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 .
Current Status of 18/546,245
This Office action is responsive to the claims of 08/11/2023. Claims 1-19 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2022/016311, international filing date 02/14/2022, which claims priority to U.S. Provisional Patent Application No. 63/149,920, filed 02/16/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the provided figures are all grainy and difficult to read. The following figures are especially difficult to read: Fig 2A, Fig 3, Fig 7, Fig 8A, and Fig 10C. The examiner recommends replacing all figures with clear figures where each element of the figures are clear and legible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
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 19 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.
Claim 19 recites the limitation " the composition of claim 138" in line one of the claim. There is insufficient antecedent basis for this limitation in the claim.
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, 2, 4, 5, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Feng (Feng, Wen-hai et al. “Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas.” Journal of virology vol. 78,4 (2004): 1893-902. doi:10.1128/jvi.78.4.1893-1902.2004) in view of Zhao (Zhao, Y., Ye, X., Shehata, M. et al. The RNA quality control pathway nonsense-mediated mRNA decay targets cellular and viral RNAs to restrict KSHV. Nat Commun 11, 3345 (2020). https://doi.org/10.1038/s41467-020-17151-2, found in IDS filed 02/17/2026) as evidenced by Cesarman (found in IDS filed 02/17/2026).
Feng teaches a therapeutic strategy for Epstein-Barr virus (EBV)- positive tumors in human patients involving the intentional induction of the lytic form of EBV infection combined with ganciclovir (GCV) (Abstract). The expression of lytic viral kinases render infected cells susceptible to antiviral-mediated cytotoxicity (Abstract). The reference teaches that the chemotherapeutics doxorubicin and gemcitabine induce lytic EBV infection (Abstract). Feng does not expressly disclose the administration/use of NMD inhibitors to induce the lytic form of the herpesvirus.
Zhao teaches that NMD suppresses KSHV lytic reactivation and that inhibition of NMD through silencing of UPF1 or UPF3X increases ORF50 expression and promotes lytic gene transcription and virion production (Abstract). While Zhao does not expressly disclose inducing lytic reactivation of EBV via inhibition of NMD, EBV and KSHV are both human gammaherpesviruses that infect B lymphocytes and establish latent infection (see Cesarman Introduction). These latent infections are etiologically linked to the development of multiple lymphoproliferative disorders (see Cesarman Introduction). Accordingly, teachings regarding modulation of latency and lytic reactivation in one human gammaherpesvirus would have been reasonably applicable to the other.
The artisan would have experience in antiviral drug development and viral pathogenesis, including familiarity with mechanisms governing herpesvirus latency and lytic reactivation. The artisan would have experience in the development and evaluation of therapeutic strategies for viral infections, including latent infections associated with gammaherpesviruses. The artisan would be knowledgeable about prior therapeutic strategies used to treat gammaherpesvirus-associated diseases.
Feng teaches that intentional induction of the EBV lytic cycle in combination with ganciclovir constitutes a therapeutic strategy for EBV-positive malignancies, wherein lytic viral kinase expression renders infected cells susceptible to antiviral-mediated cytotoxicity. Zhao teaches that inhibition of NMD enhances lytic reactivation of KSHV by increasing expression of the viral transactivator ORF50, promoting lytic gene expression. EVB and KSHV are related human gammaherpesviruses that establish latency in B lymphocytes and undergo lytic reactivation through homologous regulatory mechanisms. Given the established therapeutic method of Feng, the artisan would have been motivated to use an agent known to induce lytic reactivation, such as NMD inhibitors. The artisan would have had a reasonable expectation of increasing lytic gene expression which would have enhanced antiviral susceptibility in accordance with the known mechanism of viral-kinase-dependent activation of nucleoside analogs.
Claims 10, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Feng and Zhao as evidenced by Cesarman in view of Muni (US 6,708,822 B2).
The teachings of Feng, Zhao, and Cesarman are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the coadministration of an NMD inhibitor with a herpesvirus antiviral for therapeutic purposes. Feng additionally teaches the administration of chemotherapeutics as part of the method. The references do not teach these agents as part of a kit.
Muni teaches a kit for compounding pharmaceuticals. The kit comprises a first container comprising an active agent, a second container comprising at least one inactive agent, and instructions for use (Col 2, lines 37-40).
The artisan would have practical experience in herpesvirus pathogenesis and antiviral drug development and knowledge of established combination antiviral treatment strategies. The artisan would also understand routine pharmaceutical practices for formulating and packaging multiple therapeutic agents intended for coordinated administration.
As discussed above, it would have been obvious to co-administer an NMD inhibitor, a herpesvirus antiviral, and a chemotherapeutic agent for therapeutic purposes. It was well established in the art to provide agents intended for coordinated administration in a kit comprising separate containers and instructions for us. In the absence of any structural or functional limitations beyond containing the agents, the claimed kit represents routine packaging of an obvious therapeutic combination, yielding no more than predictable results.
Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Feng and Zhao as evidenced by Cesarman in view of Maquat (US 2016/0279110 A1).
The teachings of Feng, Zhao, and Cesarman are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the coadministration of an NMD inhibitor with a herpesvirus antiviral for therapeutic purposes. Feng additionally teaches the administration of chemotherapeutics as part of the method. The references do not teach these agents as part of a composition.
Maquat teaches compositions comprising one or more NMD inhibitors [0047] further specifying NMDI-1 (claim 7, Experimental result of [0108]-[0116]). The reference also teaches that these compositions include chemotherapeutic agents (Claim 1).
The artisan would have experience in herpesvirus therapeutics and pharmaceutical formulation and routine preparation of multi-agent pharmaceutical compositions.
As discussed above, it would have been obvious to co-administer an NMD inhibitor, a herpesvirus antiviral, and a chemotherapeutic agent for therapeutic purposes. It was well established in the art that agents intended for combination therapy may be formulated into a single pharmaceutical composition. Maquat expressly teaches such compositions for NMDI-1. In the absence of any demonstrated chemical unpredictability or unexpected pharmacological interactions between an NMD inhibitor, herpesvirus antiviral, or chemotherapeutic agent, preparing a composition comprising these agents constitutes routine formulation practice yielding no more than predictable results.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Feng, Zhao, and Muni as evidenced by Cesarman in view of Maquat.
The teachings of Feng, Zhao, Muni, and Cesarman are discussed above and are incorporated by reference into this rejection. They teach a kit comprising and NMD inhibitor and a herpesvirus antiviral. These references do no expressly disclose a specific NMD inhibitor.
Maquat teaches compositions comprising one or more NMD inhibitors [0047] further specifying NMDI-1 (claim 7, Experimental result of [0108]-[0116]).
The artisan would have practical experience in herpesvirus pathogenesis and antiviral drug development and knowledge of established combination antiviral treatment strategies. The artisan would also understand routine pharmaceutical practices for formulating and packaging multiple therapeutic agents intended for coordinated administration.
As discussed above, it would have been obvious to inhibit NMD to induce lytic reactivation (see Feng). Maquat teaches NMDI-1 as and NMD inhibitor. The artisan would have selected known NMD inhibitors, such as NMDI-1, as a routine choice of known compounds with the desired function, yielding no more than predictable results.
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Feng and Zhao as evidenced by Cesarman in view of Maquat.
The teachings of Feng, Zhao, and Cesarman are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the coadministration of an NMD inhibitor with a herpesvirus antiviral for therapeutic purposes. The references do not teach specific NMD inhibitors as part of the method.
Maquat teaches compositions comprising one or more NMD inhibitors [0047] further specifying NMDI-1 (claim 7, Experimental result of [0108]-[0116]).
The artisan would have experience in antiviral drug development and viral pathogenesis, including familiarity with mechanisms governing herpesvirus latency and lytic reactivation. The artisan would have experience in the development and evaluation of therapeutic strategies for viral infections, including latent infections associated with gammaherpesviruses. The artisan would be knowledgeable about prior therapeutic strategies used to treat gammaherpesvirus-associated diseases.
As discussed above, it would have been obvious to inhibit NMD to induce lytic reactivation (see Feng). Maquat teaches NMDI-1 as and NMD inhibitor. The artisan would have selected known NMD inhibitors, such as NMDI-1, as a routine choice of known compounds with the desired function, yielding no more than predictable results.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Feng and Zhao as evidenced by Cesarman in view of NCI (NIH National Cancer Institute: Immunotherapy to Treat Cancer).
The teachings of Feng, Zhao, and Cesarman are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the coadministration of an NMD inhibitor with a herpesvirus antiviral for therapeutic purposes. The references do not teach immunomodulator agents as part of the method.
NCI teaches that immunomodulatory agents are well-known cancer therapeutics and are used in oncology treatment regimens.
The artisan would have experience in antiviral pharmacology and oncologic therapeutics, including familiarity with mechanisms governing herpesvirus latency and lytic reactivation and virus-associated malignancies. The artisan would have experience in the development and evaluation of treatment regimens for herpes-virus associated cancers, including the use of lytic induction strategies, the use of antiviral agents, and combination oncology treatments. The artisan would be knowledgeable about established multimodal cancer treatment approaches incorporating antiviral, cytotoxic, and immunomodulatory agents.
It has been established that Feng teaches that induction of the lytic form of EBV infection in combination with an antiviral agent enhances killing of EBV-positive tumor cell. It has also been established that Zhao teaches that the inhibition of NMD promotes lytic reactivation of a gammaherpesvirus. A method using an NMD inhibitor as the lytic reactivation promoter has been made obvious in the above discussion. Virus-associated malignancies are routinely treated using multimodal oncology regimens incorporating antiviral agents and immunomodulatory therapies. Because lytic induction increases viral antigen expression and susceptibility of tumor cell to immune-related clearance, the artisan would have found it obvious to further administer an immunomodulatory agent as part of the combination therapy, yielding no more than predictable results.
Claims 10 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Feng, Zhao, and Muni as evidenced by Cesarman in view of NCI.
The teachings of Feng, Zhao, Muni, and Cesarman are discussed above and are incorporated by reference into this rejection. They teach a kit comprising an NMD inhibitor, a herpesvirus antiviral, and a cancer treatment agent (chemotherapeutic). The references do not teach immunomodulatory agents as the cancer treatment agent.
NCI teaches that immunomodulatory agents are well-known cancer therapeutics and are used in oncology treatment regimens.
The artisan would have experience in antiviral pharmacology and oncologic therapeutics, including familiarity with mechanisms governing herpesvirus latency and lytic reactivation and virus-associated malignancies. The artisan would have experience in the development and evaluation of treatment regimens for herpes-virus associated cancers, including the use of lytic induction strategies, the use of antiviral agents, and combination oncology treatments. The artisan would be knowledgeable about established multimodal cancer treatment approaches incorporating antiviral, cytotoxic, and immunomodulatory agents. The artisan would also understand routine pharmaceutical practices for formulating and packaging multiple therapeutic agents intended for coordinated administration.
As discussed above, it would have been obvious to administer and NMD inhibitor and antiviral agent in combination with an immunomodulatory agent as part of a multimodal oncology regimen for virus-associated malignancies. It is well established in the pharmaceutical arts to provide therapeutically combined agents in a kit. Absent any structural or functional limitation, providing the NMD inhibitor, antiviral agent, and immunomodulatory agent together in a kit constitutes a routine packaging choice yielding no more than predictable results.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Feng, Zhao as evidenced by Cesarman in view of Li (Li, Renfeng, and S. Diane Hayward. "Potential of protein kinase inhibitors for treating herpesvirus-associated disease." Trends in microbiology 21.6 (2013): 286-295.).
The teachings of Feng, Zhao, and Cesarman are discussed above and are incorporated by reference into this rejection. The combined teachings of these references teach the coadministration of an NMD inhibitor with a herpesvirus antiviral for therapeutic purposes. The references do not teach the herpesviruses of instant claim 6.
Li teaches that herpesviruses include HSV-1, HSV-2, VZV, CMV, HHV-7, EBV, and KSHV (pg. 286, left col, second para.). The reference also discloses that lytic induction of herpesvirus-encoded thymidine kinases and protein kinases, which are required for phosphorylation of nucleoside analog antivirals such as ganciclovir, and that phosphorylated ganciclovir is cytotoxic to tumor cells expressing these viral kinases (pg. 292, left col, second para). This establishes that the therapeutic strategy of inducing lytic replication enhances antiviral susceptibility through viral kinase expression.
The artisan would have experience in antiviral drug development and viral pathogenesis, including familiarity with mechanisms governing herpesvirus latency and lytic reactivation. The artisan would have experience in the development and evaluation of therapeutic strategies for viral infections, including latent infections associated with herpesviruses. The artisan would be knowledgeable about prior therapeutic strategies used to treat herpesvirus-associated diseases.
Feng teaches that intentional induction of the EBV lytic cycle in combination with ganciclovir constitutes a therapeutic strategy for EBV-positive malignancies, wherein lytic viral kinase expression renders infected cells susceptible to antiviral-mediated cytotoxicity. Zhao teaches that inhibition of NMD enhances lytic reactivation of KSHV by increasing expression of the viral transactivator ORF50, promoting lytic gene expression. EVB and KSHV are related human gammaherpesviruses that establish latency in B lymphocytes and undergo lytic reactivation through homologous regulatory mechanisms. Li teaches that lytic reactivation is a viable strategy for herpesviruses generally (HSV-1, HSV-2, VZV, CMV, HHV-7, EBV, and KSHV). Given the established therapeutic method of Feng, the artisan would have been motivated to use an agent known to induce lytic reactivation, such as NMD inhibitors. The artisan would have had a reasonable expectation of increasing lytic gene expression which would have enhanced antiviral susceptibility in accordance with the known mechanism of viral-kinase-dependent activation of nucleoside analogs.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625