DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application is a continuation of application no. 16/22,654, which ultimately claims priority to provisional application 61/085,594, with a filing date of 8/1/2008. The instant claims are examined with an effective filing date of 8/1/2008.
Status of the Claims
Claims 21-28 are pending and under current examination.
Claim Rejections - 35 USC § 112
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 21-28 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 21 recites the limitation “0.5 mg per mL of clevidipine”. This renders the claim indefinite because it is not clear to what volume the clevidipine is relative to.
Claim 21 recites the limitation “20% soybean oil”. This renders the claim indefinite because it is not clear what property is described by the percentage (i.e., weight or volume).
Claim 21 recites the limitation “500/8000psi”. This renders the claim indefinite because it is not clear if the pressure is a fraction (500/8000) or a range (500-8000).
Claim 21 recites the limitation “the amount of H324/78….is less than…on a weight-to-weight basis to clevidipine”. This renders the claim indefinite because it is not clear if the amount of H324/78 described by the limitation is present in the pharmaceutical composition embraced by the claims. This may be obviated by amending the claim to read “the amount of H324/78 present in the emulsion…”.
Regarding claims 22-28, claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 21-22 and 25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) in view of Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000), as evidenced by PubChem (Clevidipine, available 8/8/2005) and Zhang et. al. (Iowa State University Animal Industry Report, available 2006).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 21 and 22, Andersson teaches an oil-in-water emulsion for intravenous administration (Abstract) comprising butyroxymethyl methyl 4-(2',3'- dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate (col. 4 lines 12-14), also known as clevidipine (see PubChem, pg. 1 Synonyms and pg.4, 2.1.2 IUPAC name), a lipid phase, an emulsifier, and water (col. 1 lines 47-50). The preferred lipid phase is 10-20% soybean oil (col. 5 lines 30-31) and the preferred emulsifier is egg lecithin (col. 5 line 45). The emulsion may also contain tonicity modifying agents such as glycerol (col. 5 line 50) and pH-adjusting agents such as sodium hydroxide (col. 6 line 67). The composition may contain 0.5mg/mL clevidipine (Example 2). Zhang teaches that egg lecithin contains two types of phospholipids (pg. 1, Introduction).
The emulsion can be prepared by dissolving clevidipine in the lipid phase, optionally under heating. The emulsifier is dispersed or dissolved in the water phase or in the lipid phase. The tonicity agent may be dispersed in the water phase. The water phase is added into the lipid phase or vice versa. Preferably, the mixture is heated and a coarse emulsion is prepared with a high shear mixer. The coarse emulsion is processed by a high-pressure homogenizer. pH may be adjusted (col. 5 line 62-col. 6 line 6). In an exemplary preparation process, the mixture of water phase and lipid phase is heated to approximately 60oC (col. 6 line 21). There are no significant changes in the stability of prepared emulsions except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67). The clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58).
Regarding claim 25, Anderson teaches that there are no significant changes in the stability of autoclaved and non-autoclaved emulsions studied for 2 months except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 21 and 22, Andersson does not teach a specific temperature range for mixing and heating the various components and phases of the emulsion, a specific pH of the resultant solution, a homogenization pressure or temperature, or a weight percentage of H324/78 present in the resultant composition. However, this deficiency is cured by Floury.
Floury teaches that the increase in pressure level permits to reduce the droplet size of the emulsions produced and then to improve shelf life of the products by reducing creaming rate. In addition to the reduction of the mean droplet diameter of emulsions, ultra high-pressure homogenization can also deflocculate clusters of primary fat globules, and dispersing agglomerates uniformly. High-pressure homogenization is also expected to increase the surface activity of the emulsifying molecules and may improve the efficiency of the product (pg. 127, Introduction). Temperature can influence the size of the droplets produced during homogenization in a number of ways. The viscosity of both the oil and aqueous phases is temperature-dependent and decreases with increasing the temperature. Consequently, the minimum droplet size that can be produced may be altered because of a variation of the viscosity ratio. Heating an emulsion usually cause a slight linear reduction in the interfacial tension between the oil and water phases, which would be expected to facilitate the production of small droplets (pg. 130, 3.1 Theoretical considerations on the effect of temperature on droplets sizes).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 21, the pressure and temperature of the components during preparation of an emulsion is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pressure and temperature in order to best achieve the desired results as such would provide advantageous droplet size reduction. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Floury teaches that the homogenization pressure and temperature has a direct effect on the droplet size the resultant emulsion. The Examiner considers it prima facie obvious to optimize the pressure and temperature of the emulsion components, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the pressure and temperature would have a direct effect on the droplet size of the emulsion and therefore be an optimizable variable.
Furthermore, the pH of the composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pH in order to best achieve the desired results as such would provide advantageous stability of the composition. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Andersson teaches that there are no significant changes in the stability of prepared emulsions except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67). The Examiner considers it prima facie obvious to optimize the pH of the composition, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the pH of the composition would have a direct effect on the stability of the composition and therefore be an optimizable variable.
Regarding the order of process steps as specified in the instant claim 21, the Examiner draws attention to MPEP 2144.04(IV)(C), which states: “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results” and “any order of mixing ingredients is prima facie obvious”. Please also refer to MPEP 2111.01(II), which states: “it [is] improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order”. The Examiner therefore considers to order of performing steps taught by Andersson to read on the limitations of the instant claims.
Regarding the amount of H324/78 present in the composition as specified in claims 21 and 22, the amount of H324/78 present in the composition reflects the amount of clevidipine degradation due to light exposure and minimizing light exposure is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal concentration in order to best achieve the desired results as such would minimize degradation of clevidipine due to light exposure. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Andersson teaches that the clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58) and that there are no significant changes in the stability of prepared emulsions except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67). The instant specification defines H324/78 as a degradation product of clevidipine resulting from light exposure ([9] of the instant specification). The Examiner considers it prima facie obvious to optimize the amount of degradation product present in the composition, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the amount of light and oxygen exposure would have a direct effect on the amount of degradation product present in the composition and therefore be an optimizable variable.
Alternatively, regarding the amount of H324/78 present in the composition as recited in claims 21 and 22, although Andersson does not disclose the amount of H324/78 present in the composition as disclosed in the present claims, based on the substantially identical process using identical components, the Examiner has a reasonable basis to believe that the properties claimed in the present invention are inherent in the composition disclosed by Andersson. Because the PTO has no means to conduct analytical experiments, the burden of proof is shifted to the Applicant to prove that the properties are not inherent. ““[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).” See MPEP § 2112.
Claims 23-24 and 26-28 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) in view of Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000), as applied to claims 21-22, and 25 above, and further in view of Fennimore (U.S. Patent No. 4,150,744, issue date: 4/24/1979), as evidenced by PubChem (Clevidipine, available 8/8/2005) and Zhang et. al. (Iowa State University Animal Industry Report, available 2006).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 23-24 and 28, Andersson teaches the relevant limitation of claim 21 above. Andersson also teaches that the clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58).
Regarding claims 26 and 27, Andersson teaches that the emulsion can be filtered before being filed into suitable dosage units, often with nitrogen gassed top space (col. 6 lines 5-7).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 23-24, 26, and 28, Andersson does not teach a darkened container or secondary packaging. However, this deficiency is cured by Fennimore.
Fennimore teaches that light and oxidation can be prevented from damaging pharmaceutical solutions by packaging in opaque containers, such as metal containers (col. 1 lines 31-32). Fennimore also teaches a sealed light-tight gas-impermeable envelope for packaging a liquid-retentive vessel that contains a light-sensitive and oxygen sensitive liquid (col. 2 lines 53-62). The envelope resists entry of oxygen and light and loss of water vapor, thereby rendering the combination storable for long periods (col. 2 lines 66-68).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 23-24, 26, and 28, it would have been prima facie obvious to one of ordinary skill in the art of filing to package the clevidipine emulsion of Andersson in the light-tight packaging of Fennimore. One would have understood in view of Andersson that clevidipine is sensitive to hydrolysis and light-degradation and in view of Fennimore that opaque containers and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. One of ordinary skill in the art would have been capable of applying this known technique (opaque bottles and light-tight envelopes) to a known device ready for improvement (light-sensitive clevidipine emulsions) and the results would have been predictable to one of ordinary skill in the art (increased stability of the clevidipine emulsion that is protected from light and oxidative damage). The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Fennimore teaches that opaque bottles and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. See MPEP 2143 (I) (D).
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 21-22 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,058,672 in view of Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia, the claims of the ‘672 patent embrace a method of preparing and storing a pharmaceutical composition comprising heating an oil to between to about 70oC to about 82oC, adding to the heated oil clevidipine and heating the mixture to about 78oC to about 82oC, adding to the mixture egg yolk phospholipids, and adding an aqueous phase. The aqueous phase consists essentially of glycerin and the pH is adjusted to about 6 to about 8.8. The specification of the ‘672 patent teaches that each mL may contain 0.5 mg clevidipine in approximately 20% soybean oil emulsion for intravenous administration (col. 4 lines 50-54). Sodium hydroxide may be used to adjust the pH (col. 12 line 35). The Examiner has relied upon the specification to delineate the scope of the invention embraced by the ‘672 patent, consistent with the decision in Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. U.S. Court of Appeals Federal Circuit, 95 USPQ2d 1797.
Regarding the amount of H324/78 present in the composition as recited in the instant claims 21 and 22, although the claims of the ‘672 patent do not disclose all the characteristics and properties of the composition disclosed in the present claims, based on the substantially identical process using identical components, the Examiner has a reasonable basis to believe that the properties claimed in the present invention are inherent in the composition disclosed by the claims of the ‘672 patent. Because the PTO has no means to conduct analytical experiments, the burden of proof is shifted to the Applicant to prove that the properties are not inherent. ““[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).” MPEP § 2112
The claims of the ‘672 patent do not teach a temperature of the aqueous phase or a temperature or pressure of homogenization. However, this deficiency is cured by Floury. Floury teaches that the increase in pressure level permits to reduce the droplet size of the emulsions produced and then to improve shelf life of the products by reducing creaming rate. In addition to the reduction of the mean droplet diameter of emulsions, ultra high-pressure homogenization can also deflocculate clusters of primary fat globules, and dispersing agglomerates uniformly. High-pressure homogenization is also expected to increase the surface activity of the emulsifying molecules and may improve the efficiency of the product (pg. 127, Introduction). Temperature can influence the size of the droplets produced during homogenization in a number of ways. The viscosity of both the oil and aqueous phases is temperature-dependent and decreases with increasing the temperature. Consequently, the minimum droplet size that can be produced may be altered because of a variation of the viscosity ratio. Heating an emulsion usually cause a slight linear reduction in the interfacial tension between the oil and water phases, which would be expected to facilitate the production of small droplets (pg. 130, 3.1 Theoretical considerations on the effect of temperature on droplets sizes).
The pressure and temperature of the components during preparation of an emulsion is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pressure and temperature in order to best achieve the desired results as such would provide advantageous droplet size reduction. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Floury teaches that the homogenization pressure and temperature has a direct effect on the droplet size the resultant emulsion. The Examiner considers it prima facie obvious to optimize the pressure and temperature of the emulsion components, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the pressure and temperature would have a direct effect on the droplet size of the emulsion and therefore be an optimizable variable.
Claims 23-24 and 26-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,058,672 in view of Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000), as applied to claims 21-22 and 25 above, and further in view of Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) and Fennimore (U.S. Patent No. 4,150,744, issue date: 4/24/1979).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia, the claims of the ‘672 patent embrace the relevant limitations as described above. The claims of the ‘672 patent do not teach a darkened container, a secondary packaging, or an inert gas. However, this deficiency is cured by Andersson and Fennimore.
Andersson teaches an oil-in-water emulsion for intravenous administration (Abstract) comprising butyroxymethyl methyl 4-(2',3'- dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate (col. 4 lines 12-14), also known as clevidipine. The clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58). Fennimore teaches that light and oxidation can be prevented from damaging pharmaceutical solutions by packaging in opaque containers, such as metal containers (col. 1 lines 31-32). Andersson also teaches that the emulsion can be filtered before being filed into suitable dosage units, often with nitrogen gassed top space (col. 6 lines 5-7). Fennimore also teaches a sealed light-tight gas-impermeable envelope for packaging a liquid-retentive vessel that contains a light-sensitive and oxygen sensitive liquid (col. 2 lines 53-62). The envelope resists entry of oxygen and light and loss of water vapor, thereby rendering the combination storable for long periods (col. 2 lines 66-68).
It would have been prima facie obvious to one of ordinary skill in the art of filing to package the clevidipine emulsion of the claims of the ‘672 patent in the light-tight packaging of Fennimore. One would have understood in view of Andersson that clevidipine is sensitive to hydrolysis and light-degradation and that stable emulsions comprising clevidipine may be purged with a nitrogen headspace. One would have understood in view of Fennimore that opaque containers and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. One of ordinary skill in the art would have been capable of applying this known technique (opaque bottles, light-tight envelopes, and nitrogen gassed top space) to a known device ready for improvement (light-sensitive clevidipine emulsions) and the results would have been predictable to one of ordinary skill in the art (increased stability of the clevidipine emulsion that is protected from light and oxidative damage). The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Fennimore teaches that opaque bottles and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. See MPEP 2143 (I) (D).
Claims 21-22 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-8 of U.S. Patent No. 8,658,676,
claims 1-12 of U.S. Patent No. 10,010,537,
and claims 1-7 of U.S. Patent No. 11,103,490,
in view of Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) and Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia, the claims of the ‘676, ‘537, and ‘490 patents embrace a pharmaceutical formulation comprising clevidipine, soybean oil, egg yolk phospholipids, a tonicity modifier, and water. The pH is about 6.0 to about 8.8. The tonicity modifier may be glycerin, the pH adjuster may be sodium hydroxide, and soybean oil may be present at about 2 to about 30% w/v. The composition may contain 0.05 % clevidipine (see Table 7 of the ‘676 patent and Table 7 of the ‘490 patent). The Examiner has relied upon the specification to delineate the scope of the invention embraced by the ‘676 and ‘490 patents, consistent with the decision in Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. U.S. Court of Appeals Federal Circuit, 95 USPQ2d 1797.
The claims of the 676, ‘537, and ‘490 patents do not embrace a process for preparing the emulsion. However, this deficiency is cured by Andersson and Floury. Andersson teaches an oil-in-water emulsion for intravenous administration (Abstract) comprising butyroxymethyl methyl 4-(2',3'- dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate (col. 4 lines 12-14), also known as clevidipine (see PubChem, pg. 1 Synonyms and pg.4, 2.1.2 IUPAC name), a lipid phase, an emulsifier, and water (col. 1 lines 47-50). The preferred lipid phase is 10-20% soybean oil (col. 5 lines 30-31) and the preferred emulsifier is egg lecithin (col. 5 line 45). The emulsion may also contain tonicity modifying agents such as glycerol (col. 5 line 50) and pH-adjusting agents such as sodium hydroxide (col. 6 line 67). The composition may contain 0.5mg/mL clevidipine (Example 2).
The emulsion can be prepared by dissolving clevidipine in the lipid phase, optionally under heating. The emulsifier is dispersed or dissolved in the water phase or in the lipid phase. The tonicity agent may be dispersed in the water phase. The water phase is added into the lipid phase or vice versa. Preferably, the mixture is heated and a coarse emulsion is prepared with a high shear mixer. The coarse emulsion is processed by a high-pressure homogenizer. pH may be adjusted (col. 5 line 62-col. 6 line 6). In an exemplary preparation process, the mixture of water phase and lipid phase is heated to approximately 60oC (col. 6 line 21). There are no significant changes in the stability of prepared emulsions except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67). The clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58) and the emulsions of the invention offer much better solubility and/or less side effects of the vehicle and/or better stability than conventional solutions. Oil-in-water emulsions also prevent the compounds from adherence to the plastic infusion sets that are to be used in administrating the compounds (col. 1 lines 57-62).
Floury teaches that the increase in pressure level permits to reduce the droplet size of the emulsions produced and then to improve shelf life of the products by reducing creaming rate. In addition to the reduction of the mean droplet diameter of emulsions, ultra high-pressure homogenization can also deflocculate clusters of primary fat globules, and dispersing agglomerates uniformly. High-pressure homogenization is also expected to increase the surface activity of the emulsifying molecules and may improve the efficiency of the product (pg. 127, Introduction). Temperature can influence the size of the droplets produced during homogenization in a number of ways. The viscosity of both the oil and aqueous phases is temperature-dependent and decreases with increasing the temperature. Consequently, the minimum droplet size that can be produced may be altered because of a variation of the viscosity ratio. Heating an emulsion usually cause a slight linear reduction in the interfacial tension between the oil and water phases, which would be expected to facilitate the production of small droplets (pg. 130, 3.1 Theoretical considerations on the effect of temperature on droplets sizes).
It would have been prima facie obvious to one of ordinary skill in the art to manufacture the pharmaceutical emulsion embraced by the claims of the 676, ‘537, and ‘490 patents by the method embraced by the instant claims. One would have understood in view of Andersson that the method of making a nearly identical pharmaceutical emulsion to that embraced by the claims of the 676, ‘537, and ‘490 patents renders a composition with improved solubility, decreased side effects, and improved stability. It would have been obvious to manufacture the pharmaceutical emulsion embraced by the claims of the 676, ‘537, and ‘490 patents by the method embraced by the instant claims. One of ordinary skill in the art of filing would have been motivated to utilize such a method because Andersson teaches that the emulsions rendered by the method demonstrate improved solubility, decreased side effects, and improved stability. The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because the pharmaceutical emulsions rendered by the method of making taught by Andersson are nearly identical to those embraced by the claims of the 676, ‘537, and ‘490 patents.
The pressure and temperature of the components during preparation of an emulsion is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pressure and temperature in order to best achieve the desired results as such would provide advantageous droplet size reduction. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Floury teaches that the homogenization pressure and temperature has a direct effect on the droplet size the resultant emulsion. The Examiner considers it prima facie obvious to optimize the pressure and temperature of the emulsion components, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the pressure and temperature would have a direct effect on the droplet size of the emulsion and therefore be an optimizable variable.
Regarding the amount of H324/78 present in the composition as recited in instant claims 21 and 22, although Andersson does not disclose the amount of H324/78 present in the composition as disclosed in the present claims, based on the substantially identical process using identical components, the Examiner has a reasonable basis to believe that the properties claimed in the present invention are inherent in the composition disclosed by Andersson. Because the PTO has no means to conduct analytical experiments, the burden of proof is shifted to the Applicant to prove that the properties are not inherent. ““[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).” See MPEP § 2112.
Claims 23-24 and 26-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-8 of U.S. Patent No. 8,658,676,
claims 1-12 of U.S. Patent No. 10,010,537,
and claims 1-7 of U.S. Patent No. 11,103,490,
in view of Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) and Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000), as applied to claims 21-22 and 25 above, and further in view of Fennimore (U.S. Patent No. 4,150,744, issue date: 4/24/1979).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia, the claims of the 676, ‘537, and ‘490 patents embraced the relevant limitations as described above. The claims of the 676, ‘537, and ‘490 patents do not teach a darkened container, a secondary packaging, or an inert gas. However, this deficiency is cured by Andersson and Fennimore. Andersson teaches that the clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58). Fennimore teaches that light and oxidation can be prevented from damaging pharmaceutical solutions by packaging in opaque containers, such as metal containers (col. 1 lines 31-32). Andersson also teaches that the emulsion can be filtered before being filed into suitable dosage units, often with nitrogen gassed top space (col. 6 lines 5-7). Fennimore also teaches a sealed light-tight gas-impermeable envelope for packaging a liquid-retentive vessel that contains a light-sensitive and oxygen sensitive liquid (col. 2 lines 53-62). The envelope resists entry of oxygen and light and loss of water vapor, thereby rendering the combination storable for long periods (col. 2 lines 66-68).
It would have been prima facie obvious to one of ordinary skill in the art of filing to package the clevidipine emulsion of the claims of the 676, ‘537, and ‘490 patents in the light-tight packaging of Fennimore. One would have understood in view of Andersson that clevidipine is sensitive to hydrolysis and light-degradation and that stable emulsions comprising clevidipine may be purged with a nitrogen headspace. One would have understood in view of Fennimore that opaque containers and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. One of ordinary skill in the art would have been capable of applying this known technique (opaque bottles, light-tight envelopes, and nitrogen gassed top space) to a known device ready for improvement (light-sensitive clevidipine emulsions) and the results would have been predictable to one of ordinary skill in the art (increased stability of the clevidipine emulsion that is protected from light and oxidative damage). The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Fennimore teaches that opaque bottles and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. See MPEP 2143 (I) (D).
Claims 21-22 and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 11-30 of copending application no. 18/631,588,
and claims 29-46 of copending application no. 18/885,921
in view of Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) and Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000).
Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims render obvious the instant claims.
Inter alia, the claims of the ‘588 and ‘921 applications embrace a pharmaceutical emulsion comprising an effective amount of clevidipine, 20% soybean oil, egg yolk phospholipids, pH-adjusting agents and a tonicity modifier. The pH of the composition is from 6.0 to 8.8. The specification of the applications teach that the tonicity modifier may be glycerin and that sodium hydroxide may be used to adjust pH (see [0012] and [0047] of the ‘588 application and [25] of the ‘921 application). The Examiner has relied upon the specification to delineate the scope of the invention embraced by the claims of the ‘588 and ‘921 applications, consistent with the decision in Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. U.S. Court of Appeals Federal Circuit, 95 USPQ2d 1797.
The claims of the ‘588 and ‘921 applications do not embrace a process for preparing the emulsion. However, this deficiency is cured by Andersson and Floury. Andersson teaches an oil-in-water emulsion for intravenous administration (Abstract) comprising butyroxymethyl methyl 4-(2',3'- dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate (col. 4 lines 12-14), also known as clevidipine (see PubChem, pg. 1 Synonyms and pg.4, 2.1.2 IUPAC name), a lipid phase, an emulsifier, and water (col. 1 lines 47-50). The preferred lipid phase is 10-20% soybean oil (col. 5 lines 30-31) and the preferred emulsifier is egg lecithin (col. 5 line 45). The emulsion may also contain tonicity modifying agents such as glycerol (col. 5 line 50) and pH-adjusting agents such as sodium hydroxide (col. 6 line 67). The composition may contain 0.5mg/mL clevidipine (Example 2).
The emulsion can be prepared by dissolving clevidipine in the lipid phase, optionally under heating. The emulsifier is dispersed or dissolved in the water phase or in the lipid phase. The tonicity agent may be dispersed in the water phase. The water phase is added into the lipid phase or vice versa. Preferably, the mixture is heated and a coarse emulsion is prepared with a high shear mixer. The coarse emulsion is processed by a high-pressure homogenizer. pH may be adjusted (col. 5 line 62-col. 6 line 6). In an exemplary preparation process, the mixture of water phase and lipid phase is heated to approximately 60oC (col. 6 line 21). There are no significant changes in the stability of prepared emulsions except from a drop in the pH in the autoclaved emulsions, which could be avoided by adjusting the pH with sodium hydroxide before autoclaving (col. 6 lines 62-67). The clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58) and the emulsions of the invention offer much better solubility and/or less side effects of the vehicle and/or better stability than conventional solutions. Oil-in-water emulsions also prevent the compounds from adherence to the plastic infusion sets that are to be used in administrating the compounds (col. 1 lines 57-62).
Floury teaches that the increase in pressure level permits to reduce the droplet size of the emulsions produced and then to improve shelf life of the products by reducing creaming rate. In addition to the reduction of the mean droplet diameter of emulsions, ultra high-pressure homogenization can also deflocculate clusters of primary fat globules, and dispersing agglomerates uniformly. High-pressure homogenization is also expected to increase the surface activity of the emulsifying molecules and may improve the efficiency of the product (pg. 127, Introduction). Temperature can influence the size of the droplets produced during homogenization in a number of ways. The viscosity of both the oil and aqueous phases is temperature-dependent and decreases with increasing the temperature. Consequently, the minimum droplet size that can be produced may be altered because of a variation of the viscosity ratio. Heating an emulsion usually cause a slight linear reduction in the interfacial tension between the oil and water phases, which would be expected to facilitate the production of small droplets (pg. 130, 3.1 Theoretical considerations on the effect of temperature on droplets sizes).
It would have been prima facie obvious to one of ordinary skill in the art to manufacture the pharmaceutical emulsion embraced by the claims of the ‘588 and ‘921 applications by the method embraced by the instant claims. One would have understood in view of Andersson that the method of making a nearly identical pharmaceutical emulsion to that embraced by the claims of the ‘588 and ‘921 applications renders a composition with improved solubility, decreased side effects, and improved stability. It would have been obvious to manufacture the pharmaceutical emulsion embraced by the claims of the ‘588 and ‘921 applications by the method embraced by the instant claims. One of ordinary skill in the art of filing would have been motivated to utilize such a method because Andersson teaches that the emulsions rendered by the method demonstrate improved solubility, decreased side effects, and improved stability. The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because the pharmaceutical emulsions rendered by the method of making taught by Andersson are nearly identical to those embraced by the claims of the ‘588 and ‘921 applications.
The pressure and temperature of the components during preparation of an emulsion is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pressure and temperature in order to best achieve the desired results as such would provide advantageous droplet size reduction. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In the instant case, Floury teaches that the homogenization pressure and temperature has a direct effect on the droplet size the resultant emulsion. The Examiner considers it prima facie obvious to optimize the pressure and temperature of the emulsion components, absent unexpectedly superior properties of the claimed invention. In the instant case, one of ordinary skill in the art would have recognized that the pressure and temperature would have a direct effect on the droplet size of the emulsion and therefore be an optimizable variable.
Regarding the amount of H324/78 present in the composition as recited in instant claims 21 and 22, although Andersson does not disclose the amount of H324/78 present in the composition as disclosed in the present claims, based on the substantially identical process using identical components, the Examiner has a reasonable basis to believe that the properties claimed in the present invention are inherent in the composition disclosed by Andersson. Because the PTO has no means to conduct analytical experiments, the burden of proof is shifted to the Applicant to prove that the properties are not inherent. ““[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).” See MPEP § 2112.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 23-24 and 26-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 11-30 of copending application no. 18/631,588,
and claims 29-46 of copending application no. 18/885,921
in view of Andersson (U.S. Patent No. 5,739,152, issue date: 4/14/1998) and Floury et.al. (Innovative Food Science and Emerging Technologies, pg. 127-134, publication year: 2000), as applied to claims 21-22 and 25 above, and further in view of Fennimore (U.S. Patent No. 4,150,744, issue date: 4/24/1979).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia, the claims of the ‘588 and ‘921 applications embraced the relevant limitations as described above. The claims of the ‘588 and ‘921 applications do not teach a darkened container, a secondary packaging, or an inert gas. However, this deficiency is cured by Andersson and Fennimore. Andersson teaches that the clevidipine is sensitive to hydrolysis and light (col. 5 line 54 and line 58). Fennimore teaches that light and oxidation can be prevented from damaging pharmaceutical solutions by packaging in opaque containers, such as metal containers (col. 1 lines 31-32). Andersson also teaches that the emulsion can be filtered before being filed into suitable dosage units, often with nitrogen gassed top space (col. 6 lines 5-7). Fennimore also teaches a sealed light-tight gas-impermeable envelope for packaging a liquid-retentive vessel that contains a light-sensitive and oxygen sensitive liquid (col. 2 lines 53-62). The envelope resists entry of oxygen and light and loss of water vapor, thereby rendering the combination storable for long periods (col. 2 lines 66-68).
It would have been prima facie obvious to one of ordinary skill in the art of filing to package the clevidipine emulsion of the claims of the ‘588 and ‘921 applications in the light-tight packaging of Fennimore. One would have understood in view of Andersson that clevidipine is sensitive to hydrolysis and light-degradation and that stable emulsions comprising clevidipine may be purged with a nitrogen headspace. One would have understood in view of Fennimore that opaque containers and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. One of ordinary skill in the art would have been capable of applying this known technique (opaque bottles, light-tight envelopes, and nitrogen gassed top space) to a known device ready for improvement (light-sensitive clevidipine emulsions) and the results would have been predictable to one of ordinary skill in the art (increased stability of the clevidipine emulsion that is protected from light and oxidative damage). The artisan of ordinary skill in the art of filing would have had reasonable expectation of success because Fennimore teaches that opaque bottles and light-tight envelopes may be used to protect light and oxygen sensitive pharmaceutical liquids from degradation. See MPEP 2143 (I) (D).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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ELIZABETH ANNE MEYERSExaminer, Art Unit 1617
/KATHERINE PEEBLES/Primary Examiner, Art Unit 1617
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