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 Claims
Claims 1, 5, 8-10, 23, 33, 39-41 and 44-46 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/CN2020/10037, filed on 07/06/2020.
Claim Rejections – Withdrawn
The prior rejection of claims 9 and 10 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the applicant), regards as the invention, has been overcome by Applicant’s amendment of the claims, and is accordingly withdrawn. Specifically, Applicant’s amendment of the claims to remove the narrower ranges has overcome the rejection.
The prior rejection of claims 1, 20-21 and 39 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Labow (WO 2009/004085 A2)1 has been overcome Applicant’s cancellation of claims 20-21 and amendment of claim 1, and is accordingly withdrawn. Specifically, regarding the amendment, Applicant’s amendment of claim 1 to specify phenylarsine oxide (PAO) as the inhibitor of micromolecule PI4KIIIa has overcome the prior rejection.
The prior rejection of claims 1 and 39-40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of U.S. Patent No. 11,766,420 B2 (hereafter referred to as “Huang”) has been overcome by Applicant’s amendment of claim 1, and is accordingly withdrawn. Specifically, Applicant’s amendment of claim 1 to further limit the composition to comprise a medium chain glyceride has overcome the prior rejection.
The prior provisional rejection of claims 1 and 39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10-15, 17 and 19-21 of copending Application No. 17/995,096 has been overcome by Applicant’s amendment of claim 1, and is accordingly withdrawn. Specifically, Applicant’s amendment of claim 1 to further limit the composition to comprise a medium chain glyceride has overcome the prior rejection.
The prior provisional rejection of claims 1, 3, 5 and 39-41 on the ground of nonstatutory double patenting as being unpatentable over claims 5-6 of copending Application No. 17/995,099 in view of Olgun (Olgun, et al.; Annals of the New York Academy of Sciences, v1100, pp.400-403; 2007) has been overcome by Applicant’s cancellation of claim 3 and amendment of claim 1 and is accordingly withdrawn. Specifically, Applicant’s amendment of claim 1 to further limit the composition to comprise a medium chain glyceride has overcome the prior rejection.
The prior provisional rejection of claims 1 and 39-40 on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 18 of copending Application No. 18/697,015 has been overcome by Applicant’s amendment of claim 1, and is accordingly withdrawn. Specifically, Applicant’s amendment of claim 1 to further limit the composition to comprise a medium chain glyceride has overcome the prior rejection.
Claim Rejections - 35 USC § 103 – Maintained
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.
The prior rejection of claims 1, 5, 8-9, 23, 33 and 39-41 under 35 U.S.C. 103 as being unpatentable over Huang (EP 3290514 B1) in view of Sarpal (Sarpal, et al.; Current Research & Information on Pharmaceutical Sciences (CRIPS), v11, pp42-49; 2010)2 is maintained. Applicant has traversed the prior rejection on the following grounds:
Huang does not disclose, teach or suggest a composition comprising “medium chain glyceride” in amended claim 1;
Sarpal and Pouton are silent in regard to a specific PI4KIIIa inhibitor having a structure of formula (I), and they do not disclose, teach or suggest that medium chain glycerides can be used to efficiently deliver said specific PI4KIIIa inhibitor.
Applicant asserts that a person of ordinary skill in the art (POSITA) would encounter overdue experiments and creative labor to identify a successful lipid based formulation and select medium chain glyceride as the lipid of choice in a lipid-based formulation;
Applicant claims unexpected technical effects in stability, bioavailability and safety of the claimed PI4KIIIa inhibitor for a composition comprising mono/di-glycerides of octanoic/decanoic acid (MCM) over compositions that instead comprise, as a lipid content, a vegetable oil, with examples of sesame oil, soybean oil and tea oil, and over composition that uses dimethylsulfoxide (DMSO) as a carrier rather than comprising a lipid.
Applicant’s traverse has been considered, but is not found persuasive for the following reasons:
While Huang does not disclose a composition incorporating a lipid component with phenylarsine oxide (PAO), a person of ordinary skill in the art would know the utility of lipids, including medium chain glycerides, in forming pharmaceutical compositions with poorly water-soluble compounds such as PAO, as this was known in the art, for example per the teaching of Sarpal;
Sarpal provides exemplary/typical lipids for use in the formulation of self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS), including various medium chain glycerides, for example Miglyol 812, and Sarpal shows a wide variety of drugs that have been successfully formulated with medium chain glycerides in Sarpal’s Table 3 (page 45), including calcitriol, ciprofloxacin, dutasteride, paricalcitol, saquinavir, tipranavir and tolterodine tartrate; thus a person of ordinary skill in the art would at once recognize that the strategy of utilizing lipid-based formulations wherein the lipid is a medium chain glyceride is not dependent on the particular drug;
Applicant’s evidence, while acceptable in terms of identifying that a formulation specifically comprising mono/di-glycerides of octanoic/decanoic acid (MCM) shows unexpected stability compared to vegetable oils, does not establish that a POSITA would face overdue experimentation to discover a SEDDS or SMEDDS formulation of PAO with acceptable stability, bioavailability and safety; for example, Applicant has not established that Miglyol 812, the particular medium chain glyceride cited in the prior rejection, would not provide a stable, bioavailable and safe formulation, or any that any other medium chain glyceride would not suffice;
Applicant’s unexpected results have only established that vegetable oils would not suffice, and claim 1 does not require a specific formulation comprising a mixture of mono/di-glycerides of octanoic/decanoic acid, but rather requires only that the formulation comprise a medium chain glyceride, which is met by the prior rejection.
Reiterated Rejection:
Claims 1, 5, 8-9, 23, 33 and 39-41 are unpatentable over Huang in view of Sarpal.
Claims 1, 5, 8-9, 23, 33 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Huang (EP 3290514 B1) in view of Sarpal (Sarpal, et al.; Current Research & Information on Pharmaceutical Sciences (CRIPS), v11, pp42-49; 2010)3.
Claim 1 is drawn to a pharmaceutical composition comprising an inhibitor of micromolecule PI4KIIIa and a pharmaceutical carrier that comprises a lipid, wherein the inhibitor of micromolecule PI4KIIIa is selected from a genus that includes PAO and the lipid comprises a medium chain glyceride.
Huang discloses a method for down-regulation of PI4KIIIa kinase and membrane complexes formed thereof using certain inhibitors, as a means to treat Alzheimer’s disease (Abstract). Huang further discloses that the inhibitors useful for this method includes phenylarsine oxide (“PAO” – see paragraphs [0060]-[0061]). Huang also discloses that the materials of the invention disclosed therein can be formulated into a composition, such as a pharmaceutical composition along with a pharmaceutically acceptable carrier (paragraph [0070]).
While Huang does not disclose a pharmaceutical composition comprising a lipid, a person of ordinary skill in the art would have a reasonable expectation of success in making and using the invention of Huang with a pharmaceutical composition comprising a lipid-based self-emulsifying formulation wherein the lipid is a medium chain glyceride, because phenylarsine oxide (PAO) was known in the art to be poorly water soluble, as evidenced by Huang, and because lipid-based self-emulsifying drug delivery systems were known in the art as a successful strategy for the formulation and administration of poorly water-soluble drugs, including wherein the lipid is a medium chain glyceride, per the teaching of Sarpal.
Huang discloses an example of administration of PAO to HEK293 cells, Drosophila larva and adult flies, wherein the PAO was administered via aqueous solution but was first dissolved into dimethylsulfoxide (DMSO), an organic solvent, and then diluted into distilled water with additional DMSO to achieve the desired concentrations while maintaining a constant DMSO content at all concentrations (paragraph [0121]). The practice of pre-dissolution of PAO in an organic solvent, and using a DMSO/water mixture of the final solutions indicates that PAO is poorly soluble in water.
Sarpal provides a review of the formulation, characteristics and advantages of self-emulsifying drug delivery systems (SEDDS), which “possess potential to improve oral bioavailability of poorly water soluble drugs” (Abstract). Sarpal teaches that self-emulsifying formulations comprise isotropic mixtures of natural or synthetic oils with lipophilic or hydrophilic surfactants and co-solvent(s) which spontaneously emulsify when exposed to the fluids of the gastrointestinal tract (GIT) to form oil-in-water emulsions or micro-emulsions, and that “SEDDS” is a broad term that includes sub-categories of self-emulsifying formulations that produce droplets of particularly small size, including self-microemulsifying drug delivery systems (SMEDDS, 100-250 nm) and self-nanoemulsifying drug delivery systems (SNEDDS, <100 nm) (Introduction, page 42). Sarpal also teaches that SEDDS can offer an improvement in rate and extent of absorption resulting in reproducible blood time profiles, and that SEDDS usually provide an advantage of increased drug loading capacity when compared with lipid solutions as the solubility of poorly water soluble drugs with intermediate partition coefficients (2<1ogP<4) are typically low in natural lipids and much greater in amphiphilic surfactants, co-surfactants and co-solvents (pages 42-43, bridging paragraph). Sarpal teaches the balance of ingredient types (triglyceride/mixed glyceride, surfactant and hydrophilic co-solvent) in different lipid formulations including SEDDS and SMEDDS (Table 2, page 44), exemplary/typical lipids used in SEDDS/SMEDDS (Table 4, page 46) and exemplary known pharmaceutical agents formulated as SEDDS/SMEDDS (Table 5, page 48). Among the common lipid excipients in Table 4, Sarpal includes glycerides incorporating caprylic and/or capric esters, such as Miglyol 812, Tricaprylin, CC, Captex 355, Imwitor 988 and Akoline MCM. Sarpal concludes that self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility (Conclusion, page 49).
Applicant’s invention is unpatentable over the disclosure of Huang in view of the teaching of Sarpal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using a pharmaceutical composition comprising phenylarsine oxide (PAO), a PI4KIIIa inhibitor, in a lipid-based self-emulsifying drug delivery system wherein the lipid is a medium chain glyceride based on caprylic and/or capric esters, because Huang teaches the use of pharmaceutical compositions of PAO and shows that PAO is poorly water soluble, and Sarpal teaches that SEDDS based on lipids such as caprylic/capric glycerides are useful for the formulation and administration of poorly water soluble drugs.
Thus, the invention was prima facie obvious at the time of filing.
Claims 5 and 8 further limit claim 1 with respect to the selection of PI4KIIIa inhibitor, and each of these claims is met by the disclosure by Huang of selecting PAO.
Claim 9 further limits claim 1 with regard to the dosage of inhibitor to be included in the pharmaceutical composition being within the range of 0.01-20 mg/g. Huang discloses the preparation of aqueous solutions of PAO at concentrations of 50, 100, 200, 300, 400, and 600 μM. While, as discussed above, these solutions included an unknown amount of DMSO, a person of ordinary skill in the art would have a reasonable expectation of arriving at the corresponding concentrations in milligrams PAO/grams of solution by using the density of water for the PAO solutions. Given a molecular weight of 168 grams/mole for PAO, the micromolar concentrations listed above correspond to mg/g concentrations of 0.008, 0.017, 0.034, 0.050, 0.067 and 0.10 mg PAO/grams solution. Thus, Huang discloses several doses within the dosage range of claim 9.
Claim 23 further limits the composition of claim 1 to wherein the lipid comprises a medium chain triglyceride, and is met by the rejection above. As discussed above, Sarpal’s Table 4 provides exemplary/typical lipids for use in the formulation of SEDDS and SMEDDS, including Miglyol 812, a medium chain triacylglycerol (i.e., triester or triglyceride) that incorporates caprylic and capric esters, as well as other glycerides incorporating the same ester groups.
Claim 33 further limits claim 1 to wherein the inhibitor is PAO, the dose is within the range of 0.25-20 mg inhibitor/gram composition, and the lipid carrier is selected from a Markush group that includes medium chain triglyceride, and each of these limitations is met by the rejection above.
Claim 39 further limits claim 1 to a method for treating a PI4KIIIa-related disease, comprising administering the pharmaceutical composition of claim 1. Claim 40 further limits claim 39 to wherein the PI4KIIIa-related disease is Alzheimer’s disease. Huang elaborates that Alzheimer’s disease is related to PI4KIIIa because the product of phosphatidylinositol 4-kinase (PI4KIIIα), phosphatidylinositol-4-phosphate (PI4P) increases significantly in cerebral cortex in AD patients, and the increased level is closely related to the degree of cognitive disorder in AD patients (page 4, lines 46-48). Thus, claims 39-40 are met by the rejection above.
Claim 41 further limits claim 39 to wherein the subject to be treated is selected from a Markush group that includes human, mouse and dog. Huang discloses the treatment of mice with oral gavage of PAO in aqueous/DMSO solution (paragraphs [0125] and [0149]), as well as human-derived HEK293T cells in cell media (paragraphs [0129]-[0130]). Huang further includes a structural simulation of the binding of PAO in the active site of human PI4KIIIa (Figure 17, page 60; caption found in paragraph [0029]). Finally, Huang discloses that Alzheimer’s disease, the specific disease to be treated by the invention disclosed therein, is a disease that exists in humans or in animals such as dogs (paragraph [0042]).
Applicant’s invention is unpatentable over the disclosure of Huang in view of the teaching of Sarpal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of making a pharmaceutical composition comprising PAO, a PI4KIIIa inhibitor, in a SEDDS/SMEDDS pharmaceutical composition comprising a lipid such as Miglyol 812 including dosages within the range of 0.017-0.1 mg PAO/gram composition and using such a composition for the treatment of Alzheimer’s disease, because Huang teaches the use of pharmaceutical compositions of PAO for the treatment of Alzheimer’s, a disease of humans and dogs, with dosages in the range of approximately 0.017-0.1 mg/g, as well as showing that PAO is poorly water soluble, and because Sarpal teaches that the formulation and use of SEDDS/SMEDDS, including with medium chain triglyceride Miglyol 812, is a successful strategy for the formulation and administration of poorly water soluble drugs.
Thus, the invention was prima facie obvious at the time of filing.
The prior rejection of claims 1, 5, 8-10, 23, 33 and 39-41 under 35 U.S.C. 103 as being unpatentable over Huang in view of Sarpal and further in view of Pouton (Pouton, C.W.; Advanced Drug Delivery Reviews, v25, pp.47-58; 1997) is maintained. Applicant has traversed the rejection on the same grounds as discussed in the rejection above, which are hereby incorporated into the instant rejection. Applicant’s arguments have been considered, but are not found persuasive, for the same reasons as discussed in the rejection above, which are hereby incorporated into the instant rejection.
Reiterated Rejection:
Claims 1, 5, 8-10, 23, 33 and 39-41 are unpatentable over Huang in view of Sarpal and further in view of Pouton.
Claims 1, 5, 8-10, 23, 33 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Huang in view of Sarpal and further in view of Pouton (Pouton, C.W.; Advanced Drug Delivery Reviews, v25, pp.47-58; 1997).
The limitations of claims 1, 5, 8-9, 23, 33 and 39-41 and the disclosure of Huang and the teaching of Sarpal are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 10 further limits claim 1 with respect to the carrier content of the composition, wherein the carrier content is at least 50% in the composition.
Sarpal teaches that SEDDS/SMEDDS can be prepared with the lipid carrier in a range of 40-80% (w/w) (Table 2, page 44). While Sarpal does not teach how to determine the precise w/w % of the components in successful formulation of a SEDDS/SMEDDS composition, a person of ordinary skill in the art would have a reasonable expectation of success in determining a successful formulation, because the w/w% of each component, including the lipid carrier, in a SEDDS/SMEDDS formulation is a result-effective variable, and the determination of precise w/w % content of SEDDS/SMEDDS components was known in the art, per the teaching of Pouton.
Pouton reviews the morphology of self-emulsifying drug delivery systems (SEDDS), which are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract (Abstract, page 47). Pouton describes strategies used for formulation of SEDDS, methods used for assessment of efficiency of emulsification and practical considerations regarding the use of SEDDS for enhancement of the bioavailability of drugs from the gastro-intestinal tract. Pouton teaches that screening studies have established that it is possible to formulate isotropic SEDDS using medium-chain triglycerides and any of a group of nonionic surfactants, mostly ethoxylated oleates. Pouton further teaches that a wide range of excipients (e.g., emulsion components) have been used to form SEDDS (page 53), and provides techniques to assess the efficiency of emulsification and resulting micelle/particle size, using a model system of medium chain triglycerides such as Miglyol 840 and Miglyol 812 with either Tween surfactant (page 54, Figures 9 and 10) or Tagat (polyoxyethylene-25 glyceryl trioleate, page 55, Figure 11). Pouton additionally teaches the study of equilibrium phase behavior of SEDDS mixtures, which enables the prediction of the phases that are likely to form when the composition is diluted with water (section 3.4, pages 55-57).
Applicant’s invention is unpatentable over the disclosure of Huang in view of the teaching of Sarpal and further in view of the teaching of Pouton, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in formulating a SEDDS/SMEDDS pharmaceutical composition comprising a PI4KIIIa inhibitor and a lipid carrier such as Miglyol 812 and arriving at a >50 w/w% of the lipid carrier in the composition, for the following reasons:
The utility of pharmaceutical compositions of PAO, a known PI4KIIIa inhibitor, and poor water solubility of PAO were known in the art per the disclosure of Huang;
The utility of SEDDS/SMEDDS formulations for poorly water soluble drugs, and the typical lipid carriers used in these self-emulsifying formulations, such as caprylic/capric glycerides including Miglyol 812, were known in the art per the teaching of Sarpal;
Methods for determining the successful composition of SEDDS/SMEDDS formulations for any given set of components were known in the art and exemplified for well-known lipid carrier such as Miglyol 812, per the teaching of Pouton.
Thus, the invention was prima facie obvious at the time of filing.
Claim Rejections - 35 USC § 103 – Necessitated by New Claims
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.
Claims 1, 5, 8-9, 23, 33, 39-41 and 44 are unpatentable over Huang in view of Sarpal.
Claims 1, 5, 8-9, 23, 33, 39-41 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Huang (EP 3290514 B1) in view of Sarpal (Sarpal, et al.; Current Research & Information on Pharmaceutical Sciences (CRIPS), v11, pp42-49; 2010)4.
The limitations of claims 1, 5, 8-9, 23, 33 and 39-41 and the disclosure of Huang and the teaching of Sarpal are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 44 further limits claim 1 to wherein the composition further comprises ethanol. As discussed above, Huang discloses that the materials of the invention disclosed therein can be formulated into a composition, such as a pharmaceutical composition along with a pharmaceutically acceptable carrier (paragraph [0070]). Huang does not disclose that such a pharmaceutical composition may include ethanol as an excipient; however, a person of ordinary skill in the art would have a reasonable expectation of success to make and use a pharmaceutical composition in the form of a self-microemulsifying drug delivery system (SMEDDS, also designated as SEDDS type IIIA or IIIB – see page 44, Table 2) comprising a lipid, wherein the lipid is a medium chain glyceride, per the teaching of Sarpal discussed above, and further comprising ethanol, because Sarpal teaches that SMEDDS include co-solvents to facilitate the dispersion process and in aid in achieving faster dispersion rates, and that ethanol is an exemplary co-solvent page 44, right column, section “Co- solvents”, and page 46, Table 4). In describing SMEDDS, Sarpal specifically states that they “comprise of oils, hydrophilic surfactants (HLB>12) and co-solvents such as ethanol” (page 43, right column, first full paragraph).
Applicant’s invention is unpatentable over the disclosure of Huang in view of the teaching of Sarpal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of making a pharmaceutical composition comprising PAO, a PI4KIIIa inhibitor, in a SEDDS/SMEDDS pharmaceutical composition comprising a medium chain glyceride such as Miglyol 812 and further including ethanol, because Huang teaches the use of pharmaceutical compositions of PAO for the treatment of Alzheimer’s, a disease of humans and dogs, as well as showing that PAO is poorly water soluble, and because Sarpal teaches that the formulation and use of SEDDS/SMEDDS, including with medium chain triglyceride Miglyol 812, is a successful strategy for the formulation and administration of poorly water soluble drugs and that such compositions include co-solvents of which ethanol is known example.
Thus, the invention was prima facie obvious at the time of filing.
Claims 1, 5, 8-10, 23, 33, 39-41 and 44-46 are unpatentable over Huang in view of Sarpal and further in view of Sposito.
Claims 1, 5, 8-10, 23, 33, 39-41 and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Huang (EP 3290514 B1) in view of Sarpal (Sarpal, et al.; Current Research & Information on Pharmaceutical Sciences (CRIPS), v11, pp42-49; 2010)5 and further in view of Sposito (Sposito, et al.; International Journal of Nanomedicine, v12, pp3785-3799; 2017)
The limitations of claims 1, 5, 8-10, 23, 33, 39-41 and 44 and the disclosure of Huang and the teaching of Sarpal are discussed in the rejections above and hereby incorporated into the instant rejection.
Claim 45 further limits claim 44, regarding a pharmaceutical composition comprising a compound of Formula (I) and a medium chain glyceride and further comprising ethanol, to wherein the ethanol content of the composition is within the range of 0.1-10% (v/v).
Claim 46 further limits claim 44 to wherein the ethanol content of the composition is within the range of 0.1-8% (v/v).
As discussed in the rejection above, Huang presents compounds that anticipate the genus of Formula (I), including phenylarsine oxide (PAO) and Huang discloses pharmaceutical compositions that comprise such compounds including PAO, and Sarpal teaches the utility of self-emulsifying and self-microemulsifying drug delivery systems (SEDDS and SMEDDS, respectively) that comprise a lipid, including a medium chain glyceride such as Migloyl 812, and further comprising a co-solvent, for example ethanol. Sarpal provides a range 0f 0-wt% for co-solvent content in SMEDDS, and further teaches that “smaller quantity of co-solvents should be used in SMEDDS as larger quantities can cause drug precipitation on dispersion into aqueous phase” (page 44, Table 2 and right column section “Co-solvents”). Sarpal does not specifically recommend a “smaller quantity” of co-solvent in a range of 0.1-10% (v/v) or 0.1-8% (v/v). However, a person of ordinary skill in the art would have a reasonable expectation of success in making and using the invention of Huang in preparing a pharmaceutical composition comprising PAO and further comprising a medium chain glyceride such as or similar to Miglyol 812 and the co-solvent ethanol in a SMEDDS formulation (i.e., SEDDS type IIIA) per the teaching of Sarpal, and arriving at the claimed ethanol content within the range(s) claimed in instant claims 45-46, because it was known in the art how to formulate a SMEDDS pharmaceutical composition comprising an active drug agent wherein the lipid base comprises a medium chain glyceride and the co-solvent is ethanol at 5% (v/v), per the teaching of Sposito.
Sposito teaches a study in the development of a SEDDS formulation of type IIIA for the delivery of the poorly water-soluble antifungal agent Ravuconazole (Abstract). Sposito does not designate the formulation as a SMEDDS, however a person of ordinary skill in the art would immediately recognize that a type IIIA SEDDS formulation is a SMEDDS formulation as this is the inherent classification of the formulation and was known in the art, as evidenced by the teaching of Sarpal discussed above. Sposito presents an assortment of type IIIA formulations comprising Miglyol 810 N (page 3788, Table 2), which Sposito defines a medium chain triglyceride composed of a 70:30 ration of octanoic/decanoic acid chains (page 3787, Table 1). Of the evaluated type IIIA formulations, Sposito identifies formulation 5 (“F5”), comprised of 70% Miglyol (v/v), 5% ethanol (v/v), 15% of the surfactant Labrasol (v/v) and 10% of the surfactant Epikuron (v/v), as a stable dispersion system capable of dissolving a high loading of the drug (page 3791, left column, second paragraph, and Table 3). Sposito teaches that the F5 formulation showed robustness to dilution, without precipitation of the drug agent (page 3792, right column and page 3793, Table 4) was shown to be stable at room temperature over a 6 months test period (page 3795, Table 5). Sposito evaluates SEDDS formulation toxicity in an in vivo mouse study and shows that a SEDDS formulation corresponding to formulation F5, with 10% Labrasol and 5% ethanol, shows much lower toxicity and better tolerability compared to formulations without ethanol and with higher Labrasol (page 3795, Table 6). Sposito tests F5 in mice experimentally infected with Trypanosoma cruzi Y strain, and observed no weight loss, indicating no toxicity of the specific F5 formulation (page 3796, right column, upper paragraph). Sposito shows that the active agent Ravuconazole, administered in vitro to H9c2 cells at the IC50 concentration of 0.1 nM showed 1.8 fold greater inhibition activity compared to Ravuconazole administered as a free agent (i.e., without any excipient) (page 3797, left column, top paragraph and Figure 6). Sposito concludes that the formulation is “simple to prepare, cost-effective, stable under storage, safe in mice, and easy to administer orally” (page 3797, right column, top paragraph).
Applicant’s invention is unpatentable over the disclosure of Huang in view of the teaching of Sarpal and further in view of the teaching of Sposito, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using the invention of Huang of a pharmaceutical composition of phenylarsine oxide (PAO) wherein the composition comprises a medium chain glyceride as a lipid component and further comprises ethanol as a co-solvent, at an amount of 5% (v/v), because it was known in the art that PAO is poorly water-soluble, per the disclosure of Huang, and it was known in the art that SEDDS formulations, including SEDDS type IIIA formulations (also known as SMEDDS) are an effective strategy for improving drug solubility and bioavailability and that medium chain glyceride lipids such as the medium chain triglyceride Miglyol 812 are a very effective lipid choice for SMEDDS and that ethanol is a typical co-solvent used in SMEDDS, per the teaching of Sarpal, and it was known in the art that specific formulation of a SMEDDS composition comprising the medium chain triglyceride Miglyol 810 N and the co-solvent ethanol, with the ethanol at 5% (v/v) is simple to prepare, cost-effective, stable under storage, safe in mice, and easy to administer orally, and provides stable drug solubility upon dilution, per the teaching of Sposito.
Thus, the invention was prima facie obvious at the time of filing.
Double Patenting – Necessitated by Amendment
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 39-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of U.S. Patent No. 11,766,420 B2 (hereafter referred to as “Zhang”) in view of Sarpal (Sarpal, et al.; Current Research & Information on Pharmaceutical Sciences (CRIPS), v11, pp42-49; 2010)6.
The limitations of claims 1 and 39-40 are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 1 of Zhang claims a method for treating ameliorating or inhibiting Alzheimer's disease and its symptoms in a subject in need thereof, the method comprising administering to the subject a PI4KIIIa inhibitor. Claim 2 further limits claim 1 to wherein the PI4KIIIa inhibitor is selected from a Markush group that includes small molecule inhibitors. Claim 4 further limits claim 2 to wherein the small molecule PI4KIIIa inhibitor is selected from a Markush group that includes PAO and a PAO derivative. Claim 5 further limits claim 4 to wherein the PAO derivative is selected from a Markush group of specific compounds, many of which anticipate the genus of instant Formula (I) as claimed in claim 1.
Zhang does not claim a method of treating ameliorating or inhibiting Alzheimer’s disease and its symptoms in a subject in need thereof comprising administering a pharmaceutical composition comprising a lipid, including wherein the lipid comprises a medium chain glyceride; however, a person of ordinary skill in the art would have a reasonable expectation of success in making and using the invention of Zhang with a pharmaceutical composition comprising a lipid-based self-emulsifying formulation, including wherein the lipid is a medium chain glyceride, because phenylarsine oxide (PAO) was known in the art to be poorly water soluble, as evidenced by Huang, and because lipid-based self-emulsifying drug delivery systems were known in the art as a successful strategy for the formulation and administration of poorly water-soluble drugs, including wherein the lipid is a medium chain glyceride, per the teaching of Sarpal.
Sarpal provides a review of the formulation, characteristics and advantages of self-emulsifying drug delivery systems (SEDDS), which “possess potential to improve oral bioavailability of poorly water soluble drugs” (Abstract). Sarpal teaches that self-emulsifying formulations comprise isotropic mixtures of natural or synthetic oils with lipophilic or hydrophilic surfactants and co-solvent(s) which spontaneously emulsify when exposed to the fluids of the gastrointestinal tract (GIT) to form oil-in-water emulsions or micro-emulsions, and that “SEDDS” is a broad term that includes sub-categories of self-emulsifying formulations that produce droplets of particularly small size, including self-microemulsifying drug delivery systems (SMEDDS, 100-250 nm) and self-nanoemulsifying drug delivery systems (SNEDDS, <100 nm) (Introduction, page 42). Sarpal also teaches that SEDDS can offer an improvement in rate and extent of absorption resulting in reproducible blood time profiles, and that SEDDS usually provide an advantage of increased drug loading capacity when compared with lipid solutions as the solubility of poorly water soluble drugs with intermediate partition coefficients (2<1ogP<4) are typically low in natural lipids and much greater in amphiphilic surfactants, co-surfactants and co-solvents (pages 42-43, bridging paragraph). Sarpal teaches the balance of ingredient types (triglyceride/mixed glyceride, surfactant and hydrophilic co-solvent) in different lipid formulations including SEDDS and SMEDDS (Table 2, page 44), exemplary/typical lipids used in SEDDS/SMEDDS (Table 4, page 46) and exemplary known pharmaceutical agents formulated as SEDDS/SMEDDS (Table 5, page 48). Among the common lipid excipients in Table 4, Sarpal includes glycerides incorporating caprylic and/or capric esters, such as Miglyol 812, Tricaprylin, CC, Captex 355, Imwitor 988 and Akoline MCM. Sarpal concludes that self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility (Conclusion, page 49).
Claims 1 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10-15, 17 and 19-21 of copending Application No. 17/995,096 (reference application) in view of Sarpal.
The limitations of claims 1 and 39 and the teaching of Sarpal are discussed in the rejection above and hereby incorporated into the instant rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims regard method(s) for treatment of PI4KIIIa-related diseases comprising administering a PI4KIIIa inhibitor, and a person of ordinary skill in the art would have a reasonable expectation of modifying the claimed invention of copending Application No. 17/995,096 to administer a PI4KIIIa inhibitor in the form of a pharmaceutical composition comprising a medium chain glyceride, as such formulation was known in the art to benefit the bioavailability of administered drug compounds, per the teaching of Sarpal, as discussed in the rejection above.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5 and 39-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-6 of copending Application No. 17/995,099 in view of Olgun (Olgun, et al.; Annals of the New York Academy of Sciences, v1100, pp.400-403; 2007), and further in view of Sarpal.
The limitations of instant claims 1, 5 and 39-41, and the teaching of Sarpal, are discussed in the rejections above, and hereby incorporated into the instant rejection.
Reference claims 5-6 regard a method for preventing or treating a disease, including Alzheimer’s disease, including in a human, comprising administering a deuterated derivative of phenylarsine oxide (PAO). While instant claims 39-41 do not specifically articulate the administration of a deuterated PAO derivative, and the reference claims do not specify administering the compound in the form of a pharmaceutical composition comprising a medium chain glyceride, PAO is established by the instant Specification as well as instant claims 3 and 5 as an inhibitor of PI4KIIIa, and a person of ordinary skill in the art would have a reasonable expectation of success in administering a deuterated derivative of PAO by administering PAO because the natural abundance of deuterium provides for deuterated derivaties to be inherently present in a composition comprising PAO, per the teaching of Olgun. Olgun teaches that the natural abundance of deuterium is 1 per ~6600 hydrogen atoms (page 400). Since every preparation of the compounds disclosed in the instant application will have some measure of impurity(s) being version(s) of the compounds bearing deuterium atoms in place of hydrogen atoms, the administration of a deuterated PAO derivative is inherent in the administration of PAO. Furthermore, a person of ordinary skill in the art would have a reasonable expectation of modifying the claimed invention of copending Application No. 17/995,099 to administer a PI4KIIIa inhibitor in the form of a pharmaceutical composition comprising a medium chain glyceride, as such formulation was known in the art to benefit the bioavailability of administered drug compounds, per the teaching of Sarpal, as discussed in the rejection above.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 3-5, 10 and 15-16 of copending Application No. 18/369,521 (reference application) in view of Sarpal. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims regard method(s) for treatment of Alzheimer’s disease comprising administering a PI4KIIIa inhibitor, and because a person of ordinary skill in the art would have a reasonable expectation of modifying the claimed invention of copending Application No. 18/369,521 to administer a PI4KIIIa inhibitor in the form of a pharmaceutical composition comprising a medium chain glyceride, as such formulation was known in the art to benefit the bioavailability of administered drug compounds, per the teaching of Sarpal, as discussed in the rejection above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 18 of copending Application No. 18/697,015 in view of Sarpal. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 5 regards a method of treating a Markush group of diseases, including Alzheimer’s disease, comprising administering PAO or a PAO derivative, compounds known per the instant Specification to be PI4KIIIa inhibitors, thereby anticipating instant claims 39-40, and because claim 18 regards a pharmaceutical composition comprising PAO or a PAO derivative, and because a person of ordinary skill in the art would have a reasonable expectation of modifying the claimed invention of copending Application No. 18/697,015 to administer a PI4KIIIa inhibitor in the form of a pharmaceutical composition comprising a medium chain glyceride, as such formulation was known in the art to benefit the bioavailability of administered drug compounds, per the teaching of Sarpal, as discussed in the rejection above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s Information Disclosure Statement dated 11/06/2023.
2 Cited in Applicant’s Information Disclosure Statement, dated 01/05/2022.
3 Cited in Applicant’s Information Disclosure Statement, dated 01/05/2022.
4 Cited in Applicant’s Information Disclosure Statement, dated 01/05/2022.
5 Cited in Applicant’s Information Disclosure Statement, dated 01/05/2022.
6 Cited in Applicant’s Information Disclosure Statement, dated 01/05/2022.
