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 Claims
Claims 1-9, 11, 13, 15, and 17-29 are pending. Claims 22-25 are withdrawn.
Priority
Instant application 17/775,800, filed 05/10/2022 claims priority as follows:
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Response to Amendment
The amendment filed 08/19/2025 has been entered. Applicant has amended claims 1, 5, 9, 11, 13, and 15. Claims 10, 12, 14, and 16 have been cancelled. Claims 26-29 are new.
Claims 1-16 were previously rejected under 35 U.S.C. 112(b). In response, applicant’s amendments to the claims are sufficient to overcome the rejections. Therefore, the previous rejection of claims 1-16 under section 112(b) is withdrawn.
Claims 9, 11, 13, and 15 were previously rejected under 35 U.S.C. 103. Upon further consideration, the rejection under section 103 has been modified to include claims X, Y, and Z. See the rejection and rationale set forth further below.
Claims 9, 11, 13, and 15 were previously rejected on the ground of nonstatutory double patenting. Upon further consideration, the nonstatutory double patenting rejections has been modified to include claims X, Y, and Z. See the rejection and rationale set forth further below.
Claim Interpretation
Independent claims 1, 5, 9, 11, 13, 15, and 17-20 recite administering a compound to a patient on an administration schedule comprising daily dosing for one week, followed by a resting period of one week; or comprising daily dosing for two weeks followed by a resting period of one week. The claims are therefore being interpreted to include administering the compound to a patient for one week or two weeks, and then stopping administration.
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.
Claims 1-9, 11, 13, 15, 17-21, and 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Osada (WO 2018216795 A1; published 29 November 2018) in view of Watts et al. (Blood, vol. 132, Nov. 2018, p. 2721). Citations refer to the US pre-grant publication US 20210177826 A1, which is relied upon as an English translation of Osada.
Osada discloses compound A (as compound 37) or a salt thereof for use in a method for treating an LSD1-related disease, especially acute myelogenous leukemia (AML) and lung cancers (see, e.g., “method for potentiating an antitumor effect using a compound or a salt thereof that potently inhibits LSD1”, paragraphs [0016], [0745], [0748], [0752], and page 89, no. 37). Osada additionally discloses administering compound A on specific days during a 28-day cycle in a mouse model of small-cell lung cancer; particularly the reference discloses administering “once a day for 28 consecutive days”, wherein the specific days are each day of the 28-day cycle (para. [0749]). Osada therefore teaches daily dosing for 28 consecutive days and also teaches that the daily dose can be administered in one dose, or in two to three divided doses per day (see [0237]). Osada also teaches that administering a similar compound (Example compound 41) for 21 consecutive days was effective (Table 45, [0751]).
The difference between the instant claims and the method disclosed in Osada, is that Osada teaches daily dosing for 28 or 21 days, whereas the instant claims requiring administering compound A for one week or two weeks, and then administration is stopped. The instant claims do not necessarily require that a pattern of “one week on, one week off” or “two weeks on, one week off” is performed multiple times.
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G), it would have been prima facie obvious to modify the method of Osada to treat patients having AML by administering compound A daily for one week or two weeks, and then stopping administration. It is routine in the pharmaceutical arts for the person having ordinary skill to cease administration of a drug to a patient if the patient is not responding or if the patient experiences adverse side effects. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the number of days of before stopping administration is considered a result-effective variable that impacts, for example, the occurrence of adverse effects in a patient. Watts is relied upon as teaching that LSD1 inhibitors were known in the art to induce adverse effects in some patients including neutropenia and thrombocytopenia (page 2, “Results”). Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
Therefore, it would have been obvious to administer compound A daily for one week or two weeks, and then stop administration. Accordingly, claims 1-3, 5-7, 9, 11, 17-18, 21, and 26-29 are obvious over Osada in view of Watts.
With respect to claims 4 and 8, Osada teaches oral administration of compound A (e.g., para. [0749]). Accordingly, claims 4 and 8 are obvious over Osada.
With respect to claims 13, 15, 19, and 20, Osada teaches that compound A is also effective when administered in combination with ATRA (see Test Example 4, e.g. page 157, Table 77 and para. [0761]). It would have therefore been prima facie obvious to modify Osada’s method to administer compound A and ATRA for 21 or 28 consecutive days in view of Osada’s teachings. A skilled artisan would have been motivated to co-administer compound A and ATRA because, as taught by Osada, “the antitumor effects of the biphenyl compounds were synergistically potentiated when used in combination with…an all-trans retinoic acid”). Accordingly, claims 13, 15, 19, and 20 are obvious over Osada.
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.
US 10,723,742
Claims 1-9, 11, 13, 15, 17-21, and 26-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,723,742 (“the ‘742 patent”) in view of Osada (WO 2018216795 A1; published 29 November 2018; cited in IDS) and further in view of Watts et al. (Blood, vol. 132, Nov. 2018, p. 2721). Citations refer to the US pre-grant publication US 20210177826 A1, which is relied upon as an English translation of Osada.
The ‘742 patent recites “A method for treating a cancer patient, the method comprising administering an effective amount of the compound or a salt thereof according to claim 1 to the patient.” (claim 10). The ‘742 patent also recites the compound 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (compound A).
The ’742 patent fails to recite the patient population having acute myeloid leukemia, the dosing regimen of dosing for 21- or 28-days, or the administration of compound A in combination of ATRA required by the instant claims; and fails to recite administering compound A for one week or two weeks, and then administration is stopped.
However, these teachings are found in Osada in view of Watts as disclosed above. The teachings of Osada and Watts are incorporated herein by reference.
Applying KSR example rationales (G), it would have been prima facie obvious to modify the method of ‘742 patent to treat patients having AML by administering compound A daily for one week or two weeks, alone or in combination with ATRA, and then stopping administration. It is routine in the pharmaceutical arts for the person having ordinary skill to cease administration of a drug to a patient if the patient is not responding or if the patient experiences adverse side effects. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the number of days of before stopping administration is considered a result-effective variable that impacts, for example, the occurrence of adverse effects in a patient, such as those taught by Watts. Watts teaches that LSD1 inhibitors were known in the art to induce adverse effects in some patients including neutropenia and thrombocytopenia (page 2, “Results”). Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
US 11,510,915
Claims 1-9, 11, 13, 15, 17-21, and 26-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,510,915 (“the ‘915 patent”) in view of Yamashita (WO 2017090756 A1; published 01 June 2017) and further in view of Watts et al. (Blood, vol. 132, Nov. 2018, p. 2721). Citations refer to the US pre-grant publication US 20180354960 A1, which is relied upon as an English translation of Yamashita.
The ‘915 patent recites in claim 2 “A method for inhibiting LSD1 activity in a patient with a tumor, comprising administering a biphenyl compound or a salt thereof in an amount effective for inhibiting LSD1 activity, to a cancer patient, wherein said biphenyl compound is administered in combination with one or more antitumor agents, and wherein said biphenyl compound is selected from the group consisting of: (1) 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile” (compound A). ‘915 claim 5 recites ATRA in particular as an “antitumor agent”.
The ‘915 patent fails to recite the patient population having acute myeloid leukemia or the dosing regimen of dosing for 21- or 28-days required by the instant claims; and fails to recite administering compound A for one week or two weeks, and then administration is stopped.
However, these teachings are found in Yamashita (e.g. abstract, para. [0909], [0915]).
Applying KSR example rationale (G), it would have been prima facie obvious to modify the method of ‘915 patent to treat patients having AML by administering compound A daily for one week or two weeks, alone or in combination with ATRA, and then stopping administration. It is routine in the pharmaceutical arts for the person having ordinary skill to cease administration of a drug to a patient if the patient is not responding or if the patient experiences adverse side effects. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the number of days of before stopping administration is considered a result-effective variable that impacts, for example, the occurrence of adverse effects in a patient, such as those taught by Watts. Watts teaches that LSD1 inhibitors were known in the art to induce adverse effects in some patients including neutropenia and thrombocytopenia (page 2, “Results”). Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
US 12,419,858
Claims 1-9, 11, 13, 15, 17-21, and 26-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,419,858 (“the ‘858 patent”) in view of Osada (WO 2018216795 A1; published 29 November 2018) and further in view of Watts et al. (Blood, vol. 132, Nov. 2018, p. 2721). Citations refer to the US pre-grant publication US 20210177826 A1, which is relied upon as an English translation of Osada.
The ‘858 patent is drawn to particular crystal forms of compound A and recites “A method of treating a malignant tumor in a patient in need thereof, the method comprising administering an effective amount of the crystalline form according to claim 1 to the patient” in claim 9 and “A method of treating a malignant tumor in a patient in need thereof, the method comprising administering an effective amount of the crystalline form according to claim 1 to the patient” in claim 11.
The ‘858 patent fails to recite the patient population having acute myeloid leukemia, the dosing regimen of dosing for 21- or 28-days, or the administration of compound A in combination of ATRA required by the instant claims; and fails to recite administering compound A for one week or two weeks, and then administration is stopped.
However, these teachings are found in Osada in view of Watts as disclosed above. The teachings of Osada and Watts are incorporated herein by reference.
Applying KSR example rationale (G), it would have been prima facie obvious to modify the method of ‘858 patent to treat patients having AML by administering compound A daily for one week or two weeks, alone or in combination with ATRA, and then stopping administration. It is routine in the pharmaceutical arts for the person having ordinary skill to cease administration of a drug to a patient if the patient is not responding or if the patient experiences adverse side effects. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the number of days of before stopping administration is considered a result-effective variable that impacts, for example, the occurrence of adverse effects in a patient, such as those taught by Watts. Watts teaches that LSD1 inhibitors were known in the art to induce adverse effects in some patients including neutropenia and thrombocytopenia (page 2, “Results”). Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
Allowable Subject Matter
Please note that in the interest of compact prosecution, the following amendments to the claims are suggested in order to place the claims in condition for allowance:
For claims 1, 5, 17, 18, 19, and 20, applicant is invited to introduce an amendment specifying that:
the administration schedule is based on a 2-week cycle (for claims 1, 17 and 19) or 3-week cycle (for claims 5, 18, and 20); and
the cycle is performed two or more times.
For claims 9, 11, 13, and 15, which already specify that administration is based on a cycle, applicant is invited to introduce an amendment specifying that:
the cycle is performed two or more times.
The difference between the prior art and the proposed claims is that the proposed claims require a repeating administration schedule which is not obvious over the prior art of record. Specifically, the instant claims require either a repeating cycle comprising daily dosing for one week, followed by a resting period of one week; or a repeating cycle comprising daily dosing for two weeks, followed by a resting period of one week.
The prior art identified fails to teach or suggest modifying Osada’s dosing regimen to arrive at the aforementioned repeating cycles. Even taking general technical knowledge into consideration, the present application provides evidence of an unexpected result attributable to the repeating-cycle dosing schedule of the proposed claims which is of practical significance. In the Examples of the specification, Applicant discovered that continuous dosing of compound A induced severe thrombocytopenia and neutropenia, and that these toxicities could be effectively managed (while still maintaining anti-tumor effects) by using a repeating intermittent dosing period of 1-week on, 1 week off or 2 weeks on, 1 week off. See also Applicant’s Remarks filed 08/19/2025, pages 8-9, which elaborate on the unexpected results.
Conclusion
Claims 1-9, 11, 13, 15, 17-21, and 26-29 are rejected. Claims 22-25 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621