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 .
Formal Matters
Applicants’ responses in the reply filed on 13 July 2026 are acknowledged and have been fully considered. Claims 1-32 are pending. Claims 1-32 are under consideration in the instant office action. Claims 33-96 are canceled.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 20 September 2024 and 16 May 2023 are noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. Signed copies are attached herein.
Election/Restrictions
Applicant's election with traverse of PVP-PLA copolymer as the specific excipient; the micellar preparation dehydrated into a solid as the form of the composition; butylated hydroxyanisole as the specific further agent; sodium salt as specific salt; phosphate buffer as specific buffer; and PGLA as specific solubilizing agent; and benzalkonium chloride as specific preservative in the reply filed on 13 July 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Objections
Claim 17 is objected to because of the following informalities: Claim 17 recites “The composition of claim 7, wherein the composition comprises from about 1% to about 20% by weight the buffer.” Claim 17 should read as “The composition of claim 7, wherein the composition comprises from about 1% to about 20% by weight of the buffer.” 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 7, 15, 19, 21, 23-24, and 32 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 7 recites the limitation "the pharmaceutically acceptable excipient" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation "the first and second compounds in combination" in claim 14. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "wherein the solid form has been rehydrated in a solvent to produce a micellar solution" in claim 13. There is insufficient antecedent basis for this limitation in the claim.
Claim 21 recites the limitation "the first and second compounds in combination" in claim 19. There is insufficient antecedent basis for this limitation in the claim.
Claim 23 recites the limitation "wherein the micellar solution comprises particles having a particle size (Z.av) of 12-50 nm, 15-45 nm, or 20-40 nm." in claim 21. There is insufficient antecedent basis for this limitation in the claim.
Claim 24 recites the limitation "wherein the particles have a polydispersity index (PDi) of from about 0.05 to about 0.15.”" in claim 21. There is insufficient antecedent basis for this limitation in the claim.
Claim 32 recites “essentially free”, which is a term of degree that is not defined in the specification by any numerical limit, analytical method, or comparative standard. One of ordinary skill in the art cannot determine how much residual oxygen is permitted before the composition falls outside the claim.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 7, 18, 28, and 32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lynch et al. (US 2015/0258040, IDS reference 05/16/2023).
Note: Applicant’s specification discloses that the two enantiomers are know as HU-308 and HU-433, respectively (see paragraph 00113).
Lynch et al. disclose methods of treatment of ocular inflammation and/or neuropathic pain in a subject in need thereof, comprising administering to the subject in need thereof a CB2 target agent, a cannabimimetic agent or a combination thereof. The agent is optionally a cannabinoid, such as a non-psychotropic cannabinoid or a synthetic cannabinoid. In certain embodiments, the non-psychotropic phytocannabinoid is β-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308, or a modified CBD such as CBD-DMH. In methods of the disclosure, CBD-DMH is optionally administered in combination with a further CB2 target agent or cannabimimetic agent. The disclosure also provides ocular pharmaceutical compositions containing the CB2 target agents and/or cannabimimetic agents described herein (see abstract). HU-308 is a synthetic cannabinoid compound that binds and activates the CB2 receptor specifically. An enantiomeric derivative of HU-308, named HU-433, is also a CB2 agonist. HU-433 has been shown to have 2-3 orders of magnitude greater potency in both in vitro and in vivo systems (see paragraph 0007). In one embodiment, the agent is a cannabinoid. Optionally, the cannabinoid is a non-psychotropic cannabinoid, such as a phytocannabinoid, or a synthetic cannabinoid. In one embodiment, the non-psychotropic phytocannabinoid is β-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308 or CBD-DMH or a combination of two or more of the foregoing (paragraph 0046). In one embodiment, the composition comprises an agent that is a cannabinoid, optionally a non-psychotropic cannabinoid or a synthetic cannabinoid. The non-psychotropic cannabinoid is optionally a phytocannabinoid. In one embodiment, the non-psychotropic phytocannabinoid is β-caryophyllene or CBD and the synthetic cannabinoid is HU-433, HU-308, CBD-DMH, or a combination of two or more of the foregoing (paragraph 0052). The term “HU-433” as used herein refers to a synthetic cannabinoid agonist of the chemical structure:
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wherein the CIP configurations of the positions marked “3”, “4” and “6” in the above chemical structure are R, R and R, respectively.
The term “HU-308” as used herein refers to a synthetic cannabinoid agonist of the chemical structure:
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wherein the CIP configurations of the positions marked “3”, “4” and “6” in the above chemical structure are S, S and S, respectively (see paragraphs 0072-0073). In another embodiment of the present disclosure, the synthetic cannabinoid is HU-433, HU-308, a modified CBD (such as CBD-DMH) or combinations thereof. For example, the synthetic cannabinoid can be HU-433. For example, the synthetic cannabinoid can be HU-308. For example, the synthetic cannabinoid can be a modified CBD such as CBD-DMH or another synthetic cannabinoid that is a modified CBD with comparable activity to CBD-DMH. In an embodiment, the modified CBD is CBD-DMH. In another embodiment, the synthetic cannabinoid is a combination of HU-433, HU-308 and/or a modified CBD, optionally CBD-DMH (paragraph 0090). Accordingly, the disclosure provides an ocular formulation of cannabinoids (e.g. Beta-caryophyllene [also referred to herein as Beta-C or βc], Cannabidiol [CBD], cannabidiol-dimethylheptyl [CBD-DMH] or other modified CBDs, HU-308 and HU-433, individually or in combinations of two or more of the foregoing) for treatment of ocular diseases (paragraph 0117). In an embodiment, the ocular pharmaceutical composition contains the CB2 target agent and/or the cannabimimetic agent in an amount of from 0.01% to 10% by weight, based on the weight of the total composition (paragraph 0105). Based on this teaching both HU-308 and HU-433 may be present in the composition at 0.01% to 10% by weight of the total weight of the composition. The weight ratio of HU-308 to HU-433 or vice versa can be calculated as 0.01%/10% to 10%/0.01% which will be equal to 1:1000 to 1000:1. The oil-in-water emulsion formulations of the present disclosure, for example used in the ocular pharmaceutical compositions of cannabinoids may comprise from 0.5 to 50% oil, from 0.1 to 10% emulsifier and from 0.05 to 5% surfactant. Optionally, in order to obtain a non-viscous composition, the concentration of the non-aqueous phase should generally not exceed 25%. For more viscous formulations this concentration is increased. The agent is optionally present in an amount of 0.05 to 5% by weight of the composition (paragraph 0113). The present disclosure also includes an ocular pharmaceutical composition comprising a CB2 target agent, a cannabimimetic agent or a combination thereof and a carrier suitable for ocular administration to an eye (paragraph 0028). In an embodiment, the carrier comprises a liposome (paragraph 0031). Optionally, lipid components in the liposome formulations are phospholipids and cholesterol; excipients are tocopherol, antioxidants, viscosity-inducing agents and/or preservatives. The selection of suitable components can be made by a person skilled in the art (paragraph 0102). The inclusion of antioxidants will render the composition essentially free of oxygen and prevents the formation of impurities.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Note: The claims are examined with respect to the elected species wherein PVP-PLA copolymer as the specific excipient; the micellar preparation dehydrated into a solid as the form of the composition; butylated hydroxyanisole as the specific further agent; sodium salt as specific salt; phosphate buffer as specific buffer; and PGLA as specific solubilizing agent; and benzalkonium chloride as specific preservative.
Claims 1-28 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Lynch et al. (US 2015/0258040) in view of Smith et al. (WO2018/176158, IDS reference 05/16/2023).
Note: Applicant’s specification discloses that the two enantiomers are know as HU-308 and HU-433, respectively (see paragraph 00113).
Applicants’ claims
Applicants claim a combination of HU-308 and HU-433. Dependent claims thereof recite other additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Lynch et al. teach methods of treatment of ocular inflammation and/or neuropathic pain in a subject in need thereof, comprising administering to the subject in need thereof a CB2 target agent, a cannabimimetic agent or a combination thereof. The agent is optionally a cannabinoid, such as a non-psychotropic cannabinoid or a synthetic cannabinoid. In certain embodiments, the non-psychotropic phytocannabinoid is β-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308, or a modified CBD such as CBD-DMH. In methods of the disclosure, CBD-DMH is optionally administered in combination with a further CB2 target agent or cannabimimetic agent. The disclosure also provides ocular pharmaceutical compositions containing the CB2 target agents and/or cannabimimetic agents described herein (see abstract). HU-308 is a synthetic cannabinoid compound that binds and activates the CB2 receptor specifically. An enantiomeric derivative of HU-308, named HU-433, is also a CB2 agonist. HU-433 has been shown to have 2-3 orders of magnitude greater potency in both in vitro and in vivo systems (see paragraph 0007). In one embodiment, the agent is a cannabinoid. Optionally, the cannabinoid is a non-psychotropic cannabinoid, such as a phytocannabinoid, or a synthetic cannabinoid. In one embodiment, the non-psychotropic phytocannabinoid is β-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308 or CBD-DMH or a combination of two or more of the foregoing (paragraph 0046). In one embodiment, the composition comprises an agent that is a cannabinoid, optionally a non-psychotropic cannabinoid or a synthetic cannabinoid. The non-psychotropic cannabinoid is optionally a phytocannabinoid. In one embodiment, the non-psychotropic phytocannabinoid is β-caryophyllene or CBD and the synthetic cannabinoid is HU-433, HU-308, CBD-DMH, or a combination of two or more of the foregoing (paragraph 0052). The term “HU-433” as used herein refers to a synthetic cannabinoid agonist of the chemical structure:
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wherein the CIP configurations of the positions marked “3”, “4” and “6” in the above chemical structure are R, R and R, respectively.
The term “HU-308” as used herein refers to a synthetic cannabinoid agonist of the chemical structure:
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wherein the CIP configurations of the positions marked “3”, “4” and “6” in the above chemical structure are S, S and S, respectively (see paragraphs 0072-0073). In another embodiment of the present disclosure, the synthetic cannabinoid is HU-433, HU-308, a modified CBD (such as CBD-DMH) or combinations thereof. For example, the synthetic cannabinoid can be HU-433. For example, the synthetic cannabinoid can be HU-308. For example, the synthetic cannabinoid can be a modified CBD such as CBD-DMH or another synthetic cannabinoid that is a modified CBD with comparable activity to CBD-DMH. In an embodiment, the modified CBD is CBD-DMH. In another embodiment, the synthetic cannabinoid is a combination of HU-433, HU-308 and/or a modified CBD, optionally CBD-DMH (paragraph 0090). Accordingly, the disclosure provides an ocular formulation of cannabinoids (e.g. Beta-caryophyllene [also referred to herein as Beta-C or βc], Cannabidiol [CBD], cannabidiol-dimethylheptyl [CBD-DMH] or other modified CBDs, HU-308 and HU-433, individually or in combinations of two or more of the foregoing) for treatment of ocular diseases (paragraph 0117). In an embodiment, the ocular pharmaceutical composition contains the CB2 target agent and/or the cannabimimetic agent in an amount of from 0.01% to 10% by weight, based on the weight of the total composition (paragraph 0105). Based on this teaching both HU-308 and HU-433 may be present in the composition at 0.01% to 10% by weight of the total weight of the composition. The weight ratio of HU-308 to HU-433 or vice versa can be calculated as 0.01%/10% to 10%/0.01% which will be equal to 1:1000 to 1000:1. The oil-in-water emulsion formulations of the present disclosure, for example used in the ocular pharmaceutical compositions of cannabinoids may comprise from 0.5 to 50% oil, from 0.1 to 10% emulsifier and from 0.05 to 5% surfactant. Optionally, in order to obtain a non-viscous composition, the concentration of the non-aqueous phase should generally not exceed 25%. For more viscous formulations this concentration is increased. The agent is optionally present in an amount of 0.05 to 5% by weight of the composition (paragraph 0113). The present disclosure also includes an ocular pharmaceutical composition comprising a CB2 target agent, a cannabimimetic agent or a combination thereof and a carrier suitable for ocular administration to an eye (paragraph 0028). In an embodiment, the carrier comprises a liposome (paragraph 0031). Optionally, lipid components in the liposome formulations are phospholipids and cholesterol; excipients are tocopherol, antioxidants, viscosity-inducing agents and/or preservatives. The selection of suitable components can be made by a person skilled in the art (paragraph 0102).
Regarding claim 25, Lynch et al. already permits each active component to be present at 0.01–10 wt % of the total composition. Adding a third or fourth compound (another cannabinoid, an additional enantiomer, a residual synthetic intermediate, or a conventional excipient) at 0.015–1.5 % is therefore within the same teaching and would have been obvious for potency adjustment, stability, or simply as an unavoidable process impurity. The limitation adds no patentable distinction.
Regarding claims 26-27, Formula B is the aldehyde analogue of HU-308/HU-433 (the myrtenal-type oxidation product of the allylic hydroxymethyl group). That aldehyde is an expected synthetic intermediate (oxidation of myrtenol to myrtenal is the first step in the classic HU-308 route) and an expected oxidative degradation product of the allylic alcohol. The composition of Lynch et al. will therefore contain some amount of Formula B. Claim 26 merely recites “up to 15 wt %” of that impurity; claim 27 recites the still-broader “up to 13 %, 10 %, 5 %, 2 %, 1 %, 0.1 %, 0.01 % or 0.001 %.” Those ceilings include the zero-impurity and trace-impurity compositions that are the ordinary goal of purification. One of ordinary skill in the art would have found it obvious to reduce the aldehyde impurity to any of the recited levels by routine chromatography, recrystallization or antioxidant stabilization. No unexpected result is shown for any particular upper limit.
Regarding claims 28 and 32, Allylic alcohols such as HU-308 or HU-4333 are known to oxidize to the corresponding aldehydes. Adding a conventional antioxidant (tocopherol, BHT, ascorbate, etc.) to suppress that oxidation is standard pharmaceutical practice and is already contemplated by the “pharmaceutically acceptable excipient” language of Lynch et al. and by the optional antioxidant of claim 18. The purpose of the antioxidant is removing the effect of oxidation by removing oxygen. The limitations are therefore obvious.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Lynch et al. do not specifically teach the incorporation of PVP-PLA copolymer and its amount, the phosphate buffer and its amount; and the sodium salt and its amount; the particle sizes of the micelle and the polydispersity index and pH of the composition. These deficiencies are cured by the teachings of Smith et al.
Smith et al. teach PVP-PLA block copolymers as defined in Formula (I): I wherein, x is an initiator alcohol having a boiling point greater than 145°C, n is, on average, from 20 and 40, and m is, on average, from 10 and 40, wherein the block copolymers have a number average molecular weight (Mn) of at least 3000 Da. Polymers demonstrating flexibility in formulating multiple low-solubility active pharmaceutical ingredients (APIs) are described. Liquid and dry pharmaceutical formulations comprising an API are described, along with delivery methods, uses, and kits. APIs may include, e.g. flurbiprofen, celecoxib, acetaminophen, or propofol. Also provided is a method of synthesizing the PVP-PLA block copolymers by (i) initiating polymerization of D,L-Lactide from the initiator alcohol x to form poly(lactic acid), adding a xanthate to form a PLA macroinitiator, and polymerizing NVP onto the PLA macroinitiator, by controlled polymerization, to form the block copolymer compound of Formula (I) (see abstract).Smith et al. teach PVP-PLA block co olymers as defined in Formula I:
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wherein:
x is an initiator alcohol having a boiling point greater than 145°C,
n is, on average, from 20 and 40, and
m is, on average, from 10 and 40,
wherein the block copolymers have a number average molecular weight (Mn) of at least 3000 Da (see claim 1). A nanovehicle delivery system comprising micelles formed of the PVP-PLA block copolymers of any one of claims 1 to 70 (see claim 71). A dry pharmaceutical composition comprising the PVP-PLA block copolymers of any one of claims 1 to 70 in molecular association with at least one active pharmaceutical ingredient (API) (see claim 72). The dry pharmaceutical composition of any one of claims 72 to 81, wherein the at least one API has a solubility in water of 0.005g/L to 30g/L (paragraph 0082). In another aspect, there is provided a nanovehicle delivery system comprising micelles formed of the PVP-PLA block copolymers (paragraph 0009). By "micelle" will be understood as a supramolecular self-assembly comprised of molecules that arrange themselves in a generally spherical form in aqueous solutions. The formation of a micelle is a response to the amphipathic nature the PVP-PLA block copolymers, which contain both hydrophilic regions (PLA groups) as well as hydrophobic regions (PVP groups). A typical micelle in aqueous solution forms with the hydrophilic regions of the polymer in contact with surrounding solvent, sequestering the hydrophobic regions in the micelle center. Herein, the term "micelle" or "micellar" also may be used to refer to the structure of a dried form of a previously liquid colloidal composition of micellar nanoparticles, wherein some elements of a micellar structure are retained in dried form, or wherein the dried form readily reforms micelles upon hydration (paragraph 0067). Lyophilized cakes were reconstituted in water for injection in less than 1 min to give clear, particle-free solutions having flurbiprofen concentration of 50mg/ml pH of reconstituted solutions for the formulations obtained with both polymers was in the range from 7.2 to 7.4 as measured using an Accumet AP61 pH-meter equipped with a gel-filled epoxy-body combination electrode. Osmolality of reconstituted samples was measured with a freezing point depression 3300 Micro-Osmometer (Advanced Instruments) and it was in the range of 380 to 420 mOsm/kg. Optical transmittance was determined in 1-cm disposable polystyrene cuvettes using an Agilent Cary UV-Vis-NIR 5000 spectrometer. Themeasurements were performed at 650nm and room temperature using empty cuvette as a blank. The reconstituted solutions prepared form the cakes containing WB-4 polymer showed optical transmittance between 98% and 100%. The solutions of the samples prepared using polymer WB-7 have slightly lower transmittance, in the range 84-85%. Z-average size of micelles and their size distribution was determined at 25°C by dynamic light scattering using a Malvern Zetasizer Nano ZS equipped with 10mW He-Ne laser operating at 633nm. Z- average particle size for both reconstituted formulations of the cakes containing WB-4 and WB-7 was similar and equal to 43.9 and 43.6nm, respectively. Figure 7 shows that particle size distributions for formulations prepared using two different polymer samples WB-4 and WB-7 and reconstituted at 50mg/ml have similar shape with the volume-average size of micelles from ca. 10 to 200 nm. Values of the parameters determined upon characterization of reconstituted Flurbiprofen formulations are shown in Table 26 (paragraph 00345). In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.8. In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.6. In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.5. In one embodiment, the polydispersity index is≤1.4. In one embodiment, the polydispersity index is≤1.3. In one embodiment, the polydispersity index is≤1.2. In one embodiment, the polydispersity index is≤1.1. In one embodiment, the PDI is as measured by gel permeation chromatography with light scattering (GPC-LS) (see paragraph 00103). In one aspect, there is provided a nanovehicle delivery system comprising micelles formed of the above-described PVP-PLA block copolymers. By "nanovehicle delivery system" is meant nanoparticles formed of the above-described block co-polymers. The nanoparticles may consist of the above-describe block co-polymers in some embodiments. The nanovehicle delivery system may be useful for solubilizing another molecule, which may be of low solubility or hydrophobic. The nanovehicle delivery system may be useful for solubilizing one or more API, as described herein (paragraph 00105). In one aspect, there is provided a dry pharmaceutical composition comprising the above-described PVP-PLA block copolymers in molecular association with at least one active pharmaceutical ingredient (API) (see paragraph 00107). By "dry pharmaceutical composition" is meant a formulation prepared by drying (e.g., removing solvent) a mixture of the API and the block copolymers to form an intimate mixture of the API and the block copolymers. "Dry" here will be understood to mean "substantially dry", and indicates that the at least about 90%, at least about 95%, 96%, 97%, 98%, 99%, or 99.9%, of the solvent has been removed during the drying process. The dry pharmaceutical composition may be in the form of a cake of a powder. The term "powder" refers to a substantially dry, free-flowing, particulate material having high bulk density. Spray- dried powders typically have a bulk density in the range of about 0.05 -1.00 g/cc, more typically between about 0.2 - 0.5 g/cc. Advantageously, powders are suitable for incorporation into various non-intravenous dosage forms, including but not limited to, tablets, including rapid disintegrating tablets, caplets, capsules, sachets, solutions, suspensions, creams, gels, ointments, pessaries, suppositories, enema, drops, aerosol or dry powder inhalers, and the like. The term "cake", as compared to a powder, refers to a non-flowing, non-particulate material having a low bulk density, typically in the range of about 0.0001 - 0.05 g/cc. In accordance with the methods disclosed herein, a cake may be formed, for example, as a result of lyophilization or freeze-drying (paragraph 00108). In one embodiment, the dry pharmaceutical composition has a DLL (drug loading level) of at least 10% wt/wt of the at least one API. In one embodiment, the dry pharmaceutical composition has a DLL of at least 20% wt/wt of the at least one API. In one embodiment, the dry pharmaceutical composition has a DLL of at least 30% wt/wt of the at least one API. DLL may be selected according to the API and according to requirements, and provided that requirements for administration are met. The DLL may be 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, or greater than 30% (paragraph 00124). In one embodiment, the at least one API may be insoluble to sparingly soluble. In one embodiment, the at least one API has a solubility in water of Og/L to 33g/L. The API may be insoluble to slightly soluble (i.e., Og/L to 10g/L). In one embodiment, the at least one API has a solubility in water of Og/L to 14g/L. The API may be sparingly soluble. In one embodiment, the API has a solubility in water of 10g/L to 33g/L (paragraph 00127). For examples of overlapping amount of polymer see tables 21, 23-25, and 28-31.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Lynch et al. by utilizing the micellar nanovehicle of Smith et al which contains the same or substantially identical ingredients such as the polymers and other ingredients in amounts that overlap with the claimed ranges as recited in the instant claims because Smith et al. teach PVP-PLA block copolymers as defined in Formula (I): I wherein, x is an initiator alcohol having a boiling point greater than 145°C, n is, on average, from 20 and 40, and m is, on average, from 10 and 40, wherein the block copolymers have a number average molecular weight (Mn) of at least 3000 Da. Polymers demonstrating flexibility in formulating multiple low-solubility active pharmaceutical ingredients (APIs) are described. Liquid and dry pharmaceutical formulations comprising an API are described, along with delivery methods, uses, and kits. APIs may include, e.g. flurbiprofen, celecoxib, acetaminophen, or propofol. Also provided is a method of synthesizing the PVP-PLA block copolymers by (i) initiating polymerization of D,L-Lactide from the initiator alcohol x to form poly(lactic acid), adding a xanthate to form a PLA macroinitiator, and polymerizing NVP onto the PLA macroinitiator, by controlled polymerization, to form the block copolymer compound of Formula (I) (see abstract).Smith et al. teach PVP-PLA block copolymers as defined in Formula I:
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wherein:
x is an initiator alcohol having a boiling point greater than 145°C,
n is, on average, from 20 and 40, and
m is, on average, from 10 and 40,
wherein the block copolymers have a number average molecular weight (Mn) of at least 3000 Da (see claim 1). A nanovehicle delivery system comprising micelles formed of the PVP-PLA block copolymers of any one of claims 1 to 70 (see claim 71). A dry pharmaceutical composition comprising the PVP-PLA block copolymers of any one of claims 1 to 70 in molecular association with at least one active pharmaceutical ingredient (API) (see claim 72). The dry pharmaceutical composition of any one of claims 72 to 81, wherein the at least one API has a solubility in water of 0.005g/L to 30g/L (paragraph 0082). In another aspect, there is provided a nanovehicle delivery system comprising micelles formed of the PVP-PLA block copolymers (paragraph 0009). By "micelle" will be understood as a supramolecular self-assembly comprised of molecules that arrange themselves in a generally spherical form in aqueous solutions. The formation of a micelle is a response to the amphipathic nature the PVP-PLA block copolymers, which contain both hydrophilic regions (PLA groups) as well as hydrophobic regions (PVP groups). A typical micelle in aqueous solution forms with the hydrophilic regions of the polymer in contact with surrounding solvent, sequestering the hydrophobic regions in the micelle center. Herein, the term "micelle" or "micellar" also may be used to refer to the structure of a dried form of a previously liquid colloidal composition of micellar nanoparticles, wherein some elements of a micellar structure are retained in dried form, or wherein the dried form readily reforms micelles upon hydration (paragraph 0067). Lyophilized cakes were reconstituted in water for injection in less than 1 min to give clear, particle-free solutions having flurbiprofen concentration of 50mg/ml pH of reconstituted solutions for the formulations obtained with both polymers was in the range from 7.2 to 7.4 as measured using an Accumet AP61 pH-meter equipped with a gel-filled epoxy-body combination electrode. Osmolality of reconstituted samples was measured with a freezing point depression 3300 Micro-Osmometer (Advanced Instruments) and it was in the range of 380 to 420 mOsm/kg. Optical transmittance was determined in 1-cm disposable polystyrene cuvettes using an Agilent Cary UV-Vis-NIR 5000 spectrometer. The measurements were performed at 650nm and room temperature using empty cuvette as a blank. The reconstituted solutions prepared form the cakes containing WB-4 polymer showed optical transmittance between 98% and 100%. The solutions of the samples prepared using polymer WB-7 have slightly lower transmittance, in the range 84-85%. Z-average size of micelles and their size distribution was determined at 25°C by dynamic light scattering using a Malvern Zetasizer Nano ZS equipped with 10mW He-Ne laser operating at 633nm. Z- average particle size for both reconstituted formulations of the cakes containing WB-4 and WB-7 was similar and equal to 43.9 and 43.6nm, respectively. Figure 7 shows that particle size distributions for formulations prepared using two different polymer samples WB-4 and WB-7 and reconstituted at 50mg/ml have similar shape with the volume-average size of micelles from ca. 10 to 200 nm. Values of the parameters determined upon characterization of reconstituted Flurbiprofen formulations are shown in Table 26 (paragraph 00345). In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.8. In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.6. In one embodiment, the PVP-PLA block copolymers have a polydispersity index (PDI) of≤1.5. In one embodiment, the polydispersity index is≤1.4. In one embodiment, the polydispersity index is≤1.3. In one embodiment, the polydispersity index is≤1.2. In one embodiment, the polydispersity index is≤1.1. In one embodiment, the PDI is as measured by gel permeation chromatography with light scattering (GPC-LS) (see paragraph 00103). In one aspect, there is provided a nanovehicle delivery system comprising micelles formed of the above-described PVP-PLA block copolymers. By "nanovehicle delivery system" is meant nanoparticles formed of the above-described block co-polymers. The nanoparticles may consist of the above-describe block co-polymers in some embodiments. The nanovehicle delivery system may be useful for solubilizing another molecule, which may be of low solubility or hydrophobic. One of ordinary skill in the art would have been motivated to utilize the carrier system of Smith et al. because Smith et al. teach that the nanovehicle delivery system may be useful for solubilizing one or more API, as described herein (paragraph 00105). In one aspect, there is provided a dry pharmaceutical composition comprising the above-described PVP-PLA block copolymers in molecular association with at least one active pharmaceutical ingredient (API) (see paragraph 00107). By "dry pharmaceutical composition" is meant a formulation prepared by drying (e.g., removing solvent) a mixture of the API and the block copolymers to form an intimate mixture of the API and the block copolymers. "Dry" here will be understood to mean "substantially dry", and indicates that the at least about 90%, at least about 95%, 96%, 97%, 98%, 99%, or 99.9%, of the solvent has been removed during the drying process. The dry pharmaceutical composition may be in the form of a cake of a powder. The term "powder" refers to a substantially dry, free-flowing, particulate material having high bulk density. Spray- dried powders typically have a bulk density in the range of about 0.05 -1.00 g/cc, more typically between about 0.2 - 0.5 g/cc. Advantageously, powders are suitable for incorporation into various non-intravenous dosage forms, including but not limited to, tablets, including rapid disintegrating tablets, caplets, capsules, sachets, solutions, suspensions, creams, gels, ointments, pessaries, suppositories, enema, drops, aerosol or dry powder inhalers, and the like. The term "cake", as compared to a powder, refers to a non-flowing, non-particulate material having a low bulk density, typically in the range of about 0.0001 - 0.05 g/cc. In accordance with the methods disclosed herein, a cake may be formed, for example, as a result of lyophilization or freeze-drying (paragraph 00108). In one embodiment, the dry pharmaceutical composition has a DLL (drug loading level) of at least 10% wt/wt of the at least one API. In one embodiment, the dry pharmaceutical composition has a DLL of at least 20% wt/wt of the at least one API. In one embodiment, the dry pharmaceutical composition has a DLL of at least 30% wt/wt of the at least one API. DLL may be selected according to the API and according to requirements, and provided that requirements for administration are met. The DLL may be 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, or greater than 30% (paragraph 00124). In one embodiment, the at least one API may be insoluble to sparingly soluble. In one embodiment, the at least one API has a solubility in water of Og/L to 33g/L. The API may be insoluble to slightly soluble (i.e., Og/L to 10g/L). In one embodiment, the at least one API has a solubility in water of Og/L to 14g/L. The API may be sparingly soluble. In one embodiment, the API has a solubility in water of 10g/L to 33g/L (paragraph 00127). For examples of overlapping amount of polymer see tables 21, 23-25, and 28-31. In the case where amount of ingredients or any measurable parameters" 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). Furthermore, differences in concentration or measurable parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Lynch et al. and Smith et al. because both references teach the delivery of API containing similar ingredients.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 29-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lynch et al. (US 2015/0258040) in view of Smith et al. (WO2018/176158) as applied to claims 1-28 and 32 above, and further in view of Bromley (US 2016/0081976).
Applicants’ claims
Applicants claim a combination of HU-308 and HU-433. Claims 29-31 recite types of antioxidants.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Lynch et al. and Smith et al. are set forth above and are incorporated by reference herein.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Lynch et al. and Smith et al. do not specifically teach the antioxidants recited in claims 29-31. These deficiencies are cured by the teachings of Bromley
Bromley teaches compositions that contain water-soluble vitamin E derivative mixtures (compositions), such as tocopheryl polyethylene glycol succinate (TPGS), TPGS analogs, TPGS homologs and TPGS derivatives. The water-soluble vitamin E mixtures contain mixtures of dimers and monomers of the vitamin E derivative. Provided are products containing the water-soluble vitamin E derivative mixtures, including capsules, soft gel compositions, pre-gel compositions, emulsions and powders. Synthetic cannabinoids are among the cannabinoids that can be included as non-polar ingredients Synthetic cannabinoids include any compound having a cannabinoid-like structure or that produces effects similar to those of cannabinoids that is manufactured using chemical means, including, for example, HU 308 ([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol); rimonabant (Acomplia™; 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide) (paragraph 0497). Exemplary of non-polar ingredients that can be included in the compositions provided herein are ingredients that contain an antioxidant or have antioxidant properties, for example, a molecule that is capable of inhibiting the oxidation of other molecules. Antioxidants include molecules that scavenge free radicals. Suitable antioxidants include those that are used as ingredients in dietary supplements. The antioxidant can be a natural antioxidant or a synthetic antioxidant (paragraph 0501). Examples of antioxidants include, but are not limited to hormones, carotenoids, carotenoid terpenoids, non-carotenoid terpenoids, flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols, flavones, phenols, polyphenols, esters of phenols, esters of polyphenols, nonflavonoid phenolics, isothiocyanates, vitamins and vitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin E phosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10), ubiquinol, pyrroloquinoline quinone (PQQ), ascorbic acid, citric acid, rosemary oil, minerals, such as mineral selenium and manganese, melatonin, α-carotene, β-carotene, lycopene, lutein, zeanthin, crypoxanthin, resveratrol, eugenol, quercetin, catechin, gossypol, hesperetin, curcumin, turmeric, turmeric/curcumin blend, ferulic acid, thymol, hydroxytyrosol, thyme, olive oil, lipoic acid, including alpha-lipoic acid, glutathione, oxalic acid, tocopherol, tocopherol-derived compounds, di-alpha-tocopheryl phosphate, tocotrienols, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid, tert-butylhydroquinone, acetic acid, pectin, zeaxanthin, astaxanthin, canthaxanthin, saponins, limonoids, kaempferol, myricetin, isorhamnetin, proanthocyanidins, quercetin, rutin, luteolin, apigenin, tangeritin, naringenin, eriodictyol, flavan-3-ols (e.g., anthocyanadins), gallocatechins, epicatechin and its gallate forms, epigallocatechin and its gallate forms, theaflavin and its gallate forms, thearubigins, isoflavone phytoestrogens, genistein, daidzein, glycitein, anythocyanins, delphinidin, malvidin, pelargonidin, peonidin, and hops (Humulus lupulus L.)-containing compounds. In one example, the antioxidant includes ubiquinol. In another example, the antioxidant includes alpha-lipoic acid. In another example, the antioxidant includes pyrroloquinoline quinone (PQQ). In yet another example, the antioxidant includes a turmeric/curcumin composition (paragraph 0502).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Lynch et al. and Smith et al. by utilizing butylated hydroxyanisole as an antioxidant because Bromley teaches compositions that contain water-soluble vitamin E derivative mixtures (compositions), such as tocopheryl polyethylene glycol succinate (TPGS), TPGS analogs, TPGS homologs and TPGS derivatives. The water-soluble vitamin E mixtures contain mixtures of dimers and monomers of the vitamin E derivative. Provided are products containing the water-soluble vitamin E derivative mixtures, including capsules, soft gel compositions, pre-gel compositions, emulsions and powders. Synthetic cannabinoids are among the cannabinoids that can be included as non-polar ingredients Synthetic cannabinoids include any compound having a cannabinoid-like structure or that produces effects similar to those of cannabinoids that is manufactured using chemical means, including, for example, HU 308 ([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol); rimonabant (Acomplia™; 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide) (paragraph 0497). One of ordinary skill in the art would have been motivated to do so because Bromley teaches exemplary of non-polar ingredients that can be included in the compositions provided herein are ingredients that contain an antioxidant or have antioxidant properties, for example, a molecule that is capable of inhibiting the oxidation of other molecules. Antioxidants include molecules that scavenge free radicals. Suitable antioxidants include those that are used as ingredients in dietary supplements. The antioxidant can be a natural antioxidant or a synthetic antioxidant (paragraph 0501). Examples of antioxidants include, but are not limited to hormones, carotenoids, carotenoid terpenoids, non-carotenoid terpenoids, flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols, flavones, phenols, polyphenols, esters of phenols, esters of polyphenols, nonflavonoid phenolics, isothiocyanates, vitamins and vitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin E phosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10), ubiquinol, pyrroloquinoline quinone (PQQ), ascorbic acid, citric acid, rosemary oil, minerals, such as mineral selenium and manganese, melatonin, α-carotene, β-carotene, lycopene, lutein, zeanthin, crypoxanthin, resveratrol, eugenol, quercetin, catechin, gossypol, hesperetin, curcumin, turmeric, turmeric/curcumin blend, ferulic acid, thymol, hydroxytyrosol, thyme, olive oil, lipoic acid, including alpha-lipoic acid, glutathione, oxalic acid, tocopherol, tocopherol-derived compounds, di-alpha-tocopheryl phosphate, tocotrienols, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid, tert-butylhydroquinone, acetic acid, pectin, zeaxanthin, astaxanthin, canthaxanthin, saponins, limonoids, kaempferol, myricetin, isorhamnetin, proanthocyanidins, quercetin, rutin, luteolin, apigenin, tangeritin, naringenin, eriodictyol, flavan-3-ols (e.g., anthocyanadins), gallocatechins, epicatechin and its gallate forms, epigallocatechin and its gallate forms, theaflavin and its gallate forms, thearubigins, isoflavone phytoestrogens, genistein, daidzein, glycitein, anythocyanins, delphinidin, malvidin, pelargonidin, peonidin, and hops (Humulus lupulus L.)-containing compounds. In one example, the antioxidant includes ubiquinol. In another example, the antioxidant includes alpha-lipoic acid. In another example, the antioxidant includes pyrroloquinoline quinone (PQQ). In yet another example, the antioxidant includes a turmeric/curcumin composition (paragraph 0502). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Lynch et al., Smith et al., and Bromley because all of the references teach the delivery of active agents.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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