NON-FINAL REJECTION
This application is a 35 U.S.C. 371 (national stage) application of PCT/EP2022/063653, filed May 19, 2022, which claims benefit of foreign priority to EP application 21382455.0, filed May 19, 2021.
Claims 52-70, as amended, are pending.
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
Acknowledgment is made of applicant's claim to foreign priority under 35 U.S.C. 119(a)-(d).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Apr. 12, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 52-54, 60, and 62 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Marchante et al. (WO 2018/197663) and Saadh et al. (Sys. Rev. Pharm. 11(8):98-101 (2020)) (both cited on the IDS dated 4/12/2024).
Marchante et al. exemplify the compound of formula (I) as compound 4-S (Example 1, p. 82; a.k.a. ecubectedin or PM14), having the structural formula,
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.
Marchante et al. further exemplify the administration of compound 4-S in the treatment of three xenograft mouse models of human prostate cancer, corresponding to cell lines PC-3, DU-145, and 22Rv1 (Example 39, p. 195).
In Example 39, compound 4-S was intravenously administered once per week for 3 consecutive weeks, on Days 0, 7, and 14 (p. 196, lines 6-7), at the following dosages:
Mouse Xenograft Cell line
4-S Dosage in mg/kg
4-S Dosage in mg/m2
PC-3
1.25
3.75
DU-145
1.00
3.00
22Rv1
0.75
2.25
As evidenced by, e.g., Saadh et al. (Table 1), a multiplier of 3 is used to convert a mouse dosage in mg/kg to dosage in mg/m2, as shown in the table above. At all dosages, compound 4-S is demonstrated to achieve significant reductions in mean tumor volume compared to placebo (Tables 73, 74, and 75, pp. 196-198).
Marchante et al. further disclose that the preferred route of administration is intravenous, most preferably with an infusion time of 1 to 6 hours. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks (p. 73, line 24 to p. 74, line 2).
Marchante et al. differs from the claims in that the administration of compound 4-S at a dose of 4.5 mg/m2, with an infusion time of 3 hours, as recited by claim 52, is not exemplified.
However, Marchante et al. disclose that, for intravenous administration, suitable doses are from about 0.1 mg/kg to about 250 mg/kg of the animal's body weight, preferably from about 0.1 mg/kg and about 20 mg/kg of the animal's body weight, and more preferably from about 1 mg/kg to about 10 mg/kg of the animal's body weight (p. 75, lines 3-6).
Marchante et al. teach that an effective amount of the compound will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances; for example, the type of tumor, age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities, and severity of the disease should be taken into account (p. 74, lines 11-25).
Thus, Marchante et al. disclose, teach, and suggest methods of treating cancer comprising administering the compound of formula (I), wherein the compound is administered intravenously on day 1 once every three weeks – i.e., on Days 0, 7, and 14 – at a dose of 4.5 mg/m2, with an infusion time of three hours, as recited by claim 52.
The methods of Marchante et al. are disclosed in the treatment of various cancers, e.g., in a human, by administering a therapeutically effective amount of compound 4-S, preferably lung cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer (p. 76, line 15 to p. 77, line 4; claims 118-119), as recited by claims 53 and 54.
Marchante et al. exemplify the administration of compound 4-S to mice with human fibrosarcoma xenografts (Example 29a), as recited by claim 60.
The compounds of Marchante et al. are also disclosed in the form of pharmaceutically acceptable salts, including hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic amino acids (p. 16, line 21 to p. 17, line 6), as recited by claim 62.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the methods of treating cancer disclosed by Marchante et al. by optimizing the infusion time and dosage of compound 4-S with a reasonable expectation of success, because the reference itself teaches that adjusting drug administration, schedules, and dosages based on patient-specific variables are within the judgment of a skilled clinician.
As recognized by MPEP § 2144.05,
Generally, differences in concentration or tempera-ture will not support the patentability of subject mat-ter 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 dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
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 52-54 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46 and 47 of U.S. Patent No. US 10,538,535 in view of Marchante et al. (WO 2018/197663) and Saadh et al. (Sys. Rev. Pharm. 11(8):98-101 (2020) (both cited on the IDS dated 4/12/2024).
Reference claims 46-47 are drawn to methods of treating cancer in a patient in need thereof, including lung cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, colorectal cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer, comprising administering to said patient a therapeutically effective amount of the compound according to claim 18, having the structural formula,
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or a pharmaceutically acceptable salt thereof, e.g., hydrochloride, which is identical to the compound of formula (I) as recited by the examined claims (a.k.a. ecubectedin or PM14).
The reference claims differ from the examined claims in that the reference claims do not recite administering the compound intravenously on Day 1 once every three weeks at a dose of 4.5 mg/m2, with an infusion time of three hours, as recited by examined claim 52.
However, Marchante et al. exemplify the administration of compound 4-S (identical to the compound of reference claim 18, and to formula (I) of examined claim 52) in the treatment of three xenograft mouse models of human prostate cancer, corresponding to cell lines PC-3, DU-145, and 22Rv1 (Example 39, p. 195).
In Example 39, compound 4-S was intravenously administered once per week for 3 consecutive weeks, on Days 0, 7, and 14 (p. 196, lines 6-7), at the following dosages:
Mouse Xenograft Cell line
4-S Dosage in mg/kg
4-S Dosage in mg/m2
PC-3
1.25
3.75
DU-145
1.00
3.00
22Rv1
0.75
2.25
As evidenced by, e.g., Saadh et al. (Table 1), a multiplier of 3 is used to convert a mouse dosage in mg/kg to dosage in mg/m2, as shown in the table above. At all dosages, compound 4-S is demonstrated to achieve significant reductions in mean tumor volume compared to placebo (Tables 73, 74, and 75, pp. 196-198).
Marchante et al. further disclose that the preferred route of administration is intravenous, most preferably with an infusion time of 1 to 6 hours. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks (p. 73, line 24 to p. 74, line 2).
Marchante et al. disclose that, for intravenous administration, suitable doses are from about 0.1 mg/kg to about 250 mg/kg of the animal's body weight, preferably from about 0.1 mg/kg and about 20 mg/kg of the animal's body weight, and more preferably from about 1 mg/kg to about 10 mg/kg of the animal's body weight (p. 75, lines 3-6).
Marchante et al. teach that an effective amount of the compound will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances; for example, the type of tumor, age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities, and severity of the disease should be taken into account (p. 74, lines 11-25).
Thus, Marchante et al. disclose, teach, and suggest methods of treating cancer comprising administering the compound of formula (I), wherein the compound is administered intravenously on day 1 once every three weeks – i.e., on Days 0, 7, and 14 – at a dose of 4.5 mg/m2, with an infusion time of three hours, as recited by examined claim 52.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the methods of treating cancer recited by the reference claims by optimizing the infusion time and dosage of the claimed compound with a reasonable expectation of success, because Marchante et al. teach that adjusting drug administration, schedules, and dosages based on patient-specific variables are within the judgment of a skilled clinician.
As recognized by MPEP § 2144.05,
Generally, differences in concentration or tempera-ture will not support the patentability of subject mat-ter 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 dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claims 52-54 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-9 of U.S. Patent No. US 11,339,180 in view of Marchante et al. (WO 2018/197663) and Saadh et al. (Sys. Rev. Pharm. 11(8):98-101 (2020) (both cited on the IDS dated 4/12/2024).
Reference claims 6-9 are drawn to methods of treating cancer in a patient in need thereof, including lung cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, colorectal cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer, comprising administering to said patient a therapeutically effective amount of the compound according to claim 6, having the structural formula,
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316
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or a pharmaceutically acceptable salt thereof, e.g., hydrochloride, which is identical to the compound of formula (I) as recited by the examined claims (a.k.a. ecubectedin or PM14).
The reference claims differ from the examined claims in that the reference claims do not recite administering the compound intravenously on Day 1 once every three weeks at a dose of 4.5 mg/m2, with an infusion time of three hours, as recited by examined claim 52.
However, Marchante et al. exemplify the administration of compound 4-S (identical to the compound of reference claim 6, and to formula (I) of examined claim 52) in the treatment of three xenograft mouse models of human prostate cancer, corresponding to cell lines PC-3, DU-145, and 22Rv1 (Example 39, p. 195).
In Example 39, compound 4-S was intravenously administered once per week for 3 consecutive weeks, on Days 0, 7, and 14 (p. 196, lines 6-7), at the following dosages:
Mouse Xenograft Cell line
4-S Dosage in mg/kg
4-S Dosage in mg/m2
PC-3
1.25
3.75
DU-145
1.00
3.00
22Rv1
0.75
2.25
As evidenced by, e.g., Saadh et al. (Table 1), a multiplier of 3 is used to convert a mouse dosage in mg/kg to dosage in mg/m2, as shown in the table above. At all dosages, compound 4-S is demonstrated to achieve significant reductions in mean tumor volume compared to placebo (Tables 73, 74, and 75, pp. 196-198).
Marchante et al. further disclose that the preferred route of administration is intravenous, most preferably with an infusion time of 1 to 6 hours. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks (p. 73, line 24 to p. 74, line 2).
Marchante et al. disclose that, for intravenous administration, suitable doses are from about 0.1 mg/kg to about 250 mg/kg of the animal's body weight, preferably from about 0.1 mg/kg and about 20 mg/kg of the animal's body weight, and more preferably from about 1 mg/kg to about 10 mg/kg of the animal's body weight (p. 75, lines 3-6).
Marchante et al. teach that an effective amount of the compound will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances; for example, the type of tumor, age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities, and severity of the disease should be taken into account (p. 74, lines 11-25).
Thus, Marchante et al. disclose, teach, and suggest methods of treating cancer comprising administering the compound of formula (I), wherein the compound is administered intravenously on day 1 once every three weeks – i.e., on Days 0, 7, and 14 – at a dose of 4.5 mg/m2, with an infusion time of three hours, as recited by examined claim 52.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the methods of treating cancer recited by the reference claims by optimizing the infusion time and dosage of the claimed compound with a reasonable expectation of success, because Marchante et al. teach that adjusting drug administration, schedules, and dosages based on patient-specific variables are within the judgment of a skilled clinician.
As recognized by MPEP § 2144.05,
Generally, differences in concentration or tempera-ture will not support the patentability of subject mat-ter 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 dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Allowable Subject Matter
Claims 55-59 and 61 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 63-70 are allowed.
Citation of Additional Prior Art
Additional references made of record are considered pertinent to applicant's disclosure:
USPN 8,895,557 (cited on PTO-892).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. 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.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629