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
Applicant has withdrawn claims 32-40 in the response filed on January 23rd, 2026 is acknowledged. Applicant has amended claim 21 and added claim 41. Claims 21-31 and 41 are pending and are examined on their merits.
35 U.S.C. § 103 Rejections Maintained
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 rejection of claims 21-31under 35 U.S.C. 103 as being unpatentable over Okano et. al. First-in-human phase I study of JPH203, L-type amino acids transporter 1 inhibitor, in patients with advanced solid tumors, Journal of Clinical Oncology Volume 36, Number 15 suppl and in view of Toyoshima et al., Investigation of the Role of Transporters on the Hepatic Elimination of an LAT1 Selective Inhibitor JPH203, Journal of Pharmaceutical Sciences, 102(9), pp. 3228-3238 (2013) is maintained.
Response to Applicants Arguments
In the Remarks, received January 23rd, 2026, applicant argues that Okano doesn’t teach the non-rapid NAT2 genotype (as acknowledged in the Examiner’s Office Action, filed November 3rd, 2025) in the clinical trials of JPH203 and that Toyoshima concludes that hepatic uptake transporters (OATPs), not NAT2 haplotypes, are the determinant factors for systemic exposure. And Toyoshima teaches the impact of NAT2 variations on JPH203; systemic exposure would be "less remarkable" and that those variations in metabolic clearance would "hardly influence overall clearance”.
The Declaration under 37 C.F.R. § 1.132 concurrently filed with the Remarks argues that while Toyoshima teaches NAT2 is responsible for JPH203 metabolism, the impact of NAT2 saturation on JPH203 systemic exposure will be “less remarkable.” and predicted that the variation of metabolic clearance would “hardly influence overall clearance”; the major factors causing interindividual differences would be OATP transporters, not NAT2 haplotypes. The Declaration also points to a 16 patient study where NAT2 groups with rapid NAT2 genetic markers showed improvement 12.5% (1 patient) versus non-rapid groups at 50%. (4 patients) with JPH203.
Regarding, the applicant’s response to Toyoshima teaching systemic exposure “hardly influence the overall clearance” and the importance of NAT2 genotypes being more or less important than the OATP transporters. He does teach, of the 20 different haplotypes of the NAT2 gene, rapid NAT2 acetylators typically display 2.4–2.6 times larger total body clearance compared with slow NAT2 acetylators, using isoniazid as a representative NAT2 substrate. The interpretation of this information is that the compound of JPH203 remains in the body of a slow NAT2 genotype longer than that of a rapid NAT2 rapid genotype that process JPH203 more quickly through the body and would therefore have a greater efficacy. The applicant’s arguments are not found persuasive.
35 USC § 103 Rejection Reiterated
Similar to claim 21, Okano presented the results of a clinical study at a meeting and published abstract disclosing the treatment of biliary tract cancer (BTC) using the claimed compound, JPH203, in an effective amount/dosage (see Abstract). See also below where the teachings in Okano is compared to claim 21.
Claim 21
Okano
A method of treating a disease in a subject in need thereof, said method comprising administering an effective amount of a pharmaceutical composition comprising O-(5-amino-2-phenylbenzoxazole-7-yl) methyl-3,5-dichloro-L-tyrosine (also referred to as the name JPH203) or a pharmaceutically acceptable salt thereof to the subject
Clinical study on treating biliary tract cancer (BTC) using active compound JPH203.
Dosage of JPH203 was 60 mg/m2 (max tolerated dose). Recommended phase II dose 25 mg/m2
wherein the disease is a cancerous disease
(BTC as mentioned above)
wherein the subject has a Non-Rapid N-acetylation transfer enzyme (NAT2) gene
[not explicitly mentioned]
Although Okano teaches a clinical study of administering humans having biliary tract cancer the claimed compound JPH203, he does not explicitly state the subtype of NAT2 gene in the patient, such as the subtype of the claimed patient being a non-rapid N-acetylation transfer enzyme (NAT2) gene, e.g., slow NAT2. However, one of ordinary skill in the art would have reasonably expected an improved clinical outcome in the treatment of the cancer in patients having non-rapid NAT2 compared to intermediate or rapid NAT2. This is because it was known in the art that NAT2 is largely responsible for the metabolism of the active compound JPH203. Therefore, it would be expected that a person with a non-rapid NAT2 gene would respond better to the same amount of JPH203 than the faster subtypes. For example, see Toyoshima who demonstrates that N-acetylation transfer enzyme is largely responsible for the metabolism of JPH203.
Toyoshima teaches that the L-type amino acid transporter 1 (LAT1) forms a heterodimer with 4F2hc, a chaperon glycol protein, to induce system L-like amino acid transport activity in the plasma membrane. In a Na+-independent manner, LAT1 transports branched-chain (e.g., valine, isoleucine, and leucine) and aromatic (e.g., phenylalanine and tyrosine) amino acids into cells. LAT1 has low expression in adult humans but is located in a few normal tissues (brain, placenta, and testis). However, LAT1 has been shown to be highly expressed in many tumor cells such as non-small-cell lung cancer, thymic carcinoma, prostate cancer, oral squamous cell carcinoma, and gastric carcinoma. The fact that LAT1 expression level has been associated with cancer patient survival rates (e.g., astrocytoma, nonsmall-cell lung cancer, prostate cancer, and gastric carcinoma) demonstrates that LAT1 may be a good molecular target for both therapy and diagnosis (see Introduction).
Toyoshima specifically states that NAT2 is largely responsible for the metabolism of the LAT1 inhibitor JPH203:
“JPH203 also displays significant growth inhibition against HT-29 cells in vitro, and in vivo in nude mouse bearing HT-29 cells after intravenous administration of JPH203.15 JPH203 undergoes N acetylation to afford a metabolite 3-(4-((5-acetamide-2-phenylbenzo(d)oxazol-7-yl) methoxy)-3,5-dichlorophenyl)-2-aminopropanoic acid (NAc-JPH203),16 which also shows an inhibitory effect against LAT1. Two N-acetyl transferase (NAT) isoforms are known, NAT1 and NAT2, with NAT2 is the more predominate isoform in the liver.17”
Toyoshima, pg. 3229, col. 1 (emphasis added); and
“Because NAT2 Km—the major NAT isoform expressed in liver—was similar to OATP1B1, N-acetylation will likely be another cause for nonlinearity in JPH203 disposition at a therapeutic dose. However, because of extensive metabolism of JPH203 by NAT2, JPH203 intracellular concentration will be lower than blood unbound concentration and overall hepatic elimination will be uptake limited where the variation of metabolic clearance hardly influences overall clearance. Consequently, the impact of AT2 saturation on JPH203 systemic exposure will be less remarkable. More than 20 NAT2 haplotypes are reported.28 These haplotypes have been classified into three phenotypes: rapid, intermediate, and slow acetylators. Using isoniazid as a representative NAT2 substrate, rapid acetylators typically display 2.4–2.6 times larger total body clearance compared with slow acetylators.29,30.”
Toyoshima, pg. 3227, col. 1 (emphasis added).
Accordingly, one of ordinary skill in the art would expect that the treatment of cancer, such as the biliary tract cancer with JPH203 as done by Okano, would achieve a better outcome with slow NAT2 patients, than other subtypes, due to the role of NAT2 in JPH203 metabolism. Therefore, the invention of claim 21 was prima facie obvious at the time it was filed.
Claims 22 and 23 limit the specific type of cancer to selected from a Markush group of a number of cancer species, including biliary tract cancer; as mentioned in reference to Okano, he mentions BTC. Therefore, claim 22 and 23 are obvious for the same reasons as claim 21 above.
Claim 24 further limits claim 21 by requiring that the pharmaceutical composition
is administered as one cycle comprising a first period of a continuous administration and a
second period of drug withdrawal following the first period. As mentioned in reference to Okano, he mentions a first and second administration. Therefore, claim 24 is obvious for the same reasons as claim 21 above.
Claims 26-29 further limit the dosage range of up to 60 mg/m2 (as in claims 26 and 27) of the active compound JPH203, and up to 25mg/m2 (as in claim 28). Claim 29 requires that the dosing interval be “predetermined”; as mentioned in reference to Okano, he mentions dosages of 60 and 25 mg/m2. Therefore, claims 26-29 are obvious for the same reasons as claim 21 above.
Claim 31 further limits the patient to humans; Okano does a clinical study on humans, Therefore, claim 31 is obvious for the same reasons as claim 21 above.
Claims 25 and 30, further limit the method of the claims to the duration of the two dosage intervals, and the length of the dosage intervals. While Okano teaches multiple different dosage intervals, as well as different dosage ranges, he does not explicitly teach the claimed limitations of the “14 day total/5 day first/9 day second” limitation or the claim 30 concentration of the JPH203, one of ordinary skill in the art would have had a reasonable expectation of success in arriving at these parameters, as they are each result effective variables and only require routine optimization from starting points of both the experimental variables shown in Okano and Toyoshima. See also 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 claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.") Accordingly, the invention claims 25 and 30 were prima facie obvious at the time they were filed.
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.
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 rejection of claim 41under 35 U.S.C. 103 as being unpatentable over Okano et. al. First-in-human phase I study of JPH203, L-type amino acids transporter 1 inhibitor, in patients with advanced solid tumors, Journal of Clinical Oncology Volume 36, Number 15 suppl, Pandey, et.al., Slow Acetylator Genotype of N-Acetyl Transferase2 (NAT2) is Associated with Increased Susceptibility to Gallbladder Cancer, Cancer Biology & Therapy 6:1, 91-96, January 2007 and in further view of Toyoshima et al., Investigation of the Role of Transporters on the Hepatic Elimination of an LAT1 Selective Inhibitor JPH203, Journal of Pharmaceutical Sciences, 102(9), pp. 3228-3238 (2013) .
Claim 41 is a new claim that further limits claim 21 wherein the administration reduces the incidence of hepatic dysfunction in the subject having the non-rapid NAT2 gene compared to a subject having a Rapid NAT2 gene.
Claim 41 is obvious over of Okano, Pandey and Toshima:
Okano presented the results of a clinical study at a meeting and published abstract disclosing the treatment of biliary tract cancer (BTC) using the claimed compound, JPH203, in an effective amount/dosage (see Abstract). Okano shows the effect of JPH203 in treating BTC.
Although Okano teaches a clinical study of administering to humans having biliary tract cancer the claimed compound JPH203, he does not explicitly state the subtype of NAT2 gene in the patient, such as the subtype of the claimed patient being a non-rapid N-acetylation transfer enzyme (NAT2) gene, e.g., slow NAT2 (as reiterated in the rejection to claim 21 above).
Pandey teaches that gall bladder cancer, is a multifactorial condition that is the result of many variables including environmental factors including the NAT2 genotypes of which there are multiple polymorphs. He teaches that gall bladder cancer, of which BTC is classified as a general term, for the origin of the cancer arising from the biliary system including a network of organs (liver, gallbladder, pancreas) and ducts that produce, store, and transport bile. Specifically, that the non-rapid NAT2 gene has a higher risk that the rapid NAT2 gene for developing gallbladder cancer. For example,
“NAT2 enzyme exhibits diverse metabolic activity and is responsible for N‑acetylation of drugs and carcinogens bearing aromatic amines, and this ability is strongly dependent upon the relative tissue levels of NAT1, NAT2 and CYP1A2, as well as of other enzymes capable of detoxifying or activating this class of chemical agents. The presence of drug‑metabolizing
enzymes in biliary epithelium cells suggests heterogeneous ability to detoxicate reactive metabolites.15
“N‑acetyltransferase 2 (NAT2) is a polymorphic gene and representation of NAT2 variant alleles differ widely between populations of different ethnic or geographical locations18 with slow acetylators accounting for 10–30% and 40–70% of Oriental and Caucasian populations respectively.19,20 In our study, the frequency of slow acetylator was similar to oriental populations. In case control analysis in gallbladder cancer, we observed higher frequency of slow acetylators (47.6%) in patients as compared to controls (21.1%), with high risk which was statistically significant.”
Pandey, page 93, col 2 (emphasis added).
Toyoshima teaches that among the numerous NAT2 haplotypes, the rapid acetylators clear the JPH203 through the body, through the liver primarily, much more quickly than that of non-rapid NAT2 acetylators. The implication is that the subject with the rapid NAT2 gene is more likely to pass the compound JPH203 through the liver at a greater rate and potentially have an increased chance for hepatic dysfunction. For example,
More than 20 NAT2 haplotypes are reported.28 These haplotypes have been classified into three phenotypes: rapid, intermediate, and slow acetylators. Using isoniazid as a representative NAT2 substrate, rapid acetylators typically display 2.4–2.6 times larger total body clearance compared with slow acetylators.29,30.”
Toyoshima, pg. 3227, col. 1 (emphasis added).
Accordingly, one of ordinary skill in the art would have a reasonable expectation of success in the treatment of cancer, such as the biliary tract cancer with JPH203 as done by Okano and the condition the in the subject having the non-rapid NAT2 gene; a primary contributing factor to the development of gallbladder cancer compared to the rapid NAT2 gene as taught by Pandey, in concert with the teaching of Toyoshima that shows that rapid NAT2 haplotypes would more likely have hepatic dysfunction as a result of the 2.4-2.6% higher clearance through the liver as compared to non-rapid NAT2 haplotypes. Therefore, the invention of claim 41 was prima facie obvious at the time it was filed.
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 PAUL RANDALL GAUGER whose telephone number is (571)272-1325. The examiner can normally be reached M-F 7:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffery Lundgren can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629