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 1-3, 5-12, 23-25, 27-35 and 46-47 are pending in the instant application. Claims 12 and 35 are withdrawn.
Information Disclosure Statement (IDS)
The Information Disclosure Statements filed 12/21/2023, 05/16/2024, 05/30/2025 and 10/24/2025 were considered by the Examiner.
Response to Restriction/Election Requirement
Applicant’s election without traverse of 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one to prosecute Group I, drawn to a method of treating cancer, in the reply filed on October 24th, 2025 is acknowledged.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species is not allowable. Therefore, according to MPEP 803.02:
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability.
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
If on examination the elected species is found to be anticipated or rendered obvious by prior art, the Markush claim and claims to the elected species will be rejected, and claims to the nonelected species will be held withdrawn from further consideration.
As the elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration. Claims 1-3, 5-11, 23-25, 27-34 and 46-47 have been examined to the extent that they are readable on the elected compound 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. Since the elected species is not allowable, subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration. Claims 12 and 35 are withdrawn as being drawn to a nonelected invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-11 and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bartolozzi et al (WO 2021/102288, which claims priority to 62/939,377 filed 11/22/2019) in view of Karayama et al (Clinical and Translational Oncology (2020) 23:418–423, as cited on the IDS dated 12/21/2023) and Culler et al (WO 2019/178542 A1, as cited on the IDS dated 12/21/2023).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Bartolozzi teaches a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of an AhR antagonist, 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (claim 40, which finds support in claims 31-32 of the priority document). Bartolozzi teaches that the cancer is non-small cell lung cancer (paragraph [00108], which finds support in paragraph [0007] of the priority document).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not teach that the method includes measuring an aryl hydrocarbon receptor ligand from a fecal sample, comparing the ligand to a threshold score and determining that the patient would benefit from being treating with an AhR antagonist.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
However, Bartolozzi teaches that “effectiveness” can be assessed by any method known to one of ordinary skill in the art, including those described in the examples of this disclosure. Effectiveness in vitro may be used to extrapolate or predict some degree of effectiveness in vivo, in an animal or in a human subject. A reference or standard or comparison may be used. The term "effective" at inhibiting a receptor (such as AhR), and/or signaling mediated by the enzyme in the context of this disclosure and claims means reducing/activating the activity of the receptor and/or the activation and propagation of the signaling pathway in terms of activation of a downstream molecule or known biological effect by a detectable or measurable amount relative to the baseline activity. This can be assessed in vitro or in vivo and, in some cases, extrapolated to what an activity or benefit in vivo might be by one of ordinary skill in the art (paragraph [0068], which finds support in paragraph [0046] of the priority document).
Further, Karayama teaches a comprehensive assessment of multiple tryptophan metabolites as potential bookmarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer (title). Karayama teaches that patients with NSCLC had different plasma levels of several tryptophan metabolites compared with healthy controls. Karayama further teaches that monitoring the metabolites may be helpful in predicting the efficacy of drugs used to treat non-small cell lung cancer (page 422, left column, paragraph 1). Karayama also teaches the comparison of the metabolite levels in those undergoing cancer treatment with healthy volunteers (methods).
Also, Culler teaches the use of fecal markers for predicting response to cancer treatment. Culler teaches that analysis of fecal samples observations that are concerned with response to cancer treatment (page 2, paragraph 2). Culler teaches that metabolomic data was used to determine metabolic signatures that could differentiae response to treatment. Culler teaches that kynurenine and tryptophan was observed in fecal samples of mice receiving cancer treatment (Page 98, paragraphs 1).
As Bartolozzi teaches a method of treating cancer with an AhR antagonist and determining the effectiveness of treatment with methods that would be obvious to one of ordinary skill in the art, Karayama teaches that monitoring tryptophan levels in patients with non-small cell lung cancer can improve treatment, when comparing levels with threshold scores, and Culler teaches tryptophan was analyzed from fecal samples in patients receiving cancer treatment in order to improve treatment, one of ordinary skill in the art would have been motivated to perform the method of instant claim 1.
Regarding claim 2, as seen above, Bartolozzi teaches that the cancer is non-small cell lung cancer.
Regarding claim 3, Bartolozzi teaches that the above compound was administered to subjects that are resistant to anti-PD-L1 therapy (paragraphs [0020-0023]).
Regarding claims 5-6, as seen above, Karayama and Culler teach the monitoring of tryptophan. Culler also teaches the monitoring of kynurenine (page 93, paragraph 1), indolelactate (Table 15), and pyruvic acid (page 51).
Regarding claim 7, Culler teaches that ultra-performance liquid chromatography (UPLC) was used (page 81, paragraph 1). Further, Karayama teaches that liquid chromatography was used (methods).
Regarding claim 8, Karayama teaches that 3-HAA, a downstream metabolite of kynurenine pathway, levels were lower in patients who had a response to treatment than those who did noy (discussion, paragraph 1).
Regarding claim 9, as seem above, the compound is
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. This compound is embraced by formula (I), wherein R1 is optionally substituted heteroaryl, R2 is a heteroaryl and R3 is a substituted alkyl.
Regarding claim 10, the compound above is embraced by formula (Ia), wherein ring A is a substituted heteroaryl, ring B is a heteroaryl and R is a substituted alkyl.
Regarding claims 11 and 46, as seen above, the AhR antagonist is 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.
Claim(s) 23-34 and 46-47 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Bartolozzi et al (WO 2021/102288, which claims priority to 62/939,377 filed 11/22/2019) in view of Karayama et al (Clinical and Translational Oncology (2020) 23:418–423, as cited on the IDS dated 12/21/2023) and Culler et al (WO 2019/178542 A1, as cited on the IDS dated 12/21/2023).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Bartolozzi teaches a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of an AhR antagonist, 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (claim 40, which finds support in claims 31-32 of the priority document). Bartolozzi teaches that the cancer is non-small cell lung cancer (paragraph [00108], which finds support in paragraph [0007] of the priority document). Further, Bartolozzi teaches that compound is administered in combination with at least one additional therapy, wherein the additional therapy Is an immune checkpoint inhibitor (paragraph [0099], which finds support in paragraphs [00219]-[00220] of the priority document).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not teach that the method includes measuring an aryl hydrocarbon receptor ligand from a fecal sample, comparing the ligan to a threshold score and determining that the patient would benefit from being treating with an AhR antagonist. The
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
However, Bartolozzi teaches that “effectiveness” can be assessed by any method known to one of ordinary skill in the art, including those described in the examples of this disclosure. Effectiveness in vitro may be used to extrapolate or predict some degree of effectiveness in vivo, in an animal or in a human subject. A reference or standard or comparison may be used. The term "effective" at inhibiting a receptor (such as AhR), and/or signaling mediated by the enzyme in the context of this disclosure and claims means reducing/activating the activity of the receptor and/or the activation and propagation of the signaling pathway in terms of activation of a downstream molecule or known biological effect by a detectable or measurable amount relative to the baseline activity. This can be assessed in vitro or in vivo and, in some cases, extrapolated to what an activity or benefit in vivo might be by one of ordinary skill in the art (paragraph [0068], which finds support in paragraph [0046] of the priority document).
Further, Karayama teaches a comprehensive assessment of multiple tryptophan metabolites as potential bookmarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer (title). Karamaya teaches that patients with NSCLC had different plasma levels of several tryptophan metabolites compared with healthy controls. Karamaya further teaches that monitoring the metabolites may be helpful in predicting the efficacy of drugs used to treat non-small cell lung cancer (page 422, left column, paragraph 1). ). Karayama also teaches the comparison of the metabolite levels in those undergoing cancer treatment with healthy volunteers (methods).
Also, Culler teaches the use of fecal markers for predicting response to cancer treatment. Culler teaches that analysis of fecal samples observations arise that are concerned with response to cancer treatment (page 2, paragraph 2). Culler further teaches that metabolomic data was used to determine metabolic signatures that could differentiae response to treatment. Culler teaches that kynurenine and tryptophan was observed in fecal samples of mice receiving cancer treatment (Page 98, paragraphs 1).
As Bartolozzi teaches a method of treating cancer with an AhR antagonist and ICI and determining the effectiveness of treatment with methods that would be obvious to one of ordinary skill in the art, Karayama teaches that monitoring tryptophan levels in patients with non-small cell lung cancer can improve treatment, when comparing levels with threshold scores, and Culler teaches tryptophan was analyzed from fecal samples in patients receiving cancer treatment in order to improve treatment, one of ordinary skill in the art would have been motivated to perform the method of instant claim 23.
Regarding claim 24, as seen above, Bartolozzi teaches that the cancer is non-small cell lung cancer.
Regarding claim 25, Bartolozzi teaches that the above compound was administered to subjects that are resistant to anti-PD-L1 therapy (paragraphs [0020-0023]).
Regarding claims 27-28, as seen above, Karayama and Culler teach the monitoring of tryptophan. Culler also teaches the monitoring of kynurenine (page 93, paragraph 1), indolelactate (Table 15), and pyruvic acid (page 51).
Regarding claim 29, Culler teaches that ultra-performance liquid chromatography (UPLC) was used (page 81, paragraph 1). Further, Karayama teaches that liquid chromatography was used (methods).
Regarding claim 30, Bartolozzi teaches the ICI therapy is an anti-PD-1 antibody (paragraph [00100, which finds support in paragraphs [00219]-[00220] of the priority document).
Regarding claim 31, Karayama teaches that 3-HAA, a downstream metabolite of kynurenine pathway, levels were lower in patients who had a response to treatment than those who did noy (discussion, paragraph 1).
Regarding claim 32, as seem above, the compound is
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. This compound is embraced by formula (I), wherein R1 is optionally substituted heteroaryl, R2 is a heteroaryl and R3 is a substituted alkyl.
Regarding claim 33, the compound above is embraced by formula (Ia), wherein ring A is a substituted heteroaryl, ring B is a heteroaryl and R is a substituted alkyl.
Regarding claims 34 and 47, as seen above, the AhR antagonist is 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.
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 1-11, 23-34 and 46-47 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 9-11, 17-21, 23-24, 26-30, 31, 38 and 77-80 of copending Application No. 17/756,243 (reference application) in view of Bartolozzi et al (WO 2021/102288, which claims priority to 62/939,377 filed 11/22/2019), Karayama et al (Clinical and Translational Oncology (2020) 23:418–423, as cited on the IDS dated 12/21/2023) and Culler et al (WO 2019/178542 A1, as cited on the IDS dated 12/21/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The copending application claims a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount og the compound,
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, with at least one additional therapy, wherein the additional therapy is chosen from checkpoint inhibitors that target ligan for PD-1 (claim 78), wherein the checkpoint inhibitor is an anti-PD-L1 antibody (claim 79). The teachings of Bartolozzi, Karayama and Culler relative to claims 1-11, 23-34 and 46-47 are incorporated herein by reference. The instant claims are deemed to be obvious variants of the subject matter of the copending application for the same reasons as under 35 USC 103.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anna Grace Kuckla whose telephone number is (703)756-5610. The examiner can normally be reached Monday-Friday 7:30-5.
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/A.G.K./ Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/ Primary Examiner, Art Unit 1626
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