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 .
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/22/2025 has been entered.
Claims 1, 4, 8, 11-13, 16, 19-21 and 24 are pending in the application as of the as of the RCE filed 12/22/2025. Claim 2-3, 5-7, 9-10, 14-15, 17-18, 22-23 and 25-26 are cancelled. Claims 1, 4, 8, 11-13, 16, 19-21 and 24 examined herein.
In view of the pending claims, the 35 U.S.C. 103 rejections of record are withdrawn and new rejections are made to address the claim amendments.
The nonstatutory double patenting rejections of record are maintained and modified to address the claim amendments. Additional new nonstatutory double patenting rejections are made.
Applicant’s arguments have been fully considered and have been addressed to the extent to which they are applicable to the current new rejections.
Claim Objections
Claim 1 is objected to because of the following informalities:
In claim 1, lines 3-4, the limitation “and optionally at least one pharmaceutically acceptable excipient” does not limit the claim meaningfully since the composition already comprises the excipients cyclodextrin and citrate buffer. Applicant may amend claim 1 to read “and optionally at least one additional pharmaceutically acceptable excipient”.
Appropriate correction is required.
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.
Claims 1, 4, 8, 11-13, 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), Mead et al. (S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis, 19 April 2013, hereinafter Mead) and Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) as evidenced by PubChem CID 6005, create date 24 June 2005.
Regarding instant claim 1, Dey teaches a pharmaceutical composition comprising apomorphine as the active substance, a water miscible co-solvent, an anti-oxidant and water (Paras. [0007]-[0011]; Para. [0020]). PubChem CID 6005 evidences apomorphine to have the following structure, which is identical to the instantly claimed compound 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (see Para. [0009] of the instant specification).
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Dey teaches the compositions comprise a cyclodextrin, specifically hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD) (it is noted that SBEβCD and SBβCD stand for the same compound, i.e., sulfobutylether-beta-cyclodextrin) (Paras. [0025]-[0027]). Dey teaches exemplary formulations of apomorphine comprising 20% HBβCD (Para. [0113]; Para. [0127]). Dey teaches an exemplary formulation of apomorphine comprising 20% SBβCD (Para. [0124]). Dey teaches an embodiment of a formulation that contains 30 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 30 mg/ml) (Para. [0113]; Para. [0127]). Dey teaches other embodiments of a formulation that contains 40 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 40 mg/ml) (Para. [0111]; Para. [0112]).
Dey do not teach the S-enantiomer, (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol and 10 mM citrate buffer in the pharmaceutical composition, as instantly claimed.
Mead teaches S[+]-Apomorphine (i.e., the S-enantiomer) as an Nrf2-ARE pathway activator with antioxidant and neuroprotective properties having therapeutic potential in the treatment of amyotrophic lateral sclerosis (ALS) (Abstract). Mead teaches the S[+]-Apomorphine is considered an attractive candidate for therapeutic assessment because it lacks the unwanted effects of the parent molecule (i.e., dopamine agonism, induction of emesis) (Pg. 441, first column, first full paragraph; Pg. 446, second column, last paragraph – Pg. 447, second column, continued paragraph).
Lee teaches formulations that comprise a dopamine agonist, cyclodextrin, a suitable carrier and water (Col. 4, Lns. 22-26). Lee teaches wherein the dopamine agonist can be apomorphine (Col. 4, Lns. 27-32). Lee discusses the stability and solubility of the dopamine agonists in 10 mM citrate buffer with or without added 2-hydroxypropyl-β-cyclodextrin (HPCD) (Col. 5, Lns. 37-65). Lee teaches the addition of the HPCD brought about significant increases in the stabilities and solubilities of apomorphine (Col. 5, Lns. 55-65; FIG. 1A; FIG. 2). Lee teaches the addition of the HPCD resulted in a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine (Col. 5, Lns. 47-65).
According to MPEP 2144.09 (II) and (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). In the instant case, the apomorphine of the prior art and the instant compound (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol, are enantiomers, rendering them prima facie obvious.
Further, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. The prior art of record teaches a 10 mM citrate buffer as an excipient commonly used in the formulation of pharmaceutical compounds. Thus, it is prima facie obvious to have incorporated a 10 mM citrate buffer into the modified composition of Dey to arrive at the instant pharmaceutical composition with a reasonable expectation of success in obtaining a composition with the desired solubility, say 40 mg/ml.
According to MPEP 2144.05(II)(A), "[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). In the instant case, given the teachings of the prior art, a PHOSITA would have been motivated to similarly formulate a composition of the S-enantiomer having the desired solubility (enantiomers are mirror images with the same intermolecular forces and possess identical physical properties, such as solubility) by incorporating and optimizing the concentration of the art recognized excipients to arrive at the pharmaceutical composition of the instant claims, with a reasonable and predictable expectation of success in obtaining a composition with the desired solubility, say 40 mg/ml.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Dey, Mead and Lee to have formulated a composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (i.e., the S-enantiomer) similar to the composition of Dey, by incorporating a 10 mM citrate buffer to arrive at the composition of the instant claims with a reasonable expectation of success. Dey teaches a pharmaceutical composition comprising apomorphine, a cyclodextrin such as, hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD), wherein the solubility of apomorphine is at least 30 mg/ml or 40 mg/ml. Mead teaches S[+]-Apomorphine (i.e., the S-enantiomer) as an Nrf2-ARE pathway activator with antioxidant and neuroprotective properties having therapeutic potential in the treatment of amyotrophic lateral sclerosis (ALS). Mead teaches the S[+]-Apomorphine is considered an attractive candidate for therapeutic assessment because it lacks the unwanted effects of dopamine agonism and induction of emesis. Lee teaches formulations that comprise a dopamine agonist, specifically apomorphine. Lee teaches enhanced stability and solubility of apomorphine in a 10 mM citrate buffer with the addition of 2-hydroxypropyl-β-cyclodextrin, especially a twofold increase in solubility starting from solutions containing 20 mg/ml apomorphine. In the absence of evidence to the contrary, a PHOSITA would have been motivated to formulate a pharmaceutical composition comprising the S-enantiomer of apomorphine in a 10 mM citrate buffer, to arrive at the instant composition having a solubility of 40 mg/ml with a reasonable expectation of success. The motivation being to formulate a composition with enhanced stability and solubility that is devoid of the side-effects associated with the R-enantiomer for use as an Nrf2-ARE pathway activator in the treatment of ALS (Mead, Pg. 446, second column, last paragraph – Pg. 447, second column, continued paragraph; Lee, Col. 5, Lns. 25-30).
Regarding instant claim 4, the combined teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005, renders the pharmaceutical composition of instant claim 1, prima facie obvious. Dey teaches the formulation of apomorphine comprising 20% HBβCD (Para. [0113]; Para. [0127]). The HBβCD in the composition taught by Dey falls within the claimed ranges as in instant claim 4.
Regarding instant claim 8, the combined teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005, renders the pharmaceutical composition of instant claim 1, prima facie obvious. Dey teaches the formulation of apomorphine comprising 20% SBβCD (Para. [0124]). The SBβCD in the composition taught by Dey falls within the claimed ranges as in instant claim 8.
Regarding instant claims 11-13, the combined teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005, renders the pharmaceutical composition of instant claim 1, prima facie obvious. Dey teaches the compositions comprise an antioxidant (Paras. [0007]-[0011]; Para. [0028]). Dey teaches the antioxidant can be a sulfite, say sodium metabisulfite (Para. [0028]). Dey teaches formulations comprising 0.3% SM (SM stands for sodium metabisulfite, Para. [0075]) (Para. [0124]; Para. [0127]). The sodium metabisulfite in the composition taught by Dey falls within the claimed ranges as in instant claim 13.
Regarding instant claims 16 and 19, the combined teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005, renders the pharmaceutical composition of instant claim 1, prima facie obvious. Dey teaches the composition comprises a co-solvent (Para. [0009]), wherein the co-solvent is an alcohol (Para. [0025]). This renders the limitations of instant claims 16 and 19 prima facie obvious.
Claims 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), of Mead et al. (S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis, 19 April 2013, hereinafter Mead) and Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) as evidenced by PubChem CID 6005, create date 24 June 2005 as applied to claims 1, 4, 8, 11-13, 16 and 19 above, and further in view of Desai et al. (US 4,784,845 A, date of patent 15 November 1988, hereinafter Desai).
The teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005 are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 20-21, the combined teachings of Dey, Mead and Lee as evidenced by PubChem CID 6005, renders the pharmaceutical composition of instant claim 1, prima facie obvious.
Dey, Mead and Lee do not teach wherein the co-solvent is benzyl alcohol.
Desai teaches emulsion compositions for the parenteral administration of sparingly water soluble ionizable hydrophobic drugs (Title; Col. 2, Ln. 53 – Col. 3, Ln. 6). Desai teaches benzyl alcohol has been successfully utilized as a cosolvent and/or cosurfactant in the present invention to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs in the quick breaking, in vivo, emulsion compositions (Abstract; Col. 2, Lns. 53-64; Col. 4, Lns. 40-45). Desai teaches benzyl alcohol as a cosolvent may be present in the composition at a range of 0.2-4% W/V) (Claim 2) (this falls within the disclosed range of benzyl alcohol as in instant claim 21). Desai teaches an advantage of the emulsion composition is that it circumvents the local precipitation of the sparingly soluble drugs, thereby avoiding the localized accumulation of potentially irritating compounds (Col. 3, Lns. 16-31). Desai teaches the emulsion solubilization systems are applicable to other known commercial products and drug substances reported in the literature (Col. 3, Lns. 47-51).
Therefore, it would have been prima facie obvious to a PHOSITA before the effective filing date of the claimed invention, in view of the teachings of Dey, Mead, Lee as evidenced by PubChem CID 6005, and Desai, to have incorporated benzyl alcohol as a cosolvent in the modified composition of Dey to arrive at the instant pharmaceutical composition with a reasonable expectation of success in effectively solubilizing the S-enantiomer of apomorphine. The motivation being to provide a stable composition that does not precipitate out of solution, thereby reducing local site reactions on parenteral administration (Desai, Col. 3, Lns. 16-31).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), Mead et al. (S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis, 19 April 2013, hereinafter Mead), Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) and Desai et al. (US 4,784,845 A, date of patent 15 November 1988, hereinafter Desai) as evidenced by PubChem CID 6005, create date 24 June 2005.
Regarding instant claim 24, Dey teaches a pharmaceutical composition comprising apomorphine as the active substance, a water miscible co-solvent, an anti-oxidant and water (Paras. [0007]-[0011]; Para. [0020]). PubChem CID 6005 evidences apomorphine to have the following structure, which is identical to the instantly claimed compound 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (see Para. [0009] of the instant specification).
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Dey teaches the compositions comprise a cyclodextrin, specifically hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD) (it is noted that SBEβCD and SBβCD stand for the same compound, i.e., sulfobutylether-beta-cyclodextrin) (Paras. [0025]-[0027]). Dey teaches exemplary formulations of apomorphine comprising 20% HBβCD (Para. [0113]; Para. [0127]). Dey teaches an exemplary formulation of apomorphine comprising 20% SBβCD (Para. [0124]). Dey teaches an embodiment of a formulation that contains 30 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 30 mg/ml) (Para. [0113]; Para. [0127]). Dey teaches other embodiments of a formulation that contains 40 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 40 mg/ml) (Para. [0111]; Para. [0112]).
Dey do not teach the S-enantiomer, (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol, 10 mM citrate buffer and benzyl alcohol in the pharmaceutical composition, as instantly claimed.
Mead teaches S[+]-Apomorphine (i.e., the S-enantiomer) as an Nrf2-ARE pathway activator with antioxidant and neuroprotective properties having therapeutic potential in the treatment of amyotrophic lateral sclerosis (ALS) (Abstract). Mead teaches the S[+]-Apomorphine is considered an attractive candidate for therapeutic assessment because it lacks the unwanted effects of the parent molecule (i.e., dopamine agonism, induction of emesis) (Pg. 441, first column, first full paragraph; Pg. 446, second column, last paragraph – Pg. 447, second column, continued paragraph).
Lee teaches formulations that comprise a dopamine agonist, cyclodextrin, a suitable carrier and water (Col. 4, Lns. 22-26). Lee teaches wherein the dopamine agonist can be apomorphine (Col. 4, Lns. 27-32). Lee discusses the stability and solubility of the dopamine agonists in 10 mM citrate buffer with or without added 2-hydroxypropyl-β-cyclodextrin (HPCD) (Col. 5, Lns. 37-65). Lee teaches the addition of the HPCD brought about significant increases in the stabilities and solubilities of apomorphine (Col. 5, Lns. 55-65; FIG. 1A; FIG. 2). Lee teaches the addition of the HPCD resulted in a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine (Col. 5, Lns. 47-65) .
Desai teaches emulsion compositions for the parenteral administration of sparingly water soluble ionizable hydrophobic drugs (Title; Col. 2, Ln. 53 – Col. 3, Ln. 6). Desai teaches benzyl alcohol has been successfully utilized as a cosolvent and/or cosurfactant in the present invention to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs in the quick breaking, in vivo, emulsion compositions (Abstract; Col. 2, Lns. 53-64; Col. 4, Lns. 40-45). Desai teaches benzyl alcohol as a cosolvent may be present in the composition at a range of 0.2-4% W/V) (Claim 2) (this falls within the disclosed range of benzyl alcohol as in instant claim 21). Desai teaches an advantage of the emulsion composition is that it circumvents the local precipitation of the sparingly soluble drugs, thereby avoiding the localized accumulation of potentially irritating compounds (Col. 3, Lns. 16-31). Desai teaches the emulsion solubilization systems are applicable to other known commercial products and drug substances reported in the literature (Col. 3, Lns. 47-51).
According to MPEP 2144.09 (II) and (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). In the instant case, the apomorphine of the prior art and the instant compound (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol, are enantiomers, rendering them prima facie obvious.
Further, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. The prior art of record teaches a 10 mM citrate buffer and benzyl alcohol as excipients commonly used in the formulation of pharmaceutical compounds. Thus, it is prima facie obvious to have incorporated a 10 mM citrate buffer and benzyl alcohol into the modified composition of Dey to arrive at the instant pharmaceutical composition with a reasonable expectation of success.
According to MPEP 2144.05(II)(A), "[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). ). In the instant case, given the teachings of the prior art, a PHOSITA would have been motivated to similarly formulate a composition of the S-enantiomer having the desired solubility (enantiomers are mirror images with the same intermolecular forces and possess identical physical properties, such as solubility) by incorporating and optimizing the concentration of the art recognized excipients to arrive at the pharmaceutical composition of the instant claims, with a reasonable and predictable expectation of success in obtaining a composition with the desired solubility, say 40 mg/ml.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Dey, Mead, Lee and Desai to have formulated a composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (i.e., the S-enantiomer) similar to the composition of Dey, by incorporating a 10 mM citrate buffer and benzyl alcohol into the composition of Dey, to arrive at the instant formulation with a reasonable expectation of success, in the absence of evidence to the contrary. The motivation being to formulate a composition with enhanced stability and solubility that is devoid of the side-effects associated with the R-enantiomer for use as an Nrf2-ARE pathway activator in the treatment of ALS (Mead, Pg. 446, second column, last paragraph – Pg. 447, second column, continued paragraph; Lee, Col. 5, Lns. 25-30). The motivation being to provide a stable composition that does not precipitate out of solution, thereby reducing local site reactions on parenteral administration (Desai, Col. 3, Lns. 16-31).
Response to Arguments
Applicants argue on pages 5-6 of the response dated 12/22/2025, that “Applicant respectfully asserts that the only published aqueous solubility of (S)-(+)-apomorphine hydrochloride is 12.5 µg/mL. Since Watts, (cited regarding claims 17-18 below) teaches an "aqueous solubility of apomorphine hydrochloride is around 20 mg/ml, it is apparent that (S)-(+)- apomorphine is more than one thousand times less soluble than (R)-(-)-apomorphine⁸ used by Watts. Therefore it is not obvious that the formulations of any of the cited references could achieve the solubility of the present claims”. Applicants conclude that none of the cited references teach or suggest 10 mM citrate buffer or 40 mg/ml solubility of (S)-(+)-apomorphine, and hence a prima facie case has not been established.
Applicant's arguments have been fully considered but they are not persuasive.
While the examiner appreciates Applicant’s citing of the aqueous solubility of (S)-(+)-apomorphine as being 12.5 µg/mL, it is noted that the aqueous solubility of (S)-(+)-apomorphine is 12.5 µg/mL at pH 7.4 (taken from the cited PubChem reference).
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However, the instant claims do not recite a solubility of 40 mg/ml at a given pH. Moreover, the current 35 U.S.C. 103 rejection of record addresses all the limitations of the amended claims. As clearly articulated in the 103 rejection, Dey teaches compositions of apomorphine having a solubility of 30 mg/ml and 40 mg/ml (it is acknowledged that apomorphine in the art generally relates to the R-enantiomer). Mead teaches the S[+]-apomorphine is considered an attractive candidate for therapeutic assessment in the treatment of ALS because it lacks the unwanted effects of dopamine agonism and induction of emesis. Lee teaches the stability and solubility of dopamine agonists in 10 mM citrate buffer with added 2-hydroxypropyl-β-cyclodextrin (HPCD) led to a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine. Desai teaches benzyl alcohol has been successfully utilized to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs. Generally speaking, enantiomers are mirror images with the same intermolecular forces and possess identical physical properties, such as solubility, melting point, boiling point, density, etc.. The prior art teaches 10 mM citrate and benzyl alcohol as excipients commonly used to enhance the solubility of sparingly water soluble drugs. Therefore, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have formulated a pharmaceutical composition of S-apomorphine to arrive at the claimed composition with an enhanced solubility of 40 mg/ml, in consideration of the prior art.
Applicants have not indicated any unexpected results for the claimed pharmaceutical composition of S-apomorphine in relation to the prior art. In the absence of evidence to the contrary, the instant claims are rendered prima facie obvious over the combined teachings of the prior art - Dey, Mead, Lee and Desai.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 8, 11-13, 16, 19-21 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of U.S. Patent No. 11,459,301 B2 in view of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) and Desai et al. (US 4,784,845 A, date of patent 15 November 1988, hereinafter Desai).
Although the claims at issue are not identical, both sets of claims are drawn to a pharmaceutical composition comprising S-apomorphine or salt thereof.
The instant claims are drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (i.e., S-apomorphine) or salt forms thereof, a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Claim 10 of the reference ‘301 patent is drawn to a pharmaceutical composition comprising the S-apomorphine hydrochloride hydrate salt and a pharmaceutically acceptable excipient.
The reference ‘301 patent does not teach a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Dey teaches the pharmaceutical compositions comprising a cyclodextrin, specifically hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD) (Paras. [0025]-[0027]; Para. [0113]; ; Para. [0124]; Para. [0127]). Dey teaches these formulations contain 30 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 30 mg/ml) (Para. [0113]; Para. [0127]). Dey teaches various other formulations of apomorphine that contain 40 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 40 mg/ml) (Para. [0111]; Para. [0112]).
Lee teaches formulations that comprise a dopamine agonist, say apomorphine, cyclodextrin, a suitable carrier and water (Col. 4, Lns. 22-26). Lee discusses the stability and solubility of the dopamine agonists in 10 mM citrate buffer with or without added 2-hydroxypropyl-β-cyclodextrin (HPCD) (Col. 5, Lns. 37-65). Lee teaches the addition of the HPCD brought about significant increases in the stabilities and solubilities of apomorphine (Col. 5, Lns. 55-65; FIG. 1A; FIG. 2). Lee teaches the addition of the HPCD resulted in a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine (Col. 5, Lns. 47-65).
Desai teaches emulsion compositions for the parenteral administration of sparingly water soluble ionizable hydrophobic drugs (Title; Col. 2, Ln. 53 – Col. 3, Ln. 6). Desai teaches benzyl alcohol has been successfully utilized as a cosolvent and/or cosurfactant in the present invention to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs in the quick breaking, in vivo, emulsion compositions (Abstract; Col. 2, Lns. 53-64; Col. 4, Lns. 40-45). Desai teaches an advantage of the emulsion composition is that it circumvents the local precipitation of the sparingly soluble drugs, thereby avoiding the localized accumulation of potentially irritating compounds (Col. 3, Lns. 16-31). Desai teaches the emulsion solubilization systems are applicable to other known commercial products and drug substances reported in the literature (Col. 3, Lns. 47-51).
According to MPEP 2144.09 (II) and (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). In the instant case, the apomorphine of the prior art and the instant compound S-apomorphine, are enantiomers, rendering them prima facie obvious.
Further, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07.
Thus, given the teachings of the reference ‘301 patent in view of the prior art, Dey, Lee and Desai, a PHOSITA would have been motivated to incorporate the instantly claimed excipients in a formulation of S-apomorphine to arrive at the instant pharmaceutical composition with a reasonable expectation of success in enhancing the solubility of S-apomorphine.
The instant claims 1, 4, 8, 11-13, 16, 19-21 and 24 and claim 10 of the reference ‘301 patent are therefore not patentably distinct.
This is a nonstatutory double patenting rejection.
Claims 1, 4, 8, 11-13, 16, 19-21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4 and 7 of co-pending Application No 17/633,150 in view of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) and Desai et al. (US 4,784,845 A, date of patent 15 November 1988, hereinafter Desai).
Although the claims at issue are not identical, both sets of claims are drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
The instant claims are drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (i.e., S-apomorphine) or salt forms thereof, a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Claims 1, 4 and 7 of reference ‘150 co-pending application are drawn to a method of treating a neurodegenerative disease, the method comprising: administering a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7- tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol and at least one pharmaceutically acceptable excipient to a mammal.
The reference ‘150 co-pending application anticipates a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7- tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol. The reference ‘150 co-pending application does not teach a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Dey teaches the pharmaceutical compositions comprising a cyclodextrin, specifically hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD) (Paras. [0025]-[0027]; Para. [0113]; ; Para. [0124]; Para. [0127]). Dey teaches these formulations contain 30 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 30 mg/ml) (Para. [0113]; Para. [0127]). Dey teaches various other formulations of apomorphine that contain 40 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 40 mg/ml) (Para. [0111]; Para. [0112]).
Lee teaches formulations that comprise a dopamine agonist, say apomorphine, cyclodextrin, a suitable carrier and water (Col. 4, Lns. 22-26). Lee discusses the stability and solubility of the dopamine agonists in 10 mM citrate buffer with or without added 2-hydroxypropyl-β-cyclodextrin (HPCD) (Col. 5, Lns. 37-65). Lee teaches the addition of the HPCD brought about significant increases in the stabilities and solubilities of apomorphine (Col. 5, Lns. 55-65; FIG. 1A; FIG. 2). Lee teaches the addition of the HPCD resulted in a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine (Col. 5, Lns. 47-65).
Desai teaches emulsion compositions for the parenteral administration of sparingly water soluble ionizable hydrophobic drugs (Title; Col. 2, Ln. 53 – Col. 3, Ln. 6). Desai teaches benzyl alcohol has been successfully utilized as a cosolvent and/or cosurfactant in the present invention to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs in the quick breaking, in vivo, emulsion compositions (Abstract; Col. 2, Lns. 53-64; Col. 4, Lns. 40-45). Desai teaches an advantage of the emulsion composition is that it circumvents the local precipitation of the sparingly soluble drugs, thereby avoiding the localized accumulation of potentially irritating compounds (Col. 3, Lns. 16-31). Desai teaches the emulsion solubilization systems are applicable to other known commercial products and drug substances reported in the literature (Col. 3, Lns. 47-51).
According to MPEP 2144.09 (II) and (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). In the instant case, the apomorphine of the prior art and the instant compound S-apomorphine, are enantiomers, rendering them prima facie obvious.
Further, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07.
Thus, given the teachings of the reference ‘150 application in view of the prior art, Dey, Lee and Desai, a PHOSITA would have been motivated to incorporate the instantly claimed excipients in a formulation of (6aS)-6-methyl-5,6,6a,7- tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol to arrive at the instant pharmaceutical composition with a reasonable expectation of success in enhancing the solubility of S-apomorphine.
The instant claims 1, 4, 8, 11-13, 16, 19-21 and 24 and claims 1, 4 and 7 of the reference ‘150 co-pending application are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 8, 11-13, 16, 19-21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 88 of co-pending Application No 17/286,797 in view of Dey et al. (US 2018/0098981 A1, publication date 12 April 2018, hereinafter Dey), Lee et al. (US 5,814,638 A, 29 September 1998, hereinafter Lee) and Desai et al. (US 4,784,845 A, date of patent 15 November 1988, hereinafter Desai).
Although the claims at issue are not identical, both sets of claims are drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
The instant claims are drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (i.e., S-apomorphine) or salt forms thereof, a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Claim 88 of reference ‘797 co-pending application is drawn to a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol and at least one pharmaceutically acceptable excipient.
The reference ‘797 co-pending application anticipates a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7- tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol. The reference ‘797 co-pending application does not teach a cyclodextrin which is HPβCD or SBEβCD, a 10 mM citrate buffer, and optionally at least one additional pharmaceutically acceptable excipient OR benzyl alcohol; wherein the pharmaceutical composition has a solubility of 40 mg/mL of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol.
Dey teaches the pharmaceutical compositions comprising a cyclodextrin, specifically hydroxypropyl-β-cyclodextrin (HBβCD) or sulfobutyl-β-cyclodextrin (SBβCD) (Paras. [0025]-[0027]; Para. [0113]; ; Para. [0124]; Para. [0127]). Dey teaches these formulations contain 30 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 30 mg/ml) (Para. [0113]; Para. [0127]). Dey teaches various other formulations of apomorphine that contain 40 mg/ml apomorphine (i.e., the solubility of apomorphine has been increased to at least 40 mg/ml) (Para. [0111]; Para. [0112]).
Lee teaches formulations that comprise a dopamine agonist, say apomorphine, cyclodextrin, a suitable carrier and water (Col. 4, Lns. 22-26). Lee discusses the stability and solubility of the dopamine agonists in 10 mM citrate buffer with or without added 2-hydroxypropyl-β-cyclodextrin (HPCD) (Col. 5, Lns. 37-65). Lee teaches the addition of the HPCD brought about significant increases in the stabilities and solubilities of apomorphine (Col. 5, Lns. 55-65; FIG. 1A; FIG. 2). Lee teaches the addition of the HPCD resulted in a twofold increase in solubility starting from solutions containing 20 mg/ml of the dopamine agonist in 10 mM citrate buffer for apomorphine (Col. 5, Lns. 47-65).
Desai teaches emulsion compositions for the parenteral administration of sparingly water soluble ionizable hydrophobic drugs (Title; Col. 2, Ln. 53 – Col. 3, Ln. 6). Desai teaches benzyl alcohol has been successfully utilized as a cosolvent and/or cosurfactant in the present invention to aid in the solubilization of certain sparingly water soluble hydrophobic ionizable drugs in the quick breaking, in vivo, emulsion compositions (Abstract; Col. 2, Lns. 53-64; Col. 4, Lns. 40-45). Desai teaches an advantage of the emulsion composition is that it circumvents the local precipitation of the sparingly soluble drugs, thereby avoiding the localized accumulation of potentially irritating compounds (Col. 3, Lns. 16-31). Desai teaches the emulsion solubilization systems are applicable to other known commercial products and drug substances reported in the literature (Col. 3, Lns. 47-51).
According to MPEP 2144.09 (II) and (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). In the instant case, the apomorphine of the prior art and the instant compound S-apomorphine, are enantiomers, rendering them prima facie obvious.
Further, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07.
Thus, given the teachings of the reference ‘797 application in view of the prior art, Dey, Lee and Desai, a PHOSITA would have been motivated to incorporate the instantly claimed excipients in a formulation of (6aS)-6-methyl-5,6,6a,7- tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol to arrive at the instant pharmaceutical composition with a reasonable expectation of success in enhancing the solubility of S-apomorphine.
The instant claims 1, 4, 8, 11-13, 16, 19-21 and 24 and claim 88 of the reference ‘797 co-pending application are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 4, 8, 11-13, 16, 19-21 and 24 are rejected.
Claim 1 is objected to.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627