DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-7, 11-19 and 39-45 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/JP2024/000901, filed on 01/16/2024.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/12/2024 and 08/29/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7, 11-19 and 39-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is drawn to a method of treating a disease condition that is one of the following:
an advanced biliary tract cancer that is refractory or intolerant of standard chemotherapy in a subject;
a curatively unresectable biliary tract cancer that has become refractory or intolerant to cancer chemotherapy and has worsened in a subject;
wherein the method comprises administering to the subject a medicament containing an effective amount of a LAT1 inhibitor.
Claim 1 is indefinite because a person of ordinary skill in the art would not be able to discern the scope of the patient population that has a curatively unresectable biliary tract cancer that has become refractory or intolerant to cancer chemotherapy and has worsened1 in a subject. The claim does not define what constitutes a “worsening” of the patient’s curatively unresectable biliary tract cancer that has become refractory or intolerant to cancer chemotherapy. Since the “worsening” is listed separately from the quality of becoming refractory or intolerant to cancer chemotherapy, it is assumed that the “worsening” must be a different aspect of the cancer. Possible aspects of a cancer that could become “worse” include symptoms and cancer stage, the latter of which might separately relate to tumor size, lymph node permeation, or extent of metastasis.
The instant Specification refers to biliary tract cancer that “has worsened” 5 times, on pages 1, 3, 5, 8 and 9, but does not define what it means for a biliary tract cancer to “worsen” in any of these instances. A search of the prior art does not reveal any teaching reference for a biliary tract cancer that has “worsened”. The prior art does not even reinforce the identification of symptoms or cancer stage to be the most significant metric of what makes biliary tract cancer less survivable, which could be a separate metric of what makes a cancer “worse”: Kang (Kang, et al.; Nature: Scientific Reports, v12, article 10206, pp1-10; 2022) teaches a retrospective epidemiological and clinical study on the comparison of tumor location, stage and treatment in patients suffering from biliary tract cancer, and concludes that biliary tract cancer location is more significant in determining survivability than any other factor, with intrahepatic biliary tract cancer being associated to the lowest survivability rate (10.8%), followed by extrahepatic biliary tract cancer (19.9%), and gall bladder cancer (28.5%) (Abstract, page 1). Thus, according to Kang, intrahepatic biliary tract cancer is “worse” than the others. Given the silence of the claim, the instant disclosure, and the field of art on what it means for a biliary tract cancer to “worsen” that is separate from becoming refractory or intolerant of cancer chemotherapy, claim 1 is indefinite because a person of ordinary skill in the art would not know the metes and bounds of the claim in regard to the claimed patient population.
Claims 2-7, 11-19 and 39-45 all depend from claim 1 directly or indirectly and none resolve the indefiniteness of claim 1 in regard to the patient population that has curatively unresectable biliary tract cancer that has become refractory or intolerant to cancer chemotherapy and has worsened in a subject.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are anticipated by Endou.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Endou (U.S. PG Pub 2020/0405695 A1).
Claim 1 is drawn to a method of treating a disease condition that is one of the following:
an advanced biliary tract cancer that is refractory or intolerant of standard chemotherapy in a subject;
a curatively unresectable biliary tract cancer that has become refractory or intolerant to cancer chemotherapy and has worsened in a subject;
wherein the method comprises administering to the subject a medicament containing an effective amount of a LAT1 inhibitor.
Endou discloses a method for treating cancer, comprising administering JPH2032 or a pharmacologically acceptable salt thereof to a patient in need thereof , wherein the cancer is bile duct cancer (a type of biliary tract cancer), colorectal cancer, esophageal cancer, breast cancer or pancreatic cancer (paragraph [0012]). Endou further discloses that the compound JPH203 is an inhibitor of L-type amino acid transporter 1 (LAT1) (paragraph [0002]) and that “a particularly high therapeutic effect can be expected on bile duct cancer” (paragraph [0046]). Endou also discloses an exemplary clinical trial, wherein cancer patients, having advanced stage cancer who have been confirmed to have solid cancer and who are refractory or intolerant to standard therapy, are administered JPH203 (paragraphs [0047]-[0053]), including patients who have bile duct cancer (paragraph [0059]).
Thus, claim 1 is anticipated by the disclosure of Endou.
Claim 2 further limits claim 1 to wherein the LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine, and is met by disclosure of Endou discussed above.
Thus, claim 2 is anticipated by the disclosure of Endou.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 11-12, 14-17, 19, 40-43 and 45 are unpatentable over Endou in view of Kaira.
Claims 1-6, 11-12, 14-17, 19, 40-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Endou (U.S. PG Pub 2020/0405695 A1) in view of Kaira (Kaira, et al.; BMC Cancer, v13, article 482, pp1-12; 2013).
The limitations of claims 1-2 and the disclosure of Endou are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 3 further limits claim 2, to wherein the cancer to be treated is selected from the group consisting of extrahepatic biliary tract cancer and gall bladder cancer.
While Endou does not specify whether the patients having bile duct cancer that were treated in the exemplary clinical trial had intrahepatic bile duct cancer3 or extrahepatic bile duct cancer4, and does not report any patients having gall bladder cancer as being included in the clinical trial; however, a person of ordinary skill in the art would have a reasonable expectation of success in using the method of Endou to treat a patient having advanced stage cancer wherein the cancer is extrahepatic biliary tract cancer or gall bladder cancer, because it was known in the art that each of these cancers is a form of biliary tract cancer, and that a high level of LAT1 expression in patients with biliary tract cancer is closely correlated with advanced stage cancer, and that high LAT1 expression shows up with similar frequency in all anatomic types of biliary cancer (extrahepatic, intrahepatic, and gall bladder) and that LAT1 inhibition suppresses the growth of biliary tract cancer, per the teaching of Kaira.
Kaira teaches a study in the expression of LAT1 and biological significance of LAT1 in biliary tract cancer patients (Abstract, page 1). A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line (Abstract, page 1). The study population consisted of patients with extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC) and gallbladder carcinoma (GB) (page 2). Kaira finds that LAT1 expression was correlated with pathological biomarkers such as cellular proliferation, cell cycle regulator (p53) and angiogenesis (page 2), and was significantly associated with lymphatic permeation, vascular invasion, lymph node metastasis, Ki-67 cellular proliferation marker, and more advanced disease staging (page 6, including Table 2), and that high LAT1 expression correlated with poor overall survival (OS) (pages 6/85, bridging paragraph, and Figure 2, page 8). Kaira further teaches that in biliary tract cancer, the ratio of high LAT1 expression yielded a similar tendency among all anatomic sites (EHCC, IHCC, and GB). Kaira further teaches that LAT1 inhibition with a known small molecule LAT1 inhibitor BCH6 suppressed the growth of xenograft biliary tract cancer tumors in mice (page 8 and Figure 4, page 10) and inhibited proliferation of biliary tract cancer cells in vitro, both alone and in combination with either gemcitabine or 5-fluorouracil (page 8 and Figure 3, page 9).
Applicant’s invention is unpatentable over the disclosure of Endou in view of the teaching of Kaira, because a person of ordinary skill in the art, at the effective time of invention, would have a reasonable expectation of success in using the method of Endou to treat a patient having advanced stage cancer wherein the cancer is extrahepatic biliary tract cancer or gall bladder cancer, because it was known in the art that each of these cancers is a form of biliary tract cancer, and that a high level of LAT1 expression in patients with biliary tract cancer is closely correlated with advanced stage cancer, and that high LAT1 expression shows up with similar frequency in all anatomic types of biliary cancer (extrahepatic, intrahepatic, and gall bladder) and that LAT1 inhibition suppresses the growth of biliary tract cancer, per the teaching of Kaira.
Thus, the invention was prima facie obvious at the time of filing.
Claim 4 further limits claim 3 to wherein the cancer to be treated is extrahepatic biliary tract cancer, and is met by the rejection above.
Claim 5 further limits claim 3 to wherein the cancer to be treated is gall bladder cancer and is met by the rejection above.
Claim 6 further limits claim 3 to wherein the subject is a patient with high LAT1 expression, and is met by the rejection above.
Claim 11 further limits claim 2 to wherein the cancer to be treated is intrahepatic biliary tract cancer, and is met by the rejection above.
Claim 12 further limits claim 11 to wherein the subject is a patient with high LAT1 expression, and is met by the rejection above.
Claim 14 further limits claim 3 to wherein 1-60 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 15 further limits claim 14 to wherein 12.5-60 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 16 further limits claim 15 to wherein 12.5-25 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 19 further limits claim 3 to wherein the subject is human.
Claim 40 further limits claim 11 to wherein 1-60 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 41 further limits claim 40 to wherein 12.5-60 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 42 further limits claim 41 to wherein 12.5-25 mg/m2 of LAT1 inhibitor is administered to the subject.
Claim 45 further limits claim 11 to wherein the subject is human.
As discussed above, Endou discloses a clinical trial involving human subjects wherein the LAT1 inhibitor JPH203 is administered to the patients. Endou discloses that JPH203 may be administered by injection, the injection being intravenous, subcutaneous, intramuscular, or intravenous infusion (paragraph [0044]), and that the dosage is preferably 1-60 mg/mm2, or more preferably 10-40 mg/m2 (paragraph [0045]). In the exemplary clinical trial disclosed by Endou, On Day 1 , a predetermined dosage was administered in a single dose . The dosage was 12 mg/m² (4 cases), 25 mg/m² (3 cases), 40 mg/m² (3 cases), 60 mg/m² (6 cases), or 85 mg/m² (1 case) (paragraph [0061]), thus, Endou discloses dosing in the claimed ranges. Additionally, Endou evaluated the safety (dose limiting toxicity: DLT) and efficacy of the doses administered, for example discontinuing one case of the 12 mg/mm2 dosage group after only a single dose due to disease progression, and monitoring all patients for DLT criteria of non-hematologic toxicity, hematotoxicity, and febrile neutropenia (paragraphs [0050] and [0064]) and evaluating efficacy in terms of size change (growth/reduction) of tumor(s) and metastatic lesion(s) (paragraph [0069]). Following the method of Endou, a person of ordinary skill in the art would have a reasonable expectation of success in determining a safe and efficacious dosage of JPH203 for the treatment of patients having any of the anatomic types of biliary tract cancers indicated by Kaira as amenable to treatment with a LAT1 inhibitor in patients having high expression of LAT1: intrahepatic, extrahepatic, and gall bladder.
Applicant’s invention is unpatentable over the disclosure of Endou in view of the teaching of Kaira, because a person of ordinary skill in the art, at the effective time of invention, would have a reasonable expectation of success in using the method of Endou to treat a human patient having advanced stage cancer wherein the cancer is extrahepatic biliary tract cancer, intrahepatic biliary tract cancer, or gall bladder cancer, and determining a safe and efficacious dosage within the claimed ranges, because it was known in the art that each of these cancers is a form of biliary tract cancer, and that a high level of LAT1 expression in patients with biliary tract cancer is closely correlated with advanced stage cancer, and that high LAT1 expression shows up with similar frequency in all anatomic types of biliary cancer (extrahepatic, intrahepatic, and gall bladder) and that LAT1 inhibition suppresses the growth of biliary tract cancer, per the teaching of Kaira, and because Endou discloses administration in the claimed ranges and discloses how to determine safe and efficacious dosage by monitoring of patients for safety and efficacy criteria.
Thus, the invention was prima facie obvious at the time of filing.
Claims 1-7, 11-16, 19, 39-42 and 45 are unpatentable over Endou in view of Kaira and further in view of Wempe and Toyoshima.
Claims 1-7, 11-16, 19, 39-42 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Endou in view of Kaira, and further in view of Wempe (Wempe, et al.; Drug Metabolism and Pharmacokinetics, v27, pp155-161; 2012) and Toyoshima (Toyoshima, et al.; Journal of Pharmaceutical Sciences, v102, pp3228-3238; 2013).
The limitations of claims 1-6, 11-12, 14-16, 19, 40-42 and 45 and the disclosure of Endou and the teachings of Kaira and Wempe are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 7 further limits claim 3 to wherein the patient has a Non-Rapid (Slow and/or Intermediate) type NAT2 (N-Acetyl Transferase enzyme 2) gene.
Claim 13 further limits claim 11 to wherein the patient has a Non-Rapid (Slow and/or Intermediate) type NAT2 (N-Acetyl Transferase enzyme 2) gene.
Claim 39 further limits claim 6 to wherein the patient has a Non-Rapid (Slow and/or Intermediate) type NAT2 (N-Acetyl Transferase enzyme 2) gene.
While neither Endou nor Kaira discusses the merit of selecting a patient population wherein the patient(s) have only slow and/or intermediate type NAT2 gene, a person of ordinary skill in the art would have a reasonable expectation of success in using the method of Endou to treat a patient having a high level of LAT1 expression and advanced stage cancer wherein the cancer is any of the three anatomic types of biliary tract cancer, and further selecting the patient population having a non-rapid type NAT2 gene (i.e., slow and/or intermediate), for the following reasons:
because it was known in the art that the major metabolite of JPH203 is its N-acetyl derivative, N-acetyl-JPH2037, which is four-fold less potent than JPH203 as an LAT1 inhibitor and is formed by an N-acetyltransferase (NAT) enzyme, per the teaching of Wempe;
because it was known in the art that N-acetyl-JPH203 is found in the highest concentrations in the liver and kidney, in much higher concentrations than JPH203, and that the N-acetyl-JPH203 is much more rapidly cleared from the kidney than JPH203; per the teaching of Toyoshima;
because it was known in the art that formation of N-acetyl-JPH203 is primarily driven by NAT2, that NAT2 occurs in various haplotypes classified into rapid, intermediate and slow acetylators, and that rapid acetylators are more than twice as fast as slow acetylators, per the teaching of Toyoshima.
Wempe teaches a study in the development of an analytical method (LC/MS-MS) to monitor JPH203 and its major metabolite N-acetyl-JPH203 in biological samples (Abstract, page 155). Wempe teaches that JPH203 showed metabolic stability in liver microsomes but showed N-acetyltransferase metabolism upon exposure to S9 subcellular fractions (approximating cellular cytosolic enzyme exposure) (page 158). Wempe tracks the blood concentrations of JPH203 and its metabolite N-acetyl-JPH203 after administration of JPH203 to Sprague-Dawley rats and shows the profile in Wempe’s Figure 3, shown below (page 159):
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A person of ordinary skill in the art, studying Wempe’s Figure 3, would at once recognize that the conversion of JPH203 to its metabolite is the main pathway by which JPH203 concentration is reduced in the body, and therefore any means to select against this metabolic pathway would improve the pharmacokinetic profile of the drug. Wempe further teaches that N-Acetyl-JPH203 is a selective LAT1 inhibitor, but at fourfold lower potency than JPH203 (page 160).
Toyoshima teaches a study in the pharmacokinetics of JPH203 with focus on the hepatic elimination of the drug (Abstract, page 3228). Toyoshima teaches that two N-acetyl transferase (NAT) isoforms are known, NAT1 and NAT2, with NAT2 is the more predominant form in the liver (page 3229). Toyoshima shows, in Figure 1, shown below, (page 3232) that the plasma concentration of JPH203 is significantly elevated in Eisai hyperbulinemic rats (EHBR), that have reduced uptake of JPH203 compared to Sprague-Dawley (SD) rats, thus showing that metabolism in the liver is a significant degradation pathway for JPH203:
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Figure 1 also shows that renal clearance of NAc-JPH203 is orders of magnitude faster than for JPH203 (at right). Toyoshima further teaches that the concentration of NAc-JPH203 in liver and kidneys is orders of magnitude higher than JPH203 in both EHBR and SD rats, and that both bile clearance and renal clearance rates are orders of magnitude higher for NAc-JPH203 than for JPH203 (Table 1, page 3233). Toyoshima notes that because of extensive metabolism of JPH203 by NAT2, JPH203 intracellular concentration will be lower than blood unbound concentration (page 3237). Finally, Toyoshima observes that more than 20 NAT2 haplotypes are known, and 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. Thus, a person of ordinary skill in the art would at once recognize that patients with slow or intermediate acetylators will have reduced metabolism of JPH203, thereby improving its pharmacokinetic profile in these patients relative to other patients who have fast NAT2 type gene.
Applicant’s invention is unpatentable over the disclosure of Endou in view of the teachings of Wempe and Toyoshima, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success applying the method of Endou of treating bile duct cancer comprising the administration of JPH203, wherein the method is modified according to the teaching of Kaira to the treatment of any of the anatomic types of biliary tract cancer in a human subject having high expression of LAT1, and further selecting for a patient population that does not have a rapid NAT2 gene, because it was known in the art that NAT2 is a primary metabolic driver of the conversion of JPH203 to its metabolite NAc-JPH203, per the teaching of Toyoshima, and it was known in the art that NAc-JPH203 is the primary metabolite of JPH203 and main route for the reduction of JPH203 concentration in vivo, and is fourfold less potent than JPH203 as a LAT1 inhibitor, per the teaching of Wempe, and it was known in the art that NAT2 is found in various haplotypes, classified as either slow, intermediate or fast (rapid) acetylators, with a more than twofold difference in metabolic acetylation rate between fast and slow acetylators, per the teaching of Toyoshima. A person of ordinary skill in the art would recognize that the difference in acetylation rate, achieved by selecting the population of patient(s) that do not have the rapid NAT2 gene, would significantly impact the pharmacokinetic profile of JPH203.
Thus, the invention was prima facie obvious at the time of filing.
Claims 1-6, 11-12, 14-19 and 40-45 are unpatentable over Endou in view of Kaira and further in view of Okano, Alomi, Medscape and Wempe.
Claims 1-6, 11-12, 14-19 and 40-45 are rejected under 35 U.S.C. 103 as being unpatentable over Endou in view of Kaira, and further in view of Okano (Okano, et al.; Investigational New Drugs, v38, pp1495-1506; 2020), Alomi (Alomi, et al.; International Journal of Pharmacology and Clinical Sciences; v9, pp35-44; 2020), Medscape (Medscape Body Surface Area Dosing Calculator: https://reference.medscape.com/calculator/692/body-surface-area-based-dosing, accessed by the Examiner from the Wayback Machine Internet Archive on 25Jun2026, originally archived on 01Dec2022) and Wempe.
The limitations of claims 1-6, 11-12, 14-16, 19, 40-42 and 45 and the disclosure of Endou and the teachings of Kaira and Wempe are discussed in the rejection above and hereby incorporated into the instant rejection.
Claims 17 and 43 further limit claims 3 and 11, respectively, to wherein a fixed amount of the LAT1 inhibitor is administered intravenously continuously over a fixed time period.
Claims 18 and 44 further limit claims 17 and 43, respectively, to wherein 100 mL of the LAT1 inhibitor is administered intravenously over 90 minutes.
As discussed above, Endou discloses that JPH203 may be administered by intravenous infusion. Endou additionally discloses that an injectable formulation of JPH203 preferably comprises a pH adjusting agent and cyclodextrin as pharmaceutical excipients (paragraph [0026]) and that the formulation of JPH203 used in the exemplary clinical trial was a lyophilized formulation containing 50 mg JPH203 and 1200 mg of sulfobutyl ether-b-cyclodextrian in one vial (paragraph [0048]).
While Endou does not disclose the specific parameters of intravenous administration in regards to being continuous over a fixed period of time, a person of ordinary skill in the art would have a reasonable expectation of success at arriving at the claimed parameters of administration, for the following reasons:
because it was known in the art that 90 minutes of intravenous infusion is a suitable infusion time for treatment with JPH203, per the teaching of Okano;
because 100 mL is a known standard IV administration volume for chemotherapeutic infusion, per the teaching of Alomi;
because the required dose of JPH203 in milligrams (mg) for an average human at the claimed dosage in mg/m2 is readily soluble in 100 mL of aqueous solution, per the teachings of Medscape and Wempe.
Okano teaches the implementation and results of a first in-human phase I study of JPH203 (Abstract, page 1495), and a person of ordinary skill in the art would at once recognize that this is the same study as disclosed by Endou, when comparing the information on the background/characteristics of the patients (number, gender, age, types of cancer) provided by Endou as Table 1 (paragraph [0059]) and Okano (Table 1, page 1498). Okano teaches that patients received the dose of JPH203 via daily 90 minute intravenous infusion (page 1496).
Alomi provides a report on standardized concentration and volume for various known chemotherapeutic drugs based, showing standard volumes of infusion, including many instances of 100 mL infusion volume (pages 37-42).
Medscape provides a body surface area calculator that shows that an average human, for example, a man of 5 feet and 9 inches height and 170 pounds weight, would require less than 50 mg of JPH203 to achieve a 25 mg/m2 dose, as shown below:
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Wempe teaches a study on the pharmacokinetics of JPH203, and shows that JPH203 is readily soluble to at least 2 mM aqueous solution (pages 2-3, bridging paragraph). A person of ordinary skill in the art would readily recognize that a 2 mM solution of JPH203 in 100 mL of solution, at a molecular mass of 472.3 grams/mole, would contain 94 mg (0.2 mmol) of JPH203, showing that the solubility of JPH203 is more than sufficient to provide a dose in the claimed range(s) for an average human in a 100 mL intravenous infusion solution.
Applicant’s invention is unpatentable over the disclosure of Endou, in view of the teaching of Kaira, and further in view of the teachings of Okano, Medscape and Wempe, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success applying the method of Endou of treating bile duct cancer comprising the administration of JPH203, wherein the method is modified according to the teaching of Kaira to the treatment of any of the anatomic types of biliary tract cancer in a human subject having high expression of LAT1, and arriving at the dosing parameters of the instant claims of providing the dose by intravenous infusion in 100 mL of infusion solution over a 90 minute period, because Okano teaches the administration of the dose by intravenous infusion over 90 minutes, and Alomi shows that 100 mL is a standard infusion volume in chemotherapeutic administration, and Medscape shows how a dose within the claimed ranges (e.g., 25 mg/m2) requires less than 50 mg of JPH203, and Wempe shows that JPH203 is more than soluble enough to accommodate 50 mg of JPH203 in 100 mL of aqueous solution.
Thus, the invention was prima facie obvious at the time of filing.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 11-12, 14-19 and 40-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 7-11 of U.S. Patent No. 12,458,628 B2 (hereafter referred to as “J-Pharma”) in view of (Kaira, et al.; BMC Cancer, v13, article 482, pp1-12; 2013).
The limitations of claims 1-6, 11-12, 14-19 and 40-45 and the teaching of Kaira are discussed in the rejections above and hereby incorporated into the instant rejection.
J-Pharma’s claim 1 is drawn to a method for treating solid cancer, comprising administering JPH203 at 1-40 mg/m2 once daily by intravenous injection to a human patient in need thereof, wherein the cancer is selected from a Markush group of cancers that includes bile duct cancer (i.e., biliary tract cancer).
J-Pharma’s claim 2 further limits claim 1 to wherein the solid cancer is bile duct cancer and JPH203 is administered at 25-40 mg/m2.
J-Pharma’s claim 7 further limits claim 1 to wherein the patient is refractory or intolerant to standard therapy.
J-Pharma’s claim 8 is drawn to a method for treating cancer, comprising administering JPH203 to a patient in need thereof, wherein the cancer is selected from a Markush group that includes bile duct cancer and the patient is refractory or intolerant to standard therapy.
J-Pharma’s claim 9 further limits claim 8 to wherein the JPH203 is administered at a dosage of 1-60 mg/m2 at a time.
J-Pharma’s claim 10 further limits claim 8 to wherein the cancer is bile duct cancer.
J-Pharma’s claim 11 further limits claim 10 to wherein JPH203 is administered at 12-25 mg/m2 at a time.
While the instant claims do not specify that the patient should have advanced cancer, or that the bile duct cancer is specifically extrahepatic biliary tract cancer, intrahepatic biliary cancer, or gall bladder cancer, a person of ordinary skill in the art would have a reasonable expectation of success in applying the claimed method(s) of J-Pharma to the treatment of patients who have advanced cancer that is specifically extrahepatic biliary tract cancer, intrahepatic biliary cancer, or gall bladder cancer, for the following reasons:
because it was known in the art that JPH203 is an inhibitor of LAT1, per the teaching of Kaira, per the teaching of Kaira;
because it was known in the art that a high level of LAT1 expression in patients with biliary tract cancer is closely correlated with advanced stage cancer, per the teaching of Kaira;
because it was known in the art that high LAT1 expression shows up with similar frequency in all anatomic types of biliary cancer (extrahepatic, intrahepatic, and gall bladder) and that LAT1 inhibition suppresses the growth of biliary tract cancer, per the teaching of Kaira.
Kaira teaches a study in the expression of LAT1 and biological significance of LAT1 in biliary tract cancer patients (Abstract, page 1). A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line (Abstract, page 1). The study population consisted of patients with extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC) and gallbladder carcinoma (GB) (page 2). Kaira finds that LAT1 expression was correlated with pathological biomarkers such as cellular proliferation, cell cycle regulator (p53) and angiogenesis (page 2), and was significantly associated with lymphatic permeation, vascular invasion, lymph node metastasis, Ki-67 cellular proliferation marker, and more advanced disease staging (page 6, including Table 2), and that high LAT1 expression correlated with poor overall survival (OS) (pages 6/88, bridging paragraph, and Figure 2, page 8). Kaira further teaches that in biliary tract cancer, the ratio of high LAT1 expression yielded a similar tendency among all anatomic sites (EHCC, IHCC, and GB). Kaira further teaches that LAT1 inhibition with a known small molecule LAT1 inhibitor BCH9 suppressed the growth of xenograft biliary tract cancer tumors in mice (page 8 and Figure 4, page 10) and inhibited proliferation of biliary tract cancer cells in vitro, both alone and in combination with either gemcitabine or 5-fluorouracil (page 8 and Figure 3, page 9).
Conclusion
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Emphasis added by Examiner.
2 O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine
3 Intrahepatic bile duct cancer is synonymous with intrahepatic biliary tract cancer.
4 Extrahepatic bile duct cancer is synonymous with extrahepatic biliary tract cancer.
5 Page 7 is occupied entirely by Table 3, thus the paragraph spans across pages 6 and 8.
6 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid
7 O-[[5-(Acetylamino)-2-phenyl-7-benzoxazolyl]methyl]-3,5-dichloro-L-tyrosine
8 Page 7 is occupied entirely by Table 3, thus the paragraph spans across pages 6 and 8.
9 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid
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