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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 4, 2026 has been entered. By way of this submission, Applicant has amended claims 1, 35, and 36, and cancelled claims 33 and 34.
Claims 1, 10, 13, 15, 32, 35-36, 46-47, and 53 are pending in the application. Claims 13, 46-47, and 53 remain withdrawn from consideration, pursuant to the Restriction Requirement mailed November 9, 2023.
Claims 1, 10, 15, 32, and 35-36 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated December 4, 2025.
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.
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, 10, 15, 32, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Dong (WO2016014148A1) in view of Damstrup (Int J Rad Onco Bio Phys, 94.4: 940(2). Elsevier B.V. (Mar 15, 2016)) and Yoo (WO2016160792A1).
Dong teaches a method of treating a cancer patient (i.e., a subject in need thereof), comprising administering to the patient a DNA-PKcs inhibitor and a B7-H1 (i.e., PD-L1) blocking antibody (page 2, lines 22-25). DNA-PKcs is the catalytic subunit of DNA dependent protein kinase (i.e. DNA-PK) (page 20, line 13), therefore an inhibitor of DNA-PK’s catalytic subunit would also inhibit DNA-PK itself.
Dong further teaches that the cancer may be a colon cancer (page 2, line 29).
Dong further teaches that the anti-B7-H1 antibody and the DNA-PKcs inhibitor can be administered sequentially or simultaneously (i.e., concurrently), and at any appropriate frequency (page 16, lines 18- 30), and that the therapy may comprise one or more periods of administration (i.e., lead phases and maintenance phases) (page 18, lines 11-20), which is pertinent to claims 32 and 35-36.
Dong further teaches antibody dosages of about 10 mg/kg (page 17, lines 21-30) and a biweekly (i.e., every two weeks) dosage schedule (page 18, lines 11-15), which is pertinent to claim 15.
However, Dong does not teach the claimed anti-PD-L1 antibody avelumab, the claimed DNA-PKcs inhibitor (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol, or radiotherapy.
Damstrup teaches that M3814, a DNA-protein kinase inhibitor, increases the efficacy of radiotherapy (Results). While Damstrup does not explicitly recite the claimed formula (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol, Applicant's specification at Figure 3 indicates that M3814 is (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol. Damstrup therefore inherently teaches the claimed formula of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). MPEP 2112(I).
Damstrup further teaches that this compound is useful in treating colon cancer (Materials/Methods).
Damstrup further teaches that the radiotherapy is ionizing radiation (Materials/Methods). Applicant's specification at page 3, lines 35-36 describes ionizing radiation as gamma radiation, and since gamma rays are photons, Damstrup inherently teaches the subject matter of claim 32.
Yoo teaches the anti-PD-L1 antibody avelumab (para. 0166).
Yoo further teaches combinations of therapies including an anti-PD-L1 antibody, another anti-cancer agent, and radiotherapy (para. 0157).
Yoo further teaches that anti-PD-L1 antibodies are useful in the treatment of colon cancer and colorectal cancer (para. 0149).
Yoo further teaches that dosages may depend upon several factors, including previous or concurrent therapeutic interventions (para. 0182), which is pertinent to claim 10.
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the above references to arrive at the claimed invention. Combination therapies of an anti-PD-L1 antibody and a DNA-PK inhibitor were known in the art, as taught by Dong. The claimed anti-PD-L1 antibody avelumab and the claimed DNA-PK inhibitor were also known in the art, as taught by Yoo and Damstrup, respectively. It would have been a matter of simple substitution to combine these references to use both avelumab and (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol by methods known in the art, with nothing more than predictable results. The advantages and synergy between these two treatments was also known in the art, particularly in the context of enhancing radiotherapy.
With regards to the claimed dosage of radiotherapy, determination of dosage is routinely determined by the ordinary artisan as of the effective filing date of the claimed invention was known as result effective variables that depend on the conditions of the patients. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). Furthermore, Yoo teaches that dosages may depend upon several factors, including previous or concurrent therapeutic interventions (para. 0182: "The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject."). One of ordinary skill in the art would appreciate the amount or dosage of radiotherapy could be adjusted to achieve optimum therapeutic efficacy, especially given the guidance found in Yoo.
Applicant argues that one of ordinary skill would not have been motivated to select the specifically claimed combination of avelumab and (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol (i.e., M3814), and that such a combination produces an unexpected result of tumor growth control when compared to radiotherapy alone, M3814 and radiotherapy, or avelumab and radiotherapy.
Applicant's arguments have been considered fully but are not found to be persuasive.
As stated previously, the simple substitution of one known element for another to obtain predictable results is one such rationale that may support a rationale of obviousness. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
(2) a finding that the substituted components and their functions were known in the art;
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
MPEP 2143(1)(B).
In the instant case, Dong is explicit in teaching a method for treating a cancer patient, the method comprising administering to the patient a DNA-PKcs inhibitor and an anti-B7-H1 (i.e., anti-PD-L1) antibody (page 2, lines 22-25). Dong differs from the claimed invention by the use of the specifically recited DNA-PKcs inhibitor and anti-B7-H1 antibody.
As M3814 and avelumab were known in the art to be useful as a DNA-PK inhibitor (Damstrup) and an anti-PD-L1 antibody (Yoo), one of skill in the art could arrive at the claimed invention through simple substitution of the specific compounds taught by Damstrup and Yoo to perform the method of Dong, which relies on a generic DNA-PK inhibitor an anti-B7-H1 antibody. This is especially true since Damstrup and Yoo both teach that their respective compounds are useful in the treatment of colon cancer, and Dong also teaches the treatment of colon cancer.
With regards to Applicant's assertion of unexpected results, since Dong teaches a method for treating a cancer patient, comprising administering to the patient a DNA-PKcs inhibitor and an anti-B7-H1 antibody, this is at least a general expectation of some combination benefit over monotherapy. While Applicant's data at Figure 4A, 4B, and 4C demonstrate there is a useful synergy between M3814 and avelumab, this benefit is taught by Dong. Likewise, Damstrup teaches that M3814 increases the efficacy of radiotherapy.
"Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). MPEP 716.02(c)(II).
Applicant's disclosure does not describe any experiments performed with compounds other than avelumab and M3814. The arguments presented by Applicant do not prove that there was no reasonable expectation of synergy between a generic DNA-PK inhibitor and a generic anti-PD-L1 antibody, nor that such a synergy is unexpected and unique to the two claimed compounds. Absent such evidence, the method recited by Dong remains prejudicial to the instant claims.
This rejection is therefore maintained.
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, 10, 15, 32, and 35-36 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 38, and 40 of copending Application No. 18/684,604 in view of Damstrup and Yoo.
Applicant's amendments to the claims have addressed this issue, and this rejection is hereby withdrawn.
Claims 1, 10, 15, 32, and 35-36 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 38, and 40 of copending Application No. 18/684,604 in view of Dong, Damstrup and Yoo. This is a new grounds of rejection, necessitated by Applicant's amendments to the claims.
The '604 application claims a method for treating a disease or disorder characterized by aberrant cell growth and function in a subject, the method comprising administering to a subject in need thereof a DNA-PK inhibitor and a radionuclide (claim 1).
The '604 application further claims administration of an immune checkpoint modulator (claim 38), and that the immune checkpoint modulator may be an inhibitor of PD-L1 (claim 40).
However, the '604 application does not claim colorectal cancer specifically, or the anti-PD-L1 antibody avelumab, or the claimed DNA-PKcs inhibitor (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol, or the specific times of the treatments in phases.
Dong teaches a method of treating a cancer patient (i.e., a subject in need thereof), comprising administering to the patient a DNA-PKcs inhibitor and a B7-H1 (i.e., PD-L1) blocking antibody (page 2, lines 22-25). DNA-PKcs is the catalytic subunit of DNA dependent protein kinase (i.e. DNA-PK) (page 20, line 13), therefore an inhibitor of DNA-PK’s catalytic subunit would also inhibit DNA-PK itself.
Dong further teaches that the cancer may be a colon cancer (page 2, line 29).
Dong further teaches that the anti-B7-H1 antibody and the DNA-PKcs inhibitor can be administered sequentially or simultaneously (i.e., concurrently), and at any appropriate frequency (page 16, lines 18- 30), and that the therapy may comprise one or more periods of administration (i.e., lead phases and maintenance phases) (page 18, lines 11-20), which is pertinent to claims 32 and 35-36.
Dong further teaches antibody dosages of about 10 mg/kg (page 17, lines 21-30) and a biweekly (i.e., every two weeks) dosage schedule (page 18, lines 11-15), which is pertinent to claim 15.
Damstrup teaches that M3814, a DNA-protein kinase inhibitor, increases the efficacy of radiotherapy (Results). While Damstrup does not explicitly recite the claimed formula (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol, Applicant's specification at Figure 3 indicates that M3814 is (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol. Damstrup therefore inherently teaches the claimed formula of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). MPEP 2112(I).
Damstrup further teaches that this compound is useful in treating colon cancer (Materials/Methods).
Damstrup further teaches that the radiotherapy is ionizing radiation (Materials/Methods). Applicant's specification at page 3, lines 35-36 describes ionizing radiation as gamma radiation, and since gamma rays are photons, Damstrup inherently teaches the subject matter of claim 32.
Yoo teaches the anti-PD-L1 antibody avelumab (para. 0166).
Yoo further teaches combinations of therapies including an anti-PD-L1 antibody, another anti-cancer agent, and radiotherapy (para. 0157).
Yoo further teaches that anti-PD-L1 antibodies are useful in the treatment of colon cancer and colorectal cancer (para. 0149).
Yoo further teaches that dosages may depend upon several factors, including previous or concurrent therapeutic interventions (para. 0182), which is pertinent to claim 10.
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the above references with the claims of the '604 application to arrive at the claimed invention. The '604 application claims combination therapies of an anti-PD-L1 antibody and a DNA-PK inhibitor. The claimed anti-PD-L1 antibody avelumab and the claimed DNA-PK inhibitor were also known in the art, as taught by Yoo and Damstrup, respectively. It would have been a matter of simple substitution to combine these references to use both avelumab and (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxypyridazin-3-yl)-methanol by methods known in the art, with nothing more than predictable results. The advantages and synergy between these two treatments was also known in the art, given the teachings of Dong.
The difference between the claimed invention and the prior art is the dosage of radiotherapy recited in claim 31. However, it is noted that determination of dosage is routinely determined by the ordinary artisan as of the effective filing date of the claimed invention was known as result effective variables that depend on the conditions of the patients. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). One of ordinary skill in the art would appreciate the amount or dosage of radiotherapy could be adjusted to achieve optimum therapeutic efficacy, especially given the guidance found in Yoo.
Conclusion
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644
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