DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed April 15, 2022, is a national stage application of PCT/IB2020/059524, filed October 9, 2020, and claims the benefit of U.S. provisional application 62/915,841, filed October 16, 2019.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 12, 2026 has been entered.
Status of the Application
Applicant’s communication, received February 12, 2026, wherein claims 1-4 and 8-9 are amended, is acknowledged. The examiner notes that the claims received February 12, 2026 appear to be the same amendments entered with the advisory action mailed December 22, 2025.
Withdrawn Rejections
Applicant’s amendment, received April 24, 2025, with respect to the rejection of claims 8-9 under 35 U.S.C. § 112(b) as indefinite, has been fully considered and found to be persuasive to remove the rejection because claim 8 is amended to remove the limitation following the term including. Therefore the rejection is withdrawn.
The following is a new objection in response to Applicant’s amendments received February 12, 2026.
Claim Objections
Claim 8 is objected to because of the following informalities: Claim 8 recites: “wherein the cancer is selected from cancers of the brain, gliomas, metastatic cancers to the brain.” Please amend claim 8 to recite: “wherein the cancer is selected from cancers of the brain, gliomas, and metastatic cancers to the brain.”
Appropriate correction is required.
The following rejections are maintained from the previous office action. Applicant’s arguments are addressed following these rejections.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35
U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Cao (Cao, Y.; et al. Micro and Nano Letters 2011, vol. 6, p. 874-877; of record) in view of Miyashita (Miyashita, K.; et al. Biosci. Biotech. Biochem. 1993, vol. 57, pp. 1638-1640; of record) and Strassburger (Publication no. WO 2008083213 A2; of record).
Claim 1 recites a substituted β-cyclodextrin (CD) inclusion complex of gamma-linolenic acid (GLA), wherein the concentration of GLA is in the range of 1-20 mg/ml; the concentration of CD is in the range of 10-40% (w/v); wherein the cyclodextrin is substituted β-cyclodextrin selected from 2-hydroxypropyl-β-cyclodextrin; sulfobutylether-β-cyclodextrin, sodium salt; and 2,6-dimethyl-β-cyclodextrin; and the inclusion complex is a formulation in the form of a nanoemulsion or lyophilizate. Claims 2 and 3 require the CD:GLA molar ratio is in the range of about 2:1 to 8:1 and about 4:1, respectively, and claim 4 requires the nanoemulsion particle size is in the range of about 50 nm to 300 nm.
Cao teaches compositions of conjugated linolenic acid (abbreviated CLN therein) that are encapsulated by β-cyclodextrin (p. 874, Abstract, lines 2-3). Encapsulation of CLN by β-cyclodextrin is interpreted as formation of an inclusion complex, absent evidence to the contrary. In addition, CLN is a derivative of linolenic acid (an octadecatrienoic acid) with positions of unsaturation in different positions on the fatty acid than gamma-linolenic acid.
Cao teaches that conjugated linolenic acid (CLN) is an imprecisely defined term describing a group of positional and geometric isomers of octadecatrienoic acids with three conjugated double bonds (p. 874, left column, section 1, lines 1-5). Cao teaches that CLN has a strong potential for killing cancer cells due to its free radical scavenging capacity and anticarcinogenic activity against several carcinogen-induced animal models, including Caco-2 colon cancer cells (p. 874, left column, section 1, lines 6-12). However, Cao teaches CLN as being oxidatively unstable and having poor water solubility, and that a major thrust in CLN applications is to develop an effective method that can improve its stability and solubility (p. 874, left column, section 1, second paragraph, lines 3-9).
Cao teaches the fabrication of CLN-loaded β-CD nanoflakes (p. 874, left column, section 1, third paragraph, lines 10-11). Cao teaches that CLN-loaded β-CD nanoflakes were prepared by mixing 2.5 mL of 250 mg/mL β-CD aqueous solution with 0.5 mL of CLN alcoholic solution under nitrogen with stirring (p. 874, right column, section 2.2, first paragraph, lines 1-4). Cao teaches the content of CLN ranged from 30 to 120 mg (p. 874, right column, section 2.2, first paragraph, lines 4-5). Therefore, an approximately 3 mL solution contained 625 mg of β-CD and 30-120 mg CLN. The solution with 30 mg CLN has a concentration of 10 mg/mL CLN and 20.8% wt/vol β-CD.
Cao further teaches that after mixing for ten minutes, the solution was cooled and 10 mL of petroleum ether was added to remove the free CLN, and after centrifugation, the petroleum ether layer containing free CLN was collected (p. 874, right column, section 2.2, lines 6-9). Cao teaches that the water layer from this extraction from petroleum ether was volatilized, freeze-dried, and the white powder was stored at -20°C (p. 874, right column, section 2.2, lines 12-13). This is interpreted as satisfying the limitations of a lyophilizate recited in claim 1.
Based on the description of this method as described above, 625 mg of β-CD and 30-120 mg of CLN were used to prepare 3 mL of solution. As evidenced by Sigma Aldrich, the molecular weight of β-CD is 1134.98 g/mol and the molecular weight of a linolenic acid (noting that all linolenic acids will have the same molecular weight) is 278.43 g/mol (SDS documents for each of β-CD and linolenic acid of record; see p. 2 of each SDS). Therefore, the composition with 30 mg of CLN and 625 mg of β-CD has approximately 0.108 mmol of CLN and 0.550 mmol of β-CD for a molar ratio of 1:5.1, and the composition with 120 mg of CLN has approximately 0.431 mmol of CLN and 0.550 mmol of β-CD for a molar ratio of 1:1.27.
Cao further teaches the CLN loading and encapsulation efficiency depended on the concentration of CLN while the concentration of β-CD is kept constant (p. 875, left column, section 3.1, second paragraph, lines 11-13). Cao references table 1, which teaches that in solutions prepared from 250 mg of β-CD and 30-120 mg of CLN, encapsulation efficiency decreased from 97.8% to 94.2% as CLN content increased from 30 mg to 120 mg and that drug loading capacity increased from 10.5% to 31.2% as CLN content increased from 30 mg to 120 mg (p. 875, Table 1). Performing the same molecular weight calculations described above, the example with 30 mg of CLN and 250 mg of β-CD has a molar ratio of CLN:β-CD of approximately 1:2. Assuming the same 3 mL volume for these compositions as above, the 30 mg CLN solution has a concentration of 10 mg/mL CLN and 8.33% wt/vol β-CD.
Cao teaches that after CLN loading, CLN-loaded β-CD products are flake-shape, with about 50 nm in thickness and 1–3 μm in side length (p. 875, left column, Section 3.1, first paragraph, lines 7-9). Cao teaches that the dispersity of CLN and CLN-loaded β-CD nanoflakes in water after 2 min of ultrasonic treatment were compared, and whereas CLN is water insoluble and aggregates to form a block, CLN encapsulated in β-CD can be easily dispersed into water to form a turbid liquid (p. 875, right column, section 3.2, second paragraph, lines 1-6; p. 876, Figure 5). Given the size of the CLN-loaded β-CD nanoflakes is reasonably measured in nanometers (with thickness of 50 nm) and their formation of turbid liquid when dispersed in water, the examiner is reasonably interpreting this composition as a nanoemulsion as recited in claim 1, absent evidence to the contrary.
Finally, Cao teaches that encapsulation of CLN using β-CD improves the oxidative stability of CLN. Cao teaches the effect of oxidation on CLN and CLN-loaded β-CD nanoflakes in 1:1 water/ethanol at 50 °C. Cao teaches that CLN is unstable, with about 80% of CLN oxidized after exposure to air for 30 minutes and approximately 97% oxidized after 40 min (p. 875, right column, section 3.2, first paragraph, lines 1-6; p. 875, Figure 4a). However, Cao teaches that the oxidation rate of CLN encapsulated in β-CD is significantly slowed compared to that of free CLN, with less than 1% of CLN oxidized after 40 minutes and 35% CLN remaining after exposure to air for 280 hours (p. 875, right column, section 3.2, first paragraph, lines 6-11; p. 875, Figures 4b, 4c).
Cao does not teach the cyclodextrin inclusion complex including gamma-linolenic acid and wherein the cyclodextrin is selected from 2-hydroxypropyl-β-cyclodextrin; sulfobutylether-β-cyclodextrin, sodium salt; and 2,6-dimethyl-β-cyclodextrin, as required by independent claim 1.
Miyashita teaches the oxidation of polyunsaturated fatty acids in an aqueous solution catalyzed by Fe2+-ascorbic acid (p. 1638, left column, second paragraph, lines 1-3), explaining that these conditions were chosen due to increasing interest in the biological effects of polyunsaturated fatty acids and the need to assess stability under conditions closer to a biological system (p. 1638, left column, first paragraph, lines 14-16). Miyashita teaches that gamma-linolenic acid is rapidly oxidized by incubation with Fe2+-ascorbic acid at 37 °C in aqueous solution (p. 1639, Figure 1), including oxidizing more quickly than alpha linolenic acid (p. 1639, Figure 2). Therefore, based on the teachings of Miyashita, one of ordinary skill in the art would have recognized rapid oxidation as a potential challenge associated with using gamma-linolenic acid in a biological system.
Strassburger teaches a product comprising a guest complexed with a cyclodextrin, wherein the guest is more stable in the product and does not degrade as quickly as a product comprising the same guest without a cyclodextrin (cover page, abstract, lines 1-4). Strassburger also claims a method for reducing degradation of a guest in a product over time comprising adding a guest complexed with a cyclodextrin to the product, wherein the guest is complexed with the cyclodextrin in the presence in an emulsifier (p. 57, claim 32), and further claims the cyclodextrin comprises a β-cyclodextrin, a substituted β-cyclodextrin, and hydroxypropyl β-cyclodextrin (p. 58, claims 41-43), and teaches one such cyclodextrin is 2-hydroxypropyl β-cyclodextrin (p. 8, [0048], lines 1-2). Strassburger expressly teaches that the cyclodextrin inclusion complex may be prepared as an emulsion (p. 20, [00110], lines 3-5). Strassburger further teaches that the guest may include polyunsaturated fatty acids (p. 11, [0066], lines 1-2), and teaches gamma-linolenic acid (GLA) as one such example polyunsaturated fatty acids (p. 12, [0067], lines 1-5).
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of Cao and prepare an inclusion complex of gamma-linolenic acid and 2-hydroxypropyl-β-cyclodextrin. One of ordinary skill in the art would have been motivated to modify the method taught by Cao and prepare an inclusion complex of gamma-linolenic acid and 2-hydroxypropyl-β-cyclodextrin because Cao teaches encapsulation of conjugated linolenic acid in β-cyclodextrin, which protects it from oxidation, Miyashita teaches that gamma-linolenic acid is rapidly oxidized in aqueous solutions with catalysts in biological systems, and Strassburger teaches inclusion complexes of guest compounds in cyclodextrins for preventing or reducing guest compound degradation, specifically teaching gamma-linolenic acid as one such guest and 2-hydroxypropyl-β-cyclodextrin as one example β-cyclodextrin. Therefore, one of ordinary skill in the art, in recognizing gamma-linolenic acid as susceptible to oxidative degradation and encapsulation of linolenic acids in β-cyclodextrins as one strategy to reduce unwanted degradation, would have contemplated an inclusion complex of gamma-linolenic acid and β-cyclodextrin, including 2-hydroxypropyl-β-cyclodextrin. In addition, one of ordinary skill in the art would have further considered the method of preparing the compositions of CLN and β-cyclodextrin taught by Cao for guidance in preparing inclusion complexes of gamma-linolenic acid and 2-hydroxypropyl-β-cyclodextrin, because said method has been shown to be effective for formulating CLNs with β-cyclodextrins.
One of ordinary skill in the art would have had a reasonable expectation of success modifying the method of Cao and preparing a composition comprising an inclusion complex of gamma-linolenic acid and 2-hydroxypropyl-β-cyclodextrin because Strassburger teaches inclusion complexes of polyunsaturated fatty acids in cyclodextrins, including gamma-linolenic acid as an example polyunsaturated fatty acid and 2-hydroxypropyl-β-cyclodextrin as an example 2-hydroxypropyl-β-cyclodextrin. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success modifying the method of Cao by substituting gamma-linolenic acid in place of CLN and 2-hydroxypropyl-β-cyclodextrin in place of β-cyclodextrin, because these compounds are expressly suggested by Strassburger for formulation as inclusion complexes.
With respect to the concentration of cyclodextrin and gamma-linolenic acid required by claim 1 and the molar ratio of CD:GLA required by claims 2 and 3, in view of Cao teaching inclusion complexes with concentrations of CD and GLA that satisfy the present claims (or are just outside of the presently claimed range, such as the 8.3% w/v CD recited above) and that different ratios of CLN and CD affect the encapsulation efficiency of CLN, one of ordinary skill in the art would have recognized the concentration of gamma-linolenic acid and substituted β-CD, as well as their molar ratio, as result-effective variables.
MPEP 2144.05 at II A states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” In this instance, one of ordinary skill in the art would have considered compositions with varying concentrations of ratios of gamma-linolenic acid and β-cyclodextrin, to for example, optimize the encapsulation efficiency of gamma-linolenic acid and to adjust the drug loading capacity of the gamma-linolenic acid.
Therefore the invention taken as a whole is prima facie obvious.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Cao in view of Miyashita and Strassburger as applied to claims 1-4 above, and further in view of Kokura (Kokura, S.; et al. Cancer Research 1997, vol. 57, pp. 2200-2202; of record) and Das (Das, U. N.; et al. Prostaglandins, Leukotrienes, and Essential Fatty Acids 2004, vol. 70, pp. 539-552; of record).
Claim 8 recites a method for treatment of cancer, comprising administering to a subject in need thereof the formulation according to claim 1, wherein the cancer is selected from cancers of the brain, gliomas, and metastatic cancers to the brain. Claim 9 depends from claim 8 and requires said glioma is glioblastoma multiforme.
Cao, Miyashita, and Strassburger teach as described in the above rejections under 35 U.S.C. § 103.
Cao, Miyashita, and Strassburger do not teach a method for treatment of cancer, comprising administering to a subject in need thereof the formulation of claim 1, wherein the cancer is selected from cancers of the brain, gliomas, and metastatic cancers to the brain including leptomeningeal cancers, as required by claims 8 and 9.
Kokura teaches the effect of polyunsaturated fatty acids on cancer. Specifically, Kokura teaches administration of 4 mg/kg oleic acid, linoleic acid, α-linolenic acid, and gamma-linolenic acid (p. 2200, left column, Materials and Methods section, second paragraph, lines 1-3) in rats with carcinoma. Kokura teaches that alpha-tocopherol levels in tumor and tumor volume were reduced by treatment with gamma-linolenic acid (p. 2201, Figures 2 and 3), and further reduced when mice were subjected to hyperthermia treatment in combination with administration of gamma-linolenic acid (p. 2201, Figure 5; p. 2202, Figure 6).
Kokura teaches that although they observed a slight antitumor effect of intraarterial injection of gamma-linolenic acid, extremely high doses would likely be required for significant antitumor effects, and in this instance, the antitumor effect was obtained with polyunsaturated fatty acids administered to increase the levels of radical reaction substrates, followed by a trigger for radical reactions, hyperthermia. Kokura concludes by stating that although the prospect of obtaining an antitumor effect with polyunsaturated fatty acids alone is attractive, there are several problems with clinical application of this approach, such as hemolysis and decreased fatty acid availability because of binding to albumin (p. 2202, right column, lines 1-12).
Das teaches that polyunsaturated fatty acids, especially gamma-linolenic acid (GLA), have selective tumoricidal action especially against malignant glioma cells both in vitro and in vivo (p. 539, Abstract, lines 2-4). Das teaches that malignant astrocytomas, anaplastic astrocytoma and glioblastoma multiforme are the most common glial tumors, with an annual incidence of 3–4 per 100,000 population, and that at least 80% of malignant gliomas are glioblastomas (p. 539, left column, first paragraph, lines 7-11). Das further teaches administration of GLA to patient with glioblastoma multiforme (p. 546, Figure 3; p. 547, Figure 4). Das teaches an open label clinical study was performed on six patients with recurrent glioma or anaplastic astrocytoma, and that intratumoral injection of GLA given at the rate of 1 mg/day for 7–10 days produced a significant reduction in the tumor size without any acute side effects, and that pre- and post-treatment CT scans of three of the patients (see Figures 3-5 in Das, pp. 546, 547, and 548) showed that intratumoral injection of GLA induced significant reduction in tumor size and decrease in midline shift, an indication that tumor has regressed (p. 545, left column, first paragraph). The patient in Figure 3 and the patient in Figure 4 are reported to specifically suffer from glioblastoma multiforme (see captions of Figures 3 and 4, pp. 546-547).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the composition obvious over Cao in view of Miyashita and Strassburger for treating glioblastoma multiforme. One of ordinary skill in the art would have been motivated to administer the composition obvious over Cao in view of Miyashita and Strassburger for treating glioblastoma multiforme in view of Kokura teaching the anti-tumor benefit of intraarterial injection of gamma-linolenic acid as well as the challenges of administering polyunsaturated fatty acids, such as hemolysis and decreased fatty acid availability, and Das teaching the effectiveness in administering gamma-linolenic acid for treating glioblastoma multiforme. Therefore, given the protective effects of encapsulation of CLN and gamma-linolenic acid with β-cyclodextrin taught by Cao and Strassburger, one of ordinary skill in the art would have recognized that administering the inclusion complex obvious over Cao in view of Miyashita and Strassburger for treating glioblastoma multiforme may overcome stated challenges with administering gamma-linolenic acid as taught by Kokura, such as decreased stability and decreased bioavailability, and thus improve the utility of gamma-linolenic acid as a treatment for glioblastoma multiforme, as taught by Das.
One of ordinary skill in the art would have had a reasonable expectation of success administering the composition of claim 1 for treating glioblastoma multiforme because a lack of stability of gamma-linolenic acid in biological or biological-like systems is a recognized problem taught by Miyashita and Kokura, and thus administration of said inclusion complex, which is expected to reduce degradation of gamma-linolenic acid, as taught by Strassburger and as observed for CLN by Cao, may also reduce degradation of gamma-linolenic acid when administered for treating glioblastoma multiforme.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: In response to the previous rejections, Applicant provides the following arguments:
1. Applicant argues that Cao teaches nanoflakes of conjugated linolenic (CLN) acid and β-CD, and fails disclose substituted β-CD as claimed in the present invention. Cao also teaches conjugated linolenic acid which are different from gamma linolenic acid as is illustrated from below structures. Applicant argues that the problem Cao purports to address is "oxidation unstability” and suggests that "the oxidation stability of CLN was significantly improved" by β-CD encapsulation of CLN. Further, the disclosure of "with 0.5 mL of CLN alcoholic solution” without any consideration for pH delineates the formulation of Cao from the novel and inventive inclusion complex of the present invention. (Applicant’s remarks, pp. 5-6)
2. Applicant argues that as stated by the examiner, the solution with 30 mg CLN has a concentration of 10 mg/ml CLN and 20.8% w/vol β-CD is incorrect. Applicant refers to Table 1 of Cao, which show encapsulation efficiency of process in example 1 wherein the concentration of CLN varies from 30-120 mg and weight of β-CD is constant at 250 mg. Applicant argues that the encapsulation efficiency provides true functional ratio for CLN and β-CD.
Applicant argues that CLN and β-CD that are structurally different and therefore cannot be equated with the claimed GLA and substituted β-CD. Both the GLA and substituted β-CD are different in the structure as well as their properties, and hence inventive over Cao. Applicant argues that the molar ratio calculation as explained in the office action will not be relevant for arriving at the molar ratio as claimed in the present invention as the molecular weight of β-CD is different from substituted β-CD. Applicant states that the molecular weight of substituted β-CD like (2-hydroxypropyl)-β-CD has an average molecular weight of around 1460 g/mol, therefore true estimation of molar ratio is dependent upon the molecular weight of the substances used and therefore ratio may appear to be similar but quantum that is to be incorporated will differ significantly. (Applicant’s remarks, pp. 6-7)
3. Applicant argues that Cao fails to teach lyophilizate of GLA and substituted β-CD. Applicant argues that the present invention discloses stable lyophilizate are obtained as shown in figure 1. The photograph shows well dispersed droplets with average size of 200±85 nm." (Para [0026], page 2). Applicant further argues that the process of preparation for the present invention is different from Cao as the claimed product of the present invention as depicted in figure 1 (reproduced below) is distinct from Cao depicted in Figure 1 (c-d) (reproduced below), wherein flake shaped CLN-loaded β CD are disclosed as "after CLN loading, CLN-loaded β-CD products are flake-shape." (Applicant’s remarks, pp. 7-8)
Applicant argues that the process of the present invention provides for nanoemulsions that are colloidal particulate systems involving a medium. Applicant argues that emulsions are kinetically stable structures that are prone to destabilization, resulting in complete phase separation of the emulsion over time. Applicant argues that the present invention provides for a stable formulation of GLA as a cyclodextrin complex in either distilled water or in buffered solutions, wherein the formulated GLA is stable over time and readily administered to patients whereas Cao et al only teaches about nanoflakes (only dispersed phase) and no stable emulsion or the continuous phase. (Applicant’s remarks, p. 8).
4. Applicant argues that Strassburger pertains to stabilizing guests with a cyclodextrin and reducing the formation of guest degradation products. Applicant argues that the guest in Strassburger is predominantly a flavoring agent and the problem to overcome is of improving the flavor stability of a product when exposed to light. Applicant argues that substituted β-cyclodextrin (CD), as disclosed in Strassburger, finds application in improving the stability of flavoring agent and not with any therapeutic agent. (Applicant’s remarks, p. 9).
5. Applicant argues that Strassburger emphasizes the use of emulsifier in the complexation method as the guest is complexed with the cyclodextrin in the presence in an emulsifier and wherein the degradation of the guest is reduced by about 25% due to complexation of the guest with the cyclodextrin as compared to a control (Claim 32). Applicant argues that substituted β-cyclodextrin (CD), as in the Strassburger, is employed for improving the stability of flavoring agent. Applicant notes that Strassburger teaches: "While hydroxypropyl-β-cyclodextrin may result in superior color stability (as shown in example 40); it is less effective than β-cyclodextrin in preventing flavor off notes" (para [00152]). To overcome the disadvantage of hydroxypropyl-β-cyclodextrin, the document further teaches use of mixture as "Mixtures of β-cyclodextrin and hydroxypropyl-β- cyclodextrin may be used to gain both color stability and prevent off notes." (para [00152]). Applicant argues that a person skilled in the art inspired from the teachings of Strassburger will incorporate an emulsifier and employ a combination of β-CD and hydroxylpropyl-β-CD together. (Applicant’s remarks, p. 9).
6. Applicant argues Miyashita is drawn to oxidative stability of six kinds of typical polyunsaturated fatty acids, and the problem identified is altogether different from the present invention. Applicant notes that Miyashita teaches "The higher oxidative stability of α-LNA than of γ-LNA in an aqueous solution was also confirmed ... " (LHS, page 1639). Applicant argues that Miyashita further teaches "the oxidative stability of DHA/LA mixtures in an aqueous solution, the total concentration of DHA and LA being 1 mM in each aqueous mixture. The stability of each mixture increased with increasing molar concentration of HA, …”, and that therefore a person presented with the problem of instability will combine γ-LNA with DHA with a reasonable expectation of success, which is not the subject matter of present invention. Applicant argues that the present invention aims to provide a stable formulation of inclusion complex of GLA, where the formulated GLA is stable over time and readily administered to patients in need of treatment.
Applicant’s arguments summarized above have been fully considered but they are not found persuasive.
With respect to argument 1 above, Cao teaches that complexation of conjugated linolenic acids with cyclodextrin improves its oxidative stability. Miyashita teaches that gamma-linolenic acid is susceptible to oxidation. Therefore, the prior art acknowledges the problem of oxidative stability associated with gamma-linolenic acid, and one of ordinary skill in the art would have reasonably considered formulating gamma-linolenic acid in such a way as to reduce oxidation. As one example, one of ordinary skill in the art would have reasonably considered the methods known the prior art to reduce oxidation of other unsaturated fatty acids, such as the complexation of conjugated linolenic acids with β-CD as taught by Cao.
Regarding the substituted β-CD required by the present claims, because Strassburger teaches a product comprising a guest complexed with a cyclodextrin wherein the guest is more stable in the product and does not degrade as quickly as a product comprising the same guest without a cyclodextrin, and further suggests a substituted β-cyclodextrin for said complex, 2-hydroxypropyl β-cyclodextrin, one of ordinary skill in the art would have contemplated a substituted β-cyclodextrin in place of the β-cyclodextrin taught by Cao. Each of Cao, Miyashita, and Strassburger are concerned with oxidative degradation unsaturated fatty acid compounds, and therefore, are reasonable to combine.
With respect to the pH of the ethanolic solution of Cao, this appears to be arguing a limitation that is not present in the claims, and it is unclear how a lack of pH disclosed by Cao applies to the present claims.
With respect argument 2 above, because Cao teaches inclusion complexes with concentrations of CD and CLN that satisfy the present claims (or are just outside of the presently claimed range, such as the 8.3% CD recited above) and that different ratios of CLN and CD affect the encapsulation efficiency of CLN, one of ordinary skill in the art would have recognized the concentration of gamma-linolenic acid and substituted β-CD, as well as their molar ratio, as result-effective variables.
MPEP 2144.05 at II A states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” In this instance, one of ordinary skill in the art would have considered compositions with varying concentrations and ratios of gamma-linolenic acid and β-cyclodextrin, to for example, optimize the encapsulation efficiency of gamma-linolenic acid.
Regarding the specific molecular weights of gamma-linolenic acid and the substituted β-cyclodextrin required by the present claims, the examiner agrees with Applicant that the molecular weights of CLN and β-cyclodextrin taught by Cao will be different. Based on the description of the method of Cao, 625 mg of β-CD and 30-120 mg of CLN were used to prepare 3 mL of solution. The composition with 30 mg of CLN includes 0.108 mmol of CLN and 0.550 mmol of β-CD, which is a molar ratio of 1:5.1. The composition with 120 mg of CLN has approximately 0.431 mmol of CLN and 0.550 mmol of β-CD for a molar ratio of 1:1.27.
Sigma Aldrich provides that 2-hydroxypropyl β-CD has a molecular weight of approximately ~1396 Da (p. 3, Properties section; of record). Noting that all linolenic acids will have the same molecular weight, a composition with 30 mg of CLN and 625 mg of 2-HP-β-CD has approximately 0.108 mmol of CLN and 0.447 mmol of 2-HP-β-CD for a molar ratio of 1:4.1, and a composition with 120 mg of CLN has approximately 0.431 mmol of CLN and 0.447 mmol of 2-HP β-CD for a molar ratio of 1:1.04. Therefore, one of ordinary skill in the art, following the guidance of Cao and solely substituting the same mass of β-CD for 2-HP-β-CD, would have prepared a composition that satisfies the instant claims.
Although Table 1 of Cao teaches 250 mg of β-CD content, Cao clearly teaches in their method that to prepare CLN-loaded β-CD nanoflakes: 2.5 mL of 250 mg/mL β-CD aqueous solution was mixed with 0.5 mL of CLN alcoholic solution. Therefore, based on the description of Cao’s method, 625 mg of β-CD were used to prepare the conjugates, or one of ordinary skill in the art would have considered the method of Cao using 625 mg of β-CD.
In this instance, absent secondary considerations of non-obviousness such as superior encapsulation efficiency associated with a specific molar ratio of gamma-linolenic acid and substituted β-cyclodextrin, the specific molar ratio of these components is obvious over the cited prior art.
With respect to argument 3 above, Cao teaches both a lyophilized sample (see p. 874, right column, section 2.2; lines 12-13; the water layer was freeze-dried to obtain a white powder) and an emulsion (see p. 876, Figure 5; formation of a turbid liquid with CLN). Therefore, Cao appears to teach each formulation of claim 1. In addition, Cao teaches the nanoflakes were 50 nm in thickness. Cao does not expressly teach the size of the particle when present in the dispersion of Figure 5, however, absent a showing that the size of the particles when dispersed in water according to Figure 5 of Cao does not satisfy the limitations of present claim 4, the examiner asserts that the preponderance of evidence favors the emulsion of Cao as satisfying the limitations of claim 4.
Regarding Applicant’s argument that Cao teaches nanoflakes, Applicant appears to be arguing limitations that are not claimed. Cao teaches a lyophilized product that adopts a flake shape. The claims do not require the lyophilized product to adopt a specific shape. Similarly, with respect to the method of making, because the claims are drawn to a product (an inclusion complex), Applicant appears to be arguing limitations that are not claimed.
Regarding the properties of the claimed nanoemulsion, the examiner maintains that the size of the particles and formation of a turbid liquid strongly suggest the formation of a nanoemulsion, absent evidence to the contrary.
However, Applicant is invited to provide evidence of unpredictability regarding the formation of a nanoemulsion from a lyophilizate, which would place claims directed to the nanoemulsion in condition for allowance. As stated above, the examiner maintains that the nanoemulsion of the present claims is obvious in view of Cao disclosing the turbid composition formed from their nanometer-sized particles in water, which appears to have the same properties as a nanoemulsion. However, evidence that a resulting emulsion does not necessarily include the same size lyophilizate particles used when preparing said emulsion, or evidence that a turbid composition formed by a lyophilizate in liquid does not necessarily have the same properties as the present nanoemulsion with respect to, for example, the stability of the nanoemulsion, would offer persuasive evidence of nonobviousness to overcome this rejection.
The examiner notes that such evidence of non-obviousness would only place the claims directed to the nanoemulsion in condition for allowance.
With respect to argument 4 above, one of ordinary skill in the art would have recognized reducing oxidative degradation as one example of reducing the formation of guest degradation products, as taught by Strassburger, and therefore would have considered the teachings of Strassburger as relevant to those of Cao and Miyashita. Regarding Applicant’s argument that Strassburger is directed to improving flavor stability, although Strassburger teaches examples wherein cyclodextrin is used to improve flavor stability, because Strassburger teaches that their invention provides a product comprising a guest complexed with a cyclodextrin wherein the guest is more stable in the product and does not degrade as quickly as a product comprising the same guest without a cyclodextrin (e.g., see Abstract of Strassburger), one of ordinary skill in the art would have recognized that the teachings of Strassburger are not solely limited to complexation of flavoring agents with cyclodextrin.
With respect to argument 5 above, Strassburger teaches a method of complexation with an emulsifier, as Applicant notes, however it’s unclear how this is relevant to the present rejection, because the presently claimed formulation may be formulated as a nanoemulsion. In addition, if for some reason the emulsifier is relevant, Strassburger further claims complexation products with a cyclodextrin and guest (e.g., p. 55, claim 8), and thus one of ordinary skill in the art would have contemplated these cyclodextrin/guest complexes without an emulsifying agent.
Regarding Applicant’s arguments about Strassburger’s teachings of color stability compared with flavor stability, although Strassburger acknowledges the benefits of the combination of β-CD and 2-HP-β-CD, the examiner argues that Strassburger teaches each as unexpectedly better for preserving one property or another, but does not teach one as unable to participate in the relevant inclusion complex with gamma-linolenic acid, and thus Strassburger does not teach away from the claimed invention.
With respect to argument 6 above, Miyashita teaches that both alpha-linolenic acid and gamma-linolenic acid are subject to oxidative degradation. Therefore, one of ordinary skill in the art would have recognized a need to protect gamma-linolenic acid from oxidation, and would have considered the strategies known in the prior art to protect unsaturated fatty acids from oxidation, such as the strategy taught by Miyashita. However, one of ordinary skill in the art would have contemplated other methods for protecting unsaturated fatty acids from oxidation as well, including the complexation methods of Cao and Strassburger, and would have further recognized these methods as useful for protecting each of alpha-linolenic acid and gamma-linolenic acid. Moreover, because Miyashita teaches that gamma-linolenic acid is more susceptible to degradation than alpha-linolenic acid, one of ordinary skill in the art would have recognized gamma-linolenic acid as in greater need of protection from oxidative degradation than alpha-linolenic acid.
Moreover, Applicant presents the following arguments:
7. Applicant argues that Das teaches that GLA or its salt are effective in treatment of gliomas, which is already acknowledged in the background section of the present invention, and both Kokura and Das are silent on the problems associated stability of GLA formulation and hence, the solution provided by the present invention of therapeutically effective shelf-life stable formulation of GLA in form of inclusion complex of GLA and substituted β-CD is not obvious. (Applicant’s remarks, p. 11).
8. Applicant argues that Kokura teaches γ-linolenic acid (18:3, n-6) " .. . although the present study found a slight antitumor effect of intraarterial injection of γ-linolenic acid, extremely high doses would likely be required for significant antitumor effects. An antitumor effect has been demonstrated with polyunsaturated fatty acids in vitro, but they have failed to show efficacy in vivo (14-16)". Applicant notes that Kokura concludes that "that hyperthermia combined with γ-linolenic acid significantly increases free radical reactions in cancer tissue and is effective in suppressing tumor growth." Hence, Applicant argues that a person skilled in the art gets teaching for administration of GLA with hyperthermia for effective tumor growth control. However, the cited documents are silent on the teaching of substituted β-cyclodextrin (CD) inclusion complex with an anticancer agent, gamma-linolenic acid (GLA), to provide an effective concentration required in vivo for significant antitumor effects whereby the drug: carrier ratio is varied depending on the composition of the drug.
Moreover, Applicant argues that the use of substituted β-cyclodextrin (CD) as a carrier being loaded with an anticancer agent for managing the condition of glioblastoma multiforme that is biocompatible with good cell viability is not disclosed in any of the prior art when read alone or together. (Applicant’s remarks, pp. 11-12).
Applicant’s arguments summarized above have been fully considered but they are not found persuasive.
With respect to argument 7 above, in view of Das teaching that GLA is effective for treating gliomas and Miyashita, Kokura, and Strassburger teaching that GLA is susceptible to degradation, one of ordinary skill in the art would have contemplated a formulation that protects GLA from such degradation may also be useful for treating gliomas.
With respect to argument 8 above, one of ordinary skill in the art would have recognized that the reduced efficacy of GLA may be due to the recognized challenges associated with administering GLA, and thus administration of a formulation of GLA that protects against degradation, such as the formulation of GLA obvious over Cao in view of Miyashita and Strassburger as described above, may further improve the antitumor effect and/or lower the required dose of GLA. Moreover, because Das teaches the efficacy of GLA delivered directly to the tumor, one of ordinary skill in the art would have recognized that the mode of administration of GLA is important, would have recognized the challenges of administering GLA acknowledged by Kokura, and thus would have contemplated formulations that may reduce GLA degradation in biological conditions.
Therefore, for the reasons stated above, the previous rejection of claims 1-4 as unpatentable over Cao in view of Miyashita and Strassburger, and the previous rejection of claims 8-9 as unpatentable over Cao in view of Miyashita and Strassburger, and further in view of Kokura and Das, are maintained.
As stated above, the examiner maintains that the size of the particles and formation of a turbid liquid strongly indicate formation of a nanoemulsion, absent evidence to the contrary. However, Applicant is encouraged to provide evidence of unpredictability regarding the formation of a nanoemulsion from a lyophilizate, which may be sufficient to overcome rejections relating to the nanoemulsion and place claims directed to the nanoemulsion in condition for allowance.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693