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 . Claims 1-2, 4, 7-14 filed December 16, 2025 are currently pending.
Response to Amendment
Applicant’s amendments, filed 12/16/2025 are acknowledged. Claim 6 was canceled in its entirety. Claim 1 was amended to recite the limitation of a human subject suffering from NASH, while claim 2 is directed to wherein tocotrienol is delivered systemically at a therapeutically effective concentration 5-6 hours after delivery. Claim 4 now recites the limitation of reducing lipid accumulation in serum and liver tissues of patients suffering from NASH. Claim 7 is directed to the method of claim 1 wherein the tocotrienol is administered orally, at a therapeutically effective concentration 5-6 hours after ingestion.
In view of Applicant’s amendment, the 35 U.S.C 102(a)(1) rejection of claims 2, 4, and 6 in view of Magosso (WO2013/115636) is withdrawn as Magosso does not specifically teach wherein the patient administered tocotrienol is suffering from NASH. In addition, the pending 35 U.S.C 102(a)(1) rejection of claim 2 by Yachi is withdrawn as Yachi does not teach wherein the tocotrienol is delivered systemically at a therapeutically effective concentration of 5-6 hours after delivery. Further, the pending 35 U.S.C. 103 (a) rejection of claims 1-2, 4, and 7-14 by Magosso is withdrawn as Magosso does not specifically teach wherein the patient administered tocotrienol is suffering from NASH.
Applicant's arguments, filed 12/16/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 4 remains rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yachi (J. Clin. Biochem. Nutr. Vol. 52 pages 146-153. Published 03/01/2013).
Yachi teaches treating patients comprising TNF alpha and GaIN induced non-alcoholic steatohepatitis in a subject in need comprising administering a therapeutically effective amount of a composition comprising tocotrienols (T3) in combination with alpha-tocopherol. As shown in Table 1, said T3 tocotrienol composition comprises 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol, Table 1). Regarding claim 4, as shown in Figures 1A-1C said alpha tocopherol and tocotrienol composition effectively reduced lipid accumulation in the serum and liver tissue of TNF alpha and GaIN induced non-alcoholic steatohepatitis patients (pages 146-149, page 152). Said administration of TNF alpha and GaIN to induce non-alcoholic steatohepatitis also resulted in hepatic inflammation and hepatic fibrosis in the afflicted patient (pages 149 right col. to page 151 right col., page 152 left col.) Yachi teaches that the administration of the composition comprising alpha-tocopherol and tocotrienols resulted in the reduction of said hepatic inflammation and inhibited liver fibrosis in said patient (pages 150-151 right col., page 152 left col. and right col.)
Applicant traverses. Applicant argues that Yashi does not treat a patient currently afflicted by NASH with the claimed tocotrienol, nor the reduction of liver inflammation or liver fibrosis as required by the claims.
Response to Arguments
Applicant’s arguments, filed 12/16/2025 are acknowledged and have been carefully considered. Regarding Applicant’s assertion that Yashi does not treat a patient currently afflicted by NASH with the claimed tocotrienol composition, nor the reduction of liver inflammation or liver fibrosis, this argument is not persuasive. As shown in, Figures 1A-1C, said alpha tocopherol and tocotrienol composition effectively reduced lipid accumulation in the serum and liver tissue of TNF alpha and GaIN induced non-alcoholic steatohepatitis patients (pages 146-149, page 152). In addition, the TNF alpha and GaIN induced non-alcoholic steatohepatitis patients also resulted in hepatic inflammation and hepatic fibrosis, which was treated by the administration of the tocotrienol composition (pages 149 right col. to page 151 right col., page 152 left col.). Therefore, the rejection is maintained.
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.
Claim(s) 1-2, 4, 7-10, 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Yachi (J. Clin. Biochem. Nutr. Vol. 52 pages 146-153. Published 03/01/2013) and Magosso (WO2013/115636 published 08/08/2013).
Yachi teaches treating patients comprising TNF alpha and GaIN induced non-alcoholic steatohepatitis in a subject in need comprising orally administering a therapeutically effective amount of a composition comprising tocotrienols (T3) in combination with alpha-tocopherol. As shown in Table 1, said T3 tocotrienol composition comprises 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol, Table 1). As shown in Figures 1A-1C said alpha tocopherol and tocotrienol composition effectively reduced lipid accumulation in the serum and liver tissue of administered patients (pages 146-149, page 152). Regarding claim 2, said administration of TNF alpha and GaIN to induce non-alcoholic steatohepatitis also resulted in hepatic inflammation and hepatic fibrosis in the afflicted patient (pages 149 right col. to page 151 right col., page 152 left col.). As evidenced by page 17 of the present specification, the claimed non-alcoholic steatohepatitis is characterized by steatosis (accumulation of fat), increased inflammation and fibrosis. Regarding claim 4, Yachi teaches that the administration of the composition comprising alpha-tocopherol and tocotrienols resulted in the reduction of said hepatic inflammation and inhibited liver fibrosis in said NASH patient (pages 150-151 right col., page 152 left col. and right col.)
The difference between the present claims and that of Yachi is that Yachi does not specifically teach oral administration to human patients with non-alcoholic steatohepatitis. Nor does Yachi specifically teach wherein tocotrienol is delivered systemically at a therapeutically effective concentration 5-6 hours after delivery.
Magosso (WO2013/115636 published 08/08/2013) teaches the method of treating and preventing the development of non-fatty liver diseases comprising administering a therapeutically effective amount of a composition comprising at least one tocotrienol (claims 8-13). Non-alcoholic steatohepatitis (NASH), liver inflammation and liver fibrosis are three of 9 fatty liver disorders to be treated with the claimed tocotrienol composition (claims 8-13). Treatment of human patients with the disclosed tocotrienol methodology is embraced within the teachings of Magosso, in doses of 0.001-100 mg/kg, which reads on the therapeutically effective amount embodied within page 7 of the present specification (page 7 lines 10-15, page 10 lines 1-20, claims 8-13). Regarding claim 7, oral administration of the claimed tocotrienol composition is embodied within the teachings of Magosso (claims 14-15). Regarding claim 8, Magosso teaches administrations compositions comprising alpha-tocotrienol, gamma-tocotrienol and alpha-tocopherol to the afflicted patient (page 12 lines 20-35, claims 8-11). Regarding claim 13, Magosso teaches incorporation of additional therapeutic agents with the tocotrienol compositions, including insulin-sensitizing medications such as metformin and pioglitazone (page 10 lines 10-25).
Regarding the limitation of claims 2, 7 and 14, wherein the tocotrienol composition is formulated for release 5-6 hours after delivery, formulation of said orally administered tocotrienol composition in a delayed release is taught by Magosso wherein said composition comprises the enteric coating of hydroxypropyl methylcellulose phthalate (page 9 lines 5-15, claims 8-15). As evidenced by page 4 lines 20 through page 5 line 10 of the instant specification, an enteric coating imparts a delay in the release of the tocotrienol after passage of the composition through the stomach, preferably wherein the release of the tocotrienol occurs about 5-6 hours after ingestion. As such, the tocotrienol composition further containing the enteric coating of hydroxypropyl methylcellulose phthalate taught by Magosso reads on the claimed limitations.
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that a composition comprising tocotrienols (T3) in combination with alpha-tocopherol is efficacious at reducing hepatic inflammation and inhibiting liver fibrosis in induced NASH patients as taught by Yachi above, said skilled artisan would have readily predicted that administration of said composition comprising tocotrienols (T3) with alpha-tocopherol would have effectively treated non-alcoholic steatohepatitis in a human patient in view of Magosso, arriving at the presently claimed methodology.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, considering Magosso teaches that composition comprising tocotrienols (T3) in combination with alpha-tocopherol are efficacious at preventing the development non-alcoholic steatohepatitis in human patients, said artisan would have readily predicted that administration of the composition comprising tocotrienols (T3) in combination with alpha-tocopherol to a human patient with non-alcoholic steatohepatitis would have effectively treated the liver disorder in the afflicted patient.
Secondly, said skilled artisan would have found it prima facie obvious to formulate said composition comprising tocotrienols (T3) in combination with alpha-tocopherol of Yachi as a controlled/delayed release formulation with the enteric coating of hydroxypropyl methylcellulose phthalate in view of Magosso as Magosso teaches that enteric coating of hydroxypropyl methylcellulose phthalate is suitable for compositions comprising tocotrienols (T3) in combination with alpha-tocopherol to treat hepatic disorders. Regarding the limitation directed to wherein the controlled/delayed release of the tocotrienol composition yields the release of a therapeutically effective amount of tocotrienol about 5-6 hours after ingestion of the pharmaceutical composition, Applicant is reminded that properties that accrue from the process step of orally administering a sustained release dosage form of a tocotrienol composition to treat the fatty liver disorder non-alcoholic steatohepatitis in the afflicted patient are considered characteristic features of the claimed methodology.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the present case the burden is shifted to Applicant to prove that orally administered tocotrienol composition further comprising the enteric coating of hydroxypropyl methylcellulose phthalate embodied within the teachings of Yachi and Magosso, does not yield the release of a therapeutically effective amount of tocotrienol about 5-6 hours after ingestion of the pharmaceutical composition.
Lastly, regarding the limitation wherein the administered tocotrienol composition comprises 17-34% wt. alpha tocotrienol, 2-4% wt. beta-tocotrienol, 27-54 %wt. gamma tocotrienol, 8-23% wt. delta tocotrienol and 14-32% wt. alpha-tocopherol (claim 10), it is considered well within the capabilities of one of ordinary skill in the art to optimize the amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol in the administered tocotrienol composition to provide optimal efficacy in treating the hepatic disorder. The amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol in the administered composition are result effective parameters that will affect the physical properties of the final composition. The amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol are clearly a result effective parameter that a person of ordinary skill would routinely optimize. Optimization of parameters is a routine practice that would have been obvious for a person of ordinary skill in the art to employ and reasonably would expect success. Moreover, the amounts embraced within Yachi and Magosso provide a range of workable conditions and it would have been customary for an artisan of ordinary skill to determine the optimal amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol to best achieve the desired result. Furthermore, absent any evidence demonstrating a patentable difference between the composition and the criticality of the claimed amounts, the determination of the optimum workable range(s) given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II) (A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) “[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Applicant traverses. Applicant asserts that Yashi is directed to the prevention of fatty liver, not the therapeutic reversal of NASH pathology nor reversal of established fibrosis. Applicant further asserts that Yachi is directed to a rodent injury model and does not disclose human therapy nor an established human NASH patient and the combination of Magosso fails to cure the deficiencies of Yachi.
In addition, Applicant argues that the examiner failed to explain why it would be routine optimization to adjust the claimed combination of alpha tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol in their relative proportions in claim 10 and the examiner must have some rational underpinning as to why a skilled artisan would have arrived at the claimed invention. Applicant further asserts that the surprising discovery of induction of oval cell and hepatic progenitors afforded by the tocotrienol subject, as well as the increase in liver stem cell population is sufficient to overcome a prima facie case.
Response to Arguments
Applicant’s arguments, filed 12/16/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Yachi does not teach treating human patients with NASH comprising administering a tocotrienol to the afflicted patient, Applicant is reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case and as disclosed above, Yachi teaches that the administration of the composition comprising alpha-tocopherol and tocotrienols resulted in the reduction of said hepatic inflammation and inhibited liver fibrosis in TNF alpha and GaIN induced non-alcoholic steatohepatitis (NASH) patients (pages 150-151 right col., page 152 left col. and right col.).
Meanwhile, Magosso teaches that the same tocotrienols administered in murine NASH patients in Yachi are efficacious at treating/ameliorating the signs of liver disorder including NASH in human patients, in doses of 0.001-100 mg/kg, which reads on the therapeutically effective amount embodied within page 7 of the present specification (page 7 lines 10-15, page 10 lines 1-20, claims 8-13). Accordingly, said artisan would have readily predicted that administration of the NASH-treating composition comprising alpha-tocopherol and tocotrienols of Yachi to a human patient with NASH as taught by Magosso, said NASH-treating composition comprising alpha-tocopherol and tocotrienols would have treated NASH in the human patient.
As disclosed above, Yachi teaches an induced animal model patient with NASH being treated with alpha-tocopherol and tocotrienols. It is further noted that an induced NASH animal model (murine high fat diet) found within pages 16-18 of the instant application is what Applicant relies upon to demonstrate that treating NASH in a murine patient is correlative to treating NASH in a human patient, the same rationale as applied in the 35 U.S.C 103 (a) rejection of Yachi and Magosso above.
Next, Applicant argues that the examiner failed to explain why it would be routine optimization to adjust the claimed combination of alpha tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and alpha-tocopherol in their relative proportions in claim 10 and the examiner must have some rational underpinning as to why a skilled artisan would have arrived at the claimed invention. This argument is unavailing. Yachi teaches the T3 tocotrienol composition comprises 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol which is efficacious at treating NASH and hepatic fibrosis in a subject in need (Table 1) coupled with the knowledge that Magosso teaches administrations compositions comprising alpha-tocotrienol, gamma-tocotrienol and alpha-tocopherol to the afflicted patient with hepatic disorders (page 12 lines 20-35, claims 8-11). As recited in MPEP 2144.05, 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 the present case and contrary to Applicant’s assertion, Magosso teaches that the ratio/concentration of alpha tocotrienol, delta-tocotrienol and gamma tocotrienol are all results effective parameters that a skilled artisan would adjust depending on the purpose of the tocotrienol fed to the patient (page 8 lines 20-35). Furthermore, Applicant has not demonstrated criticality of the tocotrienol composition embraced within claim 10 from that found within the combined prior art of Yachi and Magosso above.
Lastly, Applicant asserts that the surprising discovery of oval cell and hepatic progenitor induction afforded by the tocotrienol subject as well as the increase in liver stem cell population is sufficient to overcome a prima facie case, the Examiner has reviewed said results, however said results do not overcome the rejection of record for the following reasons.
As shown in MPEP 716.02 (E); An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960).
In the instant case, the closest prior art is Yachi who teaches treating patients comprising TNF alpha and GaIN induced non-alcoholic steatohepatitis in a subject in need comprising orally administering a therapeutically effective amount of a T3 composition comprising 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol, wherein the administration of the composition comprising alpha-tocopherol and tocotrienols resulted in the reduction of said hepatic inflammation and inhibited liver fibrosis in said NASH patient (pages 149 right col. to page 151 right col., page 152 left col., Figures 1A-1C, Table 1).
Applicants have provided no comparative data to the closest prior art of record to show that 1) the claimed tocotrienol composition results in oval cell and hepatic progenitor induction and increase in liver stem cell population in the NASH patient compared to the NASH patient administered a T3 composition comprising 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol taught by Yachi above. In essence, there is no positive control experiment between the instantly claimed NASH patient administered a tocotrienol composition and the NASH patient administered a T3 composition comprising 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol as taught by Yachi.
Data must be provided that demonstrates that the instantly claimed methodology of administering a NASH patient a distinct tocotrienol composition performs better than the prior art NASH treating regimen of 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol as taught by Yachi in order to demonstrate that the claimed combination possesses a property not shared with the closest prior art. Applicant must also show that the different results of the between the instantly claimed and those of the prior art are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP 716.02(B) and Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
MPEP 716.02(d) addresses the subject of unexpected results commensurate in scope with the claimed invention: "[W]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. See In re Peterson, 315 F. 3d 1325, 1329-31 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003). As cited in MPEP 716.02(D) “[T]o establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
In the present case, the unexpected results are not commensurate in scope. Claims 1, 2 , 4, 7-9, 11-14 are directed to the administration of “an effective amount of a tocotrienol” to a subject suffering from NASH. The limitation of “an effective amount of a tocotrienol” embraces any amount of any species of tocotrienol. Additionally, this limitation is taught by the T3 composition comprising distinct amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol (37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol) to induced NASH patients as taught by Yachi. In the instant specification, Applicant administers a “tocotrienol rich fraction (TRF)” of distinct components or concentrations of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol to treat said murine NASH patients wherein ovel cell to hepatocyte transdifferentiation is shown as well as induction of stem niche cells of the liver (pages 9-10 for concentration of TRF; pages 16-18, Figure 1). Applicant has not demonstrated criticality of the ratio/concentration of tocotrienols in the TRF composition for their capacity to induce oval cell and hepatic progenitors an increase in liver stem cell population. For example, does this surprising result occur with any amount of any species of tocotrienol, as embraced in the independent claims? Nor has Applicant demonstrated that the T3 composition of Yachi does not afford these same surprising results. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness and the rejection is maintained.
Claim(s) 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Yachi (J. Clin. Biochem. Nutr. Vol. 52 pages 146-153. Published 03/01/2013) and Magosso (WO2013/115636 published 08/08/2013) as applied to claims 1-2, 4, 7-10 and 13-14 in view of Kim (Molecular Nutrition and Food Research Vol. 62 pages 1-10 published 2018).
As disclosed above, Yachi teaches that the administration of the composition comprising alpha-tocopherol and 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol resulted in the reduction of said hepatic inflammation and inhibited liver fibrosis in TNF alpha and GaIN induced non-alcoholic steatohepatitis (NASH) patients (pages 150-151 right col., page 152 left col. and right col.). Meanwhile, Magosso teaches that the same tocotrienols administered in murine NASH patients in Yachi are efficacious at treating/ameliorating the signs of liver disorder including NASH in human patients, in doses of 0.001-100 mg/kg, which reads on the therapeutically effective amount embodied within page 7 of the present specification (page 7 lines 10-15, page 10 lines 1-20, claims 8-13). Accordingly, said artisan would have readily predicted that administration of the NASH-treating composition comprising alpha-tocopherol and tocotrienols of Yachi to a human patient with NASH as taught by Magosso, said NASH-treating composition comprising alpha-tocopherol and tocotrienols would have treated NASH in the human patient. It is noted that an induced NASH animal model (murine high fat diet) found within pages 16-18 of the instant application is what Applicant relies upon to demonstrate that treating NASH in a murine patient is correlative to treating NASH in a human patient, the same rationale as applied in the 35 U.S.C 103 (a) rejection of Yachi and Magosso above.
The difference between the combination of Yachi and Magosso and that of the present claims is that the combination of Magosso does not specifically teach administration of a single tocotrienol compound.
Kim (Molecular Nutrition and Food Research Vol. 62 pages 1-10 published 2018) teaches treating patients with NASH induced by a high fat diet a composition comprising gamma-tocotrienol (abstract, page 2 left col.). The NASH animal model induced by a high fat diet is the same animal model found in pages 16-18 of the instant application. Kim teaches that administration of said gamma-tocotrienol composition reduced lipid triglycerides in the afflicted patient and suppressed induced fibrosis (pages 4-6, Figures 3-4)
Therefore, one of ordinary skill in the art of treating non-alcoholic steatohepatitis in a subject in need knowing that a composition comprising distinct amounts of alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol (37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol) is efficacious at treating NASH in a human subject in need as taught by the combination of Yachi and Magosso above, said skilled artisan would have found it prima facie obvious to administer a tocotrienol composition containing only gamma-tocotrienol in view of Kim, arriving at the presently claimed.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, both a composition comprising 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol and a composition comprising gamma-tocotrienol are each efficacious at treating NASH and reducing fibrosis in a subject in need. Accordingly, said artisan would have readily predicted that administration of a composition containing gamma-tocotrienol would have treated NASH in the afflicted human patient.
Regarding the limitation wherein the single tocotrienol is alpha-tocotrienol (claim 12), as demonstrated in the combination of Yachi and Magosso above or in Kim, compositions containing a blend of comprising 37% alpha tocotrienol, 4% beta-tocotrienol, 45% gamma-tocotrienol and 10.7% delta tocotrienol or compositions containing only one tocotrienol (gamma-tocotrienol) are each advantageous at treating NASH and reducing hepatic fibrosis in an afflicted patient. In view of the efficacious results with alpha tocotrienol, beta tocotrienol, gamma tocotrienol and delta tocotrienol as taught by Yachi and Magosso, and the efficacious results with the single gamma tocotrienol results as taught by Kim, said skilled artisan would have readily predicted that composition containing a single tocotrienol containing alpha, beta, gamma or delta tocotrienol would have effectively treated NASH in the afflicted human patient, absent factual evidence to the contrary.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621