraph 87). The polymer is very general (paragraph 95). The microemulsion can be sterile filtered prior to combining it with the sterilized polymer solution (paragraph 92). Droplet size is preferably between 50 and 120 nm (paragraph 27). Note that there is no mention of a preservative in the formulation.
Masucci et al discusses emulsions (title). Oil droplet size must be reduced to a point where the condensed phase droplets do not travel due to gravity/buoyancy (5th page, 3d paragraph). Lower limit is based on the concentration of the emulsifier; as particles get smaller, there is more surface area for the emulsifier to stabilize. If there is not enough emulsifier for the surface area, the emulsion will be unstable (7th page, 3d paragraph). The actual droplet size is dependent on mixing (7th page, 4th paragraph). This reference discusses the relationship between droplet size and stability in emulsions.
Therefore, it would be obvious to use the process of Forman et al to make the formulation of the competing claims, as a simple substitution of one known element (the method of Forman et al) for another (the unspecified method of the competing claims) yielding expected results (the formulation of the competing claims). As Forman et al describes a fairly general method using very similar materials as the competing claims, an artisan in this field would attempt this method with a reasonable expectation of success.
In addition, it would be obvious to optimize the mixing of the emulsion of step a to optimize the particle size for maximum stability, as discussed by Masucci et al. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.”) (MPEP2144.05.II). Alternatively, as step c involves further mixing, which will affect the droplet size, any droplet size at step a will be equivalent, because it will not change the final droplet size, which is set by the mixing at step c.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants argue that this rejection be held in abeyance as the examined claims were filed first. However, until this rejection is overcome, it will remain valid.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658