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 .
Election/Restrictions
Applicant's election without traverse of Group I, claims 1-16, 25, 26, and 28 in the reply filed on 03/31/2026 is acknowledged. The elected species are as follows:
Post-transplant lymphoproliferative disorder (PTLD)
Claims 14, 15, and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/31/2026.
In view of the search of the prior art, the species election was expanded to broadly include lymphoma. As such, claims 12, 13, 15, and 26 are under examination.
Claims 1-13, 16, 25 and 26 are under examination.
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application No. PCT/EP2022/055647 filed on 03/04/2022. This application also claims priority to EP application 21161105.8, filed on March 05, 2021 and EP application 21208340.6, filed on November 15, 2021.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Claim 23 is 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.
The term “about” in claim 23 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 23 recites “greater than or equal to about 5,000 copies/ug DNA in blood and/or greater than or equal to about 1,000 copies/100 ul plasma.”
Claim Rejections - 35 USC § 112 – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
• (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, the instant claims are broadly drawn to a method for PTLD by administering an IDO1 inhibitor. It is noted that the term “preventing” was interpreted in an absolute sense to mean to always keep something from happening or arising. The level of skill in the art is high and would include, e.g., Ph.D. level scientists.
Baker et al. (Children (Basel), July 2021, hereinafter, “Baker”) evidences that PTLD is not preventable (Abstract). Baker evidences that there is also no consensus on the prevention of PTLD (Abstract). Baker evidences that 12% of patients across different types of transplants succumbed to PTLD (Table 2). As such, the art offers no predictability for the prevention of PTLD with the use of IDO1 inhibitor therapy in any subject.
The Specification only exemplifies and reduces to practice treating PTLD in mice with epacadostat treatment (Figure 9-13). The Specification do show a reduction of tumors within mice following PTLD treatment (Figure 13). However, the Specification offers no reasonable direction or working example for the absolute prevention of PTLD in virtually any subject in-vivo.
In view of the foregoing, a vast quantity of experimentation, including expansive clinical trials, would be needed to use the invention based on the content of the disclosure.
Taken together, the claim contains subject matter which was not described in the Specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.
Claim(s) 1, 2, 10 – 13, 25, and 26, are rejected under 35 U.S.C. 103 as being unpatentable over Abdulla et al (Acta Oncologica, Feb 2021, hereinafter, “Abdulla”), in view of Nakamura et al (Int J Hematology, 2015, hereinafter, “Nakamura”) and Jacobson et al. (Oncology, 2010, hereinafter, “Jacobson”).
Abdulla teaches that Indoleamine 2,3-deoxygenase (IDO) can be expressed both by tumor cells and cells involved in the microenvironment (Abstract). Abdulla teaches that IDO is crucial for tumor immune escape (Abstract). Abdulla also teaches that IDO1 is elevated in patients with primary diffuse large B-cell lymphoma that is associated with Epstein-Barr virus (EBV) co-infection (Abstract).
Nakamura teaches that IDO is increased in tumors and inhibits T-cell activity (Abstract). Nakamura also teaches that IDO catalyzes the metabolism of tryptophan, the rate-limiting step, along the kynurenine pathway and that IDO inhibitors are effective are an effective treatment for lymphoma (Abstract).
Regarding claims 1 and 2, Abdulla teaches that IDO1 is a target for EBV associated lymphomas (Abstract, Figure 3). Nakamura teaches that the IDO inhibitor 1-MT is effective at treating lymphoma (Figure 3).
The references do not explicitly teach using IDO inhibitors for treating PTLD.
However, regarding claims 10-13, 25 and 26, as taught by Jacobson, PTLD is a term used for a wide range of lymphomas including diffuse large B-cell lymphoma, Burkitt/Burkitt-like lymphoma, myeloma, T-cell lymphoma and classical Hodgkin in transplant patients (¶2). Jacobson teaches that PTLD is a group of lymphomas that occur in transplant patients and is associated with EBV (¶1,2). Jacobson teaches that while PTLD can exhibit in a more aggressive clinical course, many of the treatments to specifically treat lymphoma remain the same (¶2, Chemotherapy). For example, rituximab is known to be a treatment for lymphoma and is used to treat PTLD as well (Antibody Therapy, Chemotherapy). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to treat PTLD with the same treatments as patients who have not had transplants but are diagnosed with lymphomas because the underlying symptoms and disease is the same.
Abdulla and Nakamura are considered to be analogous to the claim invention because they that cancers can be treated with IDO1 inhibitors. Abdulla teaches that IDO1 is a target for treatment in patients with primary diffuse large B-cell lymphoma (Title). Nakamura teaches that the IDO inhibitor 1-MT is effective at treating lymphoma (Figure 3). Jacobson teaches that PTLD are lymphomas that occur in transplant patients and that lymphoma in transplant patients can be treated with the same drugs as patients diagnosed with lymphoma who have not had transplants (¶1,2, Antibody Therapy, Chemotherapy).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use 1-MT, as taught by Nakamura, to treat diffuse B-cell lymphoma, as taught by Abdulla, because doing so would effectively target the inhibitory microenvironment and allow T-cells to target cancer cells. One of ordinary skill in the art would have had a reasonable expectation of success in using an IDO inhibitor to treat lymphoma given that is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 3 - 5 are rejected under 35 U.S.C. 103 over Abdulla, Nakamura, and Jacobson as applied to claims 1, 2, 10 – 13, 25, and 26, above, and further view of Liu et al (Bioorganic & Medicinal Chemistry Letters, 2020, hereinafter, “Liu”).
As discussed above, claims 1, 2, 10 – 13, 25, and 26, are rendered prima facie obvious by the teachings of Abdulla, Nakamura, and Jacobson.
The references fail to teach a hydroxylamidine such as epacadostat.
However, Liu teaches the identification of novel hydroxyamidine derivatives that function as IDO1 inhibitors (Abstract). Liu teaches that these inhibitors can be used in cancer immunotherapy (Abstract). Liu also teaches the structure of epacadostat and its in-vivo use for treating Lewis lung cancer (Figure 1, Figure 3).
Regarding claim 3-5, Liu teaches that hydroxyamidine derivatives such as Epacadostat are IDO1 inhibitors and are therapeutic treatments for cancer immunotherapy (Figure 3).
Abdulla, Nakamura, Jacobson, and Liu are considered to be analogous to the claim invention because they that cancers can be treated with IDO1 inhibitors. Abdulla teaches that IDO1 is a target for treatment in patients with primary diffuse large B-cell lymphoma (Title). Nakamura teaches that the IDO inhibitor 1-MT is effective at treating lymphoma (Figure 3). Jacobson teaches that PTLD are lymphomas that occur in transplant patients and that lymphoma in transplant patients can be treated with the same drugs as patients diagnosed with lymphoma who have not had transplants (¶1,2, Antibody Therapy, Chemotherapy). Liu teaches the hydroxyamidine derivative epacadostat is a IDO1 inhibitor and used as a therapeutic treatment for cancer immunotherapy (Figure 3).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use epacadostat, as taught by Liu, to treat diffuse B-cell lymphoma (a lymphoma found in PTLD patients), as taught by Abdulla, Nakamura, and Jacobson, because doing so would effectively target the inhibitory microenvironment and allow T-cells to target cancer cells. One of ordinary skill in the art would have had a reasonable expectation of success in using an IDO inhibitor, such as epacadostat, to treat lymphoma given that is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 3, 6 and 7 are rejected under 35 U.S.C. 103 over Abdulla, Nakamura, and Jacobson as applied to claims 1, 2, 10 – 13, 25, and 26, above, and further view of Salloum et al (WO 2019227090 A1, hereinafter, “Salloum”).
As discussed above, claims 1, 2, 10 – 13, 25, and 26, are rendered prima facie obvious by the teachings of Abdulla, Nakamura, and Jacobson.
The references fail to teach a 1-4(arcylcyclohex-1-yl)propenamide such as linrodostat.
However, Salloum teaches methods and compositions to limit neurotoxicity that can occur as a side effect of the treatment of cancer patients with redirected T-cell therapies (Abstract). Salloum teaches that T-cell therapy for B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma in conjuction with IDO inhibitors such as BMS-986205 (linrodostat) and epacadostat (Page 1, lines 18-27; Claim 3). Salloum teaches the motivation of using linrodostat as IDO upregulation being tied to immune tolerance and that IDO overexpression in cancer has been implicated in establishing an immune-suppressive microenvironment (Page 41, lines 19-30).
Regarding claim 3, 6 and 7 Salloum teaches the combination therapy of T cells with linrodostat (Page 1, lines 18-27; Claim 3).
Abdulla, Nakamura, Jacobson, and Salloum are considered to be analogous to the claim invention because they that cancers can be treated with IDO1 inhibitors. Abdulla teaches that IDO1 is a target for treatment in patients with primary diffuse large B-cell lymphoma (Title). Nakamura teaches that the IDO inhibitor 1-MT is effective at treating lymphoma (Figure 3). Jacobson teaches that PTLD are lymphomas that occur in transplant patients and that lymphoma in transplant patients can be treated with the same drugs as patients diagnosed with lymphoma who have not had transplants (¶1,2, Antibody Therapy, Chemotherapy).. Salloum teaches linrodostat is a IDO1 inhibitor and is used as a therapeutic treatment for cancer immunotherapy (Page 1, lines 18-27; Claim 3).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use linrodostat, as taught by Salloum, as a single drug therapy, as taught by Nakamura, to treat diffuse B-cell lymphoma (a lymphoma found in PTLD patients), as taught by Abdulla, Nakamura, and Jacobson, because doing so would effectively target the inhibitory microenvironment and allow T-cells to target cancer cells. One of ordinary skill in the art would have had a reasonable expectation of success in using an IDO inhibitor, such as linrodostat, to treat lymphoma given that is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 3, 8 and 9 are rejected under 35 U.S.C. 103 over Abdulla and Nakamura as applied to claims 1, 2, 10 – 13, 25, and 26 above, and further view of Sahebjam et al (Poster, 32nd Annual society for Immunotherapy of Cancer, 2017, hereinafter, “Sahebjam”).
As discussed above, claims 1, 2, 10 – 13, 25, and 26 are rendered prima facie obvious by the teachings of Abdulla, Nakamura, and Jacobson.
The references fail to teach a 1,2-diamino- or 1-hydroxy-2-amino-substituted aromatic such as KHK2455.
However, Sahebjam teaches that KHK2455 as a monotherapy or in conjunction with Mogamulizumab, a monoclonal antibody, are used for cancer immunotherapies (Background). Sahebjam teaches the safety profile of different dosages of KHK2455 and teaches detection of KHK2455 within patients (Pharmacodynamics).
Regarding claim claims 3, 8 and 9, Sahebjam teaches that KHK2455 is a selective IDO-1 inhibitor and has been used in immunotherapy in several types of cancers (Background).
Abdulla, Nakamura, Jacobson and Sahebjam are considered to be analogous to the claim invention because they that cancers can be treated with IDO1 inhibitors. Abdulla teaches that IDO1 is a target for treatment in patients with primary diffuse large B-cell lymphoma (Title). Nakamura teaches that the IDO inhibitor 1-MT is effective at treating lymphoma (Figure 3). Jacobson teaches that PTLD are lymphomas that occur in transplant patients and that lymphoma in transplant patients can be treated with the same drugs as patients diagnosed with lymphoma who have not had transplants (¶1,2, Antibody Therapy, Chemotherapy). Sahebjam teaches KHK2455 is a IDO1 inhibitor and is used as a therapeutic treatment for cancer immunotherapy (Background).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use KHK2455, as taught by Sahebjam, as a single drug therapy, as taught by Nakamura, to treat diffuse B-cell lymphoma (a lymphoma found in PTLD patients), as taught by Abdulla, Nakamura, and Jacobson, because doing so would effectively target the IDO1 pathway and resulting inhibitory microenvironment and allow T-cells to target cancer cells. One of ordinary skill in the art would have had a reasonable expectation of success in using an IDO inhibitor, such as KHK2455, to treat lymphoma given that is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Conclusion
NO CLAIMS ARE ALLOWED
The prior art made of record and not relied upon is considered pertinent to applicant'sdisclosure:
Kanarky et al (Blood, 2016)
Badaway et al (Int J Tryptophan Res, 2019)
Chartier et al (Liver Transplantation, 2020)
Basso et al (Pediatr Transplantation, 2013)
Meeting Abstracts (32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part One, 2017)
Cheong et al (Expert opinion on Therapeutic Patents, 2018)
Laurent et al (Haematologica, 2016)
Jin et al (ACS Med Chem lett, 2021)
Fafi-Kremer et al (J Immuno Cancer, 2017)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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