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/CN2022/106270 filed on 07/18/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in CHINA on 07/19/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claims 1 and 5-10 are objected to because of the following informalities:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
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In the instant case, reference to a compound disclosed in Chinese patent publication number CN107849045B is improper and the actual compounds should be recited in the claim. Thus claim 1 and claims 5-10 dependent upon claim 1 are objected to.
Appropriate correction is required.
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 2-8 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.
Regarding claims 2-5, the use of parentheses renders the claims indefinite because it is unclear whether the limitation(s) within the parentheses are part of the claimed invention. See MPEP § 2173.05(d). With respect to claims 2 and 4, it is unclear why 10-20, 2-4 and 1.5-6 are within parentheses. Claim 3 is rejected since it is dependent upon rejected claim 2. With respect to claim 5, it is unclear why C1-4 alkyl is within parentheses.
Regarding claim 5, the word "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following “preferably” are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 5 recites the broad recitation cyclodextrin is selected from the group consisting of a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, (C1-4 alkyl)-a-cyclodextrin, (C1-4 alkyl)-b-cyclodextrin, (C1-4alkyl)-g-cyclodextrin, hydroxyl-(C1-4 alkyl)-a-cyclodextrin, hydroxyl-(C1-4alkyl)-b-cyclodextrin, hydroxyl-(C1-4alkyl)-g-cyclodextrin, carboxyl-(C1-4alkyl)-a-cyclodextrin, carboxyl-(C1-4alkyl)-b-cyclodextrin, carboxyl-(C1-4alkyl)-g- cyclodextrin, a-cyclodextrin ethers, b-cyclodextrin ethers, g-cyclodextrin ethers, a-cyclodextrin sulfobutyl ether, b-cyclodextrin sulfobutyl ether, and g-cyclodextrin sulfobutyl ether; and the claim also recites “preferably said cyclodextrin is hydroxypropyl-b-cyclodextrin”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 6 is further indefinite since it recites “the deacetylase inhibitor” instead of “the histone deacetylase inhibitor”. Thus it is unclear if the deacetylase inhibitor is the histone deacetylase inhibitor as referred to in claim 1 or if “the deacetylase inhibitor” is a different type of compound. Claims 7-8 are rejected since they are dependent upon claim 6. For the sake of compact prosecution, claim 6 is being interpreted as “the deacetylase inhibitor” is “the histone deacetylase inhibitor” and examined herewith.
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 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-54 of U.S. Patent No. 10,227,347 B2 in view of Bastin et al. U.S. Publication No. 20180072661 A1.
Claims 1-10 of the instant application claim a pharmaceutical composition comprising a histone deacetylase inhibitor (HDACI) and an excipient wherein the histone deacetylase inhibitor is a compound disclosed in the Chinese patent publication number CN107849045B, or a pharmaceutically acceptable salt, a solvate, an amide, an ester, an ether, a chemically protected form, and a prodrug thereof such as a compound of Formula I
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; and the excipient is at least one of or a combination of two or more of cyclodextrin, arginine, and meglumine.
Claims 1-54 of ‘347 claim the same compounds as claimed in the instant claims as well as a pharmaceutical composition comprising pharmaceutically acceptable auxiliary ingredients and the compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is provided in a form of an oral preparation or an intravenous injection preparation. ‘347 defines said auxiliary ingredients as cyclodextrin, arginine or meglumine (column 122 lines 34-35). Thus claim 54 of ‘347 claims a pharmaceutical composition comprising cyclodextrin, arginine or meglumine and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
‘347 does not claim the mass ratios of the excipient to the inhibitor and the concentration of the HDAC inhibitor in the composition as well as a method of preparing the composition as claimed.
However, it is obvious and within the skill of an ordinary skilled artisan to vary and/or optimize the amounts of ingredients in a composition such that optimal properties of the composition and optimal treatment is achieved. Furthermore, it has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
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); 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). 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, Bastin et al. teaches pharmaceutical compositions comprising certain inhibitors of HDAC (histone deacetylase) activity and one or more additional ingredients selected from cyclodextrin, arginine, and meglumine (abstract, [0002], [0025]). Bastin et al. further teaches a method of preparing a composition by combining: (a) a histone deacetylase inhibitor (HDACi) and (b) one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine; and optionally one or more other additional pharmaceutically acceptable ingredients (as described herein) [0031]-[0032].
Bastin teaches in one preferred embodiment, the composition is added to a saline or glucose solution (e.g., into a typical 1 L intravenous saline or glucose bag), and the resulting composition (e.g., formulation) is used for administration by intravenous infusion [0064]. The pharmaceutical compositions comprise, at least, the following components: (a) an HDACi; and (b) one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine [0068]- [0071]. In one embodiment, the pharmaceutical composition further comprises one or more other additional ingredients (e.g., pharmaceutically acceptable carriers, etc.) [0072].
Bastin teaches the cyclodextrin is selected from: α-cyclodextrin; β-cyclodextrin; γ-cyclodextrin; (C1-4alkyl)-α-cyclodextrin; (C1-4alkyl)-β-cyclodextrin; (C1-4alkyl)-γ-cyclodextrin; (hydroxy-C1-4alkyl)-α-cyclodextrin; (hydroxy-C1-4alkyl)-β-cyclodextrin; (hydroxy-C1-4alkyl)-γ-cyclodextrin; (carboxy-C1-4alkyl)-α-cyclodextrin; (carboxy-C1-4alkyl)-β-cyclodextrin; (carboxy-C1-4alkyl)-γ-cyclodextrin; saccharide ethers of α-cyclodextrin; saccharide ethers of β-cyclodextrin; saccharide ethers of γ-cyclodextrin; and sulfobutyl ethers of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin [0388]- [0394].
Bastin teaches that the concentration of the HDACi in the formulation is at least 0.01 mg/mL up to and including 500 mg/mL, wherein in one embodiment, the HDACi concentration is 10-500 mg/mL, such as about 50 mg/mL [0442]- [0450].
Bastin further teaches if cyclodextrin is present, the molar ratio of cyclodextrin to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 1.785 (0.5x3.57) to 17.85 (5x3.57) [0454]-[0459].
Bastin teaches that if arginine is present, the molar ratio of arginine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 0.285 (0.5x0.57) to 2.85 (5x0.57) [0460]-[0465].
Bastin teaches that if meglumine is present, the molar ratio of meglumine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 0.307 (0.5x0.613) to 3.1 (5x0.613) [0466]-[0471].
Bastin further teaches a method of preparing a composition by combining an HDACi and one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine; and optionally one or more other additional pharmaceutically acceptable ingredients as described therein [0473]. For example an appropriate amount of pure, dry HDACi may be dissolved in a solution of salt former e.g., arginine, meglumine or cyclodextrin in water at a suitable concentration as described therein, wherein solubilization may be achieved over a period of from about 1 minute to about 1 hour by stirring, for example, using a magnetic stirrer, paddle stirrer, or turbine mixer, with or without the application of heat [0474]. The resulting solution is then diluted to the final volume, e.g., with the appropriate grade of water, and stirred for a further period of time until the solution is homogenous [0474]. The solution is passed through a suitable filter (e.g., sterilizing grade 0.2 μm filter) and placed in appropriate containers (e.g., vials, ampoules, etc.) in a suitable pharmaceutical manufacturing environment, and sealed/capped [0476]. Thus Bastin teaches the same method of preparation as claimed in claim 10 of the instant application.
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 the claims of ‘347 which claim a pharmaceutical composition comprising a histone deacetylase inhibitor (HDACI) and an excipient wherein the excipient is at least one of cyclodextrin, arginine, and meglumine, but does not claim how to prepare the formulation including appropriate amounts; with the teaching of Bastin which specifically teaches how to prepare formulations comprising an HDACi; and one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine. Thus Bastin specifically provides guidance of how to formulate HDAC inhibitor formulations which include the excipients as claimed in the instant claims. Thus an ordinary skilled artisan would have been motivated to consult the prior art to provide appropriate guidance to prepare the formulation claimed in ‘347.
Bastin teaches that the concentration of the HDACi in the formulation is at least 0.01 mg/mL up to and including 500 mg/mL, wherein in one embodiment, the HDACi concentration is 10-500 mg/mL, such as about 50 mg/mL, which overlaps with the concentration as claimed in claim 9 of the instant application [0442]- [0450].
Bastin further teaches if cyclodextrin, arginine or meglumine are present, the molar ratio of cyclodextrin, arginine or meglumine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 1.785 to 17.85 for cyclodextrin to HDACi, 0.285 to 2.85 for arginine to HDACi, and 0.307 to 3.1 for meglumine to HDACi, which overlap with the ratios as claimed in claims 2-4 of the instant application. Thus, a person of ordinary skill in the art would have been motivated to prepare the formulation of ‘347 based on the teachings of Bastin with a reasonable expectation of success since both ‘347 and Bastin deal with formulating HDAC inhibitor compositions with the same excipients.
Thus the amounts as claimed overlap with the amounts as taught in Bastin and therefore 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.").
Thus the cited claims of the instant application are rendered obvious in view of the claims of ‘347.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 5-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. U.S. Publication No. 2018/0134709 A1.
Claims 1 and 5-8 of the instant application claim a pharmaceutical composition comprising a histone deacetylase inhibitor (HDACI) and an excipient wherein the histone deacetylase inhibitor is a compound disclosed in the Chinese patent publication number CN107849045B, or a pharmaceutically acceptable salt, a solvate, an amide, an ester, an ether, a chemically protected form, and a prodrug thereof such as a compound of Formula I
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; and the excipient is at least one of or a combination of two or more of cyclodextrin, arginine, and meglumine.
Chen et al. teaches purinyl-N-hydroxyl pyrimidine formamide derivatives having PI3K and HDAC difunctional targets, said purinyl-N-hydroxyl pyrimidine formamide derivatives of Formula I have the following structure:
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wherein X is O, and R1, R2, and R3 are as claimed in claim 2 of the instant application [0008]-[0012]. Chen et al. teaches the same compounds as claimed in claim 3 of the instant application ([0083] and [0120]-[0329]).
Chen et al. further teaches a pharmaceutically acceptable pharmaceutical composition of said purinyl-N-hydroxyl pyrimidine formamide derivative; such pharmaceutical composition is prepared by the purinyl-N-hydroxyl pyrimidine formamide derivatives as disclosed therein and its salt or hydrate with pharmaceutically acceptable auxiliary ingredients [0106]. Chen et al. teaches that said auxiliary ingredients are cyclodextrin, arginine or meglumine [0106]. Chen et al. teaches that said cyclodextrin is selected from α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, (C1-4 alkyl)-α-cyclodextrins, (C1-4 alkyl)-β-cyclodextrins, (C1-4 alkyl)-γ-cyclodextrins, (hydroxyl-C1-4 alkyl)-α-cyclodextrins, (hydroxyl-C1-4 alkyl)-β-cyclodextrins, (hydroxyl-C1-4 alkyl)-γ-cyclodextrins, (carboxyl-C1-4 alkyl)-α-cyclodextrins, (carboxyl-C1-4 alkyl)-β-cyclodextrins, (carboxyl-C1-4 alkyl)-γ-cyclodextrins, carbohydrate ether of α-cyclodextrins, carbohydrate ether of β-cyclodextrins, carbohydrate ether of γ-cyclodextrins, sulfobutyl ether of α-cyclodextrins, sulfobutyl ether of β-cyclodextrins and sulfobutyl ether of γ-cyclodextrins [0106]. Chen et al. further teaches said auxiliary ingredients also comprise pharmaceutically acceptable carrier, adjuvant or agent [0106]. Chen et al. teaches said pharmaceutical composition can be in liquid form wherein, said liquid form can be the form of aqueous solution; wherein the pharmaceutical composition also comprises water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution or Ringer's solution containing lactate [0107].
Chen et al. specifically claims a pharmaceutical composition comprising pharmaceutically acceptable auxiliary ingredients and the purinyl-N-hydroxyl pyrimidine formamide derivative according to claim 1 or a salt or a hydrate thereof (see claim 56). Claim 61 of Chen et al. specifically claims that the pharmaceutical composition is an HDAC inhibitor.
Thus, the cited claims of the instant application are anticipated since Chen et al. specifically discloses and claims a pharmaceutical composition comprising a histone deacetylase inhibitor (HDACI) and an excipient wherein the histone deacetylase inhibitor is a compound disclosed in the Chinese patent publication number CN107849045B such as a compound of Formula I having the following structure:
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; and the excipient is at least one of cyclodextrin, arginine, and meglumine, and also comprising a pharmaceutically acceptable carrier, selected from water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution or Ringer's solution containing lactate.
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 2-4, 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. U.S. Publication No. 2018/0134709 A1 as applied to claims 1 and 5-8 above and further in view of Bastin et al. U.S. Publication No. 20180072661 A1.
The cited claims of the instant application claim certain mass ratios of the excipient to the inhibitor and the concentration of the HDAC inhibitor in the composition as well as a method of preparing the composition.
Chen et al. is as set forth above.
Chen et al. does not teach the mass ratios of the excipient to the inhibitor and the concentration of the HDAC inhibitor in the composition as well as a method of preparing the composition as claimed.
However, it is obvious and within the skill of an ordinary skilled artisan to vary and/or optimize the amounts of ingredients in a composition such that optimal properties of the composition and optimal treatment is achieved. Furthermore, it has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
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); 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). 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, Bastin et al. teaches pharmaceutical compositions comprising certain inhibitors of HDAC (histone deacetylase) activity and one or more additional ingredients selected from cyclodextrin, arginine, and meglumine (abstract, [0002], [0025]). Bastin et al. further teaches a method of preparing a composition by combining: (a) a histone deacetylase inhibitor (HDACi) and (b) one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine; and optionally one or more other additional pharmaceutically acceptable ingredients (as described herein) [0031]-[0032].
Bastin teaches in one preferred embodiment, the composition is added to a saline or glucose solution (e.g., into a typical 1 L intravenous saline or glucose bag), and the resulting composition (e.g., formulation) is used for administration by intravenous infusion [0064]. The pharmaceutical compositions comprise, at least, the following components: (a) an HDACi; and (b) one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine [0068]- [0071]. In one embodiment, the pharmaceutical composition further comprises one or more other additional ingredients (e.g., pharmaceutically acceptable carriers, etc.) [0072].
Bastin teaches the cyclodextrin is selected from: α-cyclodextrin; β-cyclodextrin; γ-cyclodextrin; (C1-4alkyl)-α-cyclodextrin; (C1-4alkyl)-β-cyclodextrin; (C1-4alkyl)-γ-cyclodextrin; (hydroxy-C1-4alkyl)-α-cyclodextrin; (hydroxy-C1-4alkyl)-β-cyclodextrin; (hydroxy-C1-4alkyl)-γ-cyclodextrin; (carboxy-C1-4alkyl)-α-cyclodextrin; (carboxy-C1-4alkyl)-β-cyclodextrin; (carboxy-C1-4alkyl)-γ-cyclodextrin; saccharide ethers of α-cyclodextrin; saccharide ethers of β-cyclodextrin; saccharide ethers of γ-cyclodextrin; and sulfobutyl ethers of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin [0388]- [0394].
Bastin teaches that the concentration of the HDACi in the formulation is at least 0.01 mg/mL up to and including 500 mg/mL, wherein in one embodiment, the HDACi concentration is 10-500 mg/mL, such as about 50 mg/mL [0442]- [0450].
Bastin further teaches if cyclodextrin is present, the molar ratio of cyclodextrin to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 1.785 (0.5x3.57) to 17.85 (5x3.57) [0454]-[0459].
Bastin teaches that if arginine is present, the molar ratio of arginine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 0.285 (0.5x0.57) to 2.85 (5x0.57) [0460]-[0465].
Bastin teaches that if meglumine is present, the molar ratio of meglumine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 0.307 (0.5x0.613) to 3.1 (5x0.613) [0466]-[0471].
Bastin further teaches a method of preparing a composition by combining an HDACi and one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine; and optionally one or more other additional pharmaceutically acceptable ingredients as described therein [0473]. For example an appropriate amount of pure, dry HDACi may be dissolved in a solution of salt former e.g., arginine, meglumine or cyclodextrin in water at a suitable concentration as described therein, wherein solubilization may be achieved over a period of from about 1 minute to about 1 hour by stirring, for example, using a magnetic stirrer, paddle stirrer, or turbine mixer, with or without the application of heat [0474]. The resulting solution is then diluted to the final volume, e.g., with the appropriate grade of water, and stirred for a further period of time until the solution is homogenous [0474]. The solution is passed through a suitable filter (e.g., sterilizing grade 0.2 μm filter) and placed in appropriate containers (e.g., vials, ampoules, etc.) in a suitable pharmaceutical manufacturing environment, and sealed/capped [0476]. Thus Bastin teaches the same method of preparation as claimed in claim 10 of the instant application.
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 Chen et al. which teaches a pharmaceutical composition comprising a histone deacetylase inhibitor (HDACI) and an excipient wherein the excipient is at least one of cyclodextrin, arginine, and meglumine, and also comprising a pharmaceutically acceptable carrier, selected from water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution or Ringer's solution containing lactate, but does not specifically provide guidance as to how to prepare the formulation including appropriate amounts; with the teaching of Bastin which specifically teaches how to prepare formulations comprising an HDACi; and one or more of the following additional ingredients: cyclodextrin, arginine, and meglumine. Thus Bastin specifically provides guidance of how to formulate HDAC inhibitor formulations which include the excipients as claimed in the instant claims. Thus an ordinary skilled artisan would have been motivated to consult the prior art to provide appropriate guidance to prepare the formulation of Chen et al.
Bastin teaches that the concentration of the HDACi in the formulation is at least 0.01 mg/mL up to and including 500 mg/mL, wherein in one embodiment, the HDACi concentration is 10-500 mg/mL, such as about 50 mg/mL, which overlaps with the concentration as claimed in claim 9 of the instant application [0442]- [0450].
Bastin further teaches if cyclodextrin, arginine or meglumine are present, the molar ratio of cyclodextrin, arginine or meglumine to HDACi is at least 0.5 up to and including 5, which corresponds to a mass ratio of 1.785 to 17.85 for cyclodextrin to HDACi, 0.285 to 2.85 for arginine to HDACi, and 0.307 to 3.1 for meglumine to HDACi, which overlap with the ratios as claimed in claims 2-4 of the instant application. Thus, a person of ordinary skill in the art would have been motivated to prepare the formulation of Chen et al. based on the teachings of Bastin with a reasonable expectation of success since both Chen et al. and Bastin deal with formulating HDAC inhibitor compositions with the same excipients.
Thus the amounts as claimed overlap with the amounts as taught in Bastin and therefore 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.").
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-10 are rejected. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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