DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Preliminary Amendment
2. Examiner notes that the preliminary amendment filed 11/21/2023, making amendments to the specification, has been entered into the record.
Priority
3. This application claims benefit of 63/375,653 filed 09/14/2022.
4. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
5. The disclosure of the prior-filed application, Application No. 63/375,653, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The recitations "performance-impairing cognitive decline, damage to bone, damage to liver, and damage to kidneys", "heart attack, heart failure, or stroke" and "lung, head, or neck cancer" in claims 11-13 are not disclosed or supported by provisional application 63/375,653. Accordingly, the priority date of claims 1-10 and 14 is 09/14/2022 and the priority data of claims 11-13 is 09/14/2023.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 03/25/2024 complies with the provisions of 37 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered on the merits. See attached copy of PTO-1449.
Status of the claims
7. The claims filed on 09/14/2023 have been entered. Claims 1-14 are pending and are currently examined.
Claim Objections
8. Claim 1 is objected to because of the following informalities: the recitation of “a subject” (line 1 of claim 1), which means any subject including those who do not require any treatment. Appropriate correction is required. Examiner suggests that Applicant consider including the phrase “in need thereof” immediately after the recitation “in a subject”.
Claim Rejections - 35 USC § 112
9. 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.
10. Claims 10-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a human immunodeficiency (HIV) infection required by claim 1, wherein such method would necessarily decrease the risk of “progression of HIV-associated comorbidities” required by claim 1, does not reasonably provide enablement for decreasing the “risk of acquisition”. The limitation of “risk of acquisition” recited in claim 10 is not defined in the specification, therefore, the above recitation would encompass “prevents comorbidity diseases before acquisition”. The “progression” in claim 10 indicates the presence of comorbidities and this cannot be “at risk” or preventable. Further, claim 10 recites “HIV-associated comorbidity”, which requires presence of both HIV and one or more comorbidities.
As stated in MPEP § 2164.08, “The courts have repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” See also In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Here, the specification of the instant application does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Namely, that a person of skill in the art, at the time of filing of the instant application, would not be enabled to use the methods as claimed to decrease the risk acquisition of an HIV-comorbidity (i.e., prevent a comorbidity before acquisition) with respect to the teachings of the instant disclosure without undue experimentation.
As stated in MPEP § 2164.01(a), “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”.”
The applicant’s attention is drawn to in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), where the court set forth eight factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. They are: (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.
It is noted that all of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
11. (A,B) The nature of the invention and the breadth of the claims: The claimed invention is directed to a method for treating HIV in a subject, wherein the method “decreases the risk of acquisition or progression of HIV-associated comorbidities.”
Examiner is interpreting the recitation of “decreases the risk of acquisition” of claim 10 to encompass preventing a comorbidity before its acquisition in a subject with HIV, and thus the claimed scope is extremely broad with regards to the comorbidities being treated.
12. (C,E) The state of the prior art and the predictability or lack thereof in the art:
The state of the prior art in a field such as experimental therapeutics is such that it involves screening both in vitro and in vivo to determine whether a compound and method of using such compound exhibit the desired treatment of the desired disease and myriads of associated comorbidities. The state of the art teaches that the population of individuals infected with HIV is very heterogeneous. For example, Erlandson, K.M. and Karris, M.Y. “HIV and Aging: Reconsidering the Approach to Management of Co-Morbidities” Infect Dis Clin North Am 2019 Sep, 33(3):796-786 (“Erlandson and Karris”) describe HIV as a multi-morbidity complex chronic disease and that the infected population is heterogeneous based on differences in exposure to type and duration of antiretroviral therapies (ART), immunosuppression, age, and trauma among other factors (see pg. 1, para. 1). Erlandson and Karris, further describe that research guiding clinical management for the aging HIV population that have increased rates of comorbidities is still “nascent with many unanswered questions.” Similarly, Lerner, Andrea M., et al. “Comorbidities in Persons with HIV: The Lingering Challenge” JAMA 2020 Jan, 323(1):19-20 (“Lerner et al.”) describe that identification, mitigation, and treatment of HIV-associated comorbidities continue to be a challenge even with ART and that research and clinical trials are still needed (see pg. 20, column 2, para. 2; pg. 6, para. 2). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles established that the contemporary knowledge in the art would prevent one of ordinary skill from accepting any method of treatment on its face.
13. (F,G) The amount of direction provided and the presence of working examples:
Applicant provides examples of Pevonedistat (“MLN”) inhibition of Cullin 2 neddylation in vitro (e.g., ACH2 cells among others). Applicant further provides examples of MLN decreasing the amount of HIV virus produced, reduction in viral infectivity, an increase in the amount and favorable cellular distribution of APOBEC3G, leading to apoptosis of infected T cells. The provided in vitro data, as discussed above, are not examples of actually treating a disease in a patient suffering from HIV, or any HIV-associated comorbidities. Rather, the suggestion of treatment by the methods of the instant application is based on extrapolation of known mechanisms of NEA1 inhibition on HIV production. Further, the suggestion of treatment of HIV by the methods of the instant application via these known mechanisms would necessarily decrease the progression of known HIV-associated comorbidities. However, it is inconceivable from the disclosed in vitro data as to how the claimed methods can decrease the risk of acquisition of a myriad of HIV-associated comorbidities. Therefore, lack of working examples for disease or disorders which are not already present in a subject with HIV is a critical factor to be considered, especially where there is unpredictability of the art.
14. (D,H) The level of one of ordinary skill and the quantity of experimentation needed to make or use the invention based on the content of the disclosure: The relative skill of those in the art is high. However, that factor is outweighed by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances).
Because of the known unpredictability of the art (as discussed in above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that the claimed method would be capable of decreasing the risk of comorbidities (i.e., preventing the acquisition) before acquisition.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). A review of the state of the art fails to reveal that any cancer not caused by immunodeficiency or any potential damage to bone, liver, or kidney would be an HIV-associated comorbidity. Thus, in order to translate the suggestion in the instant disclosure to practice claimed methods with the full range of the claimed scope, one of skill in the art would have to undertake a novel and extensive research program across several subdisciplines (e.g., cancer and tumor oncology, cardiovascular, hepatology, among others) to determine whether the methods of the claimed invention could successfully treat a patient suffering from said HIV-associated comorbidity. Furthermore, in vivo and in vitro assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy. This is undue experimentation given the limited guidance and direction provided in the instant application.
15. Accordingly, the inventions of claims 10-13 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Claim Rejections - 35 USC § 103
16. 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.
17. Claim(s) 1-6 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Stanley. David J., et al. “Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G” PLoS Pathog. 2012 Dec; 8(12): e1003085 (“Stanley et al.”).
18. Regarding claims 1-2, Stanley et al. teaches the compound MLN4924 (i.e., Pevonedistat; “MLN” in the instant application) inhibits the NEDD8 cascade, blocks the action of Vif, and thus has potent anti-HIV activity in vitro. Stanley et al. further suggests that inhibition of the NEDD8 cascade alone, or in combination with existing antiretroviral drugs, could prove to be a useful treatment for HIV (see id. pg. 1, abstract; pg. 2, Author summary; pg. 10, para. 2). For example, Stanley et al. demonstrates that MLN reduced infectivity of HIV in the presence of APOBEC3G (“A3G”) in HEK293 cells co transfected with the HIVNIA-3 fully infectious molecular clone of HIV and mammalian expression construct containing A3G (see id. pg. 2, para. 3 and Fig. 1).
Stanley et al., differs from the instantly claimed invention in that it teaches the use of MLN for NEDD8 inhibition in vitro using cultured cell models of HIV infection and claim 1 of the instant application recites “administering to the subject”, which is an in vivo method. However, Stanley et al. further teaches "MLN4924 represents an alternative approach to inhibiting Vif: it is highly selective for the NEDD8 E1; it is validated in mouse models of cancer and currently in clinical trials" (see id. pg. 10, left col. para. 2). Thus, Stanley et al. teaches both in vitro validation of MLN for the treatment of HIV infection and that MLN has been validated in mouse models. One of skill in the art at the time of filing would be motivated to combine these teachings with a reasonable expectation of success. Specifically, these combined teachings provide a prima facia case for obviousness to a skilled artisan that substituting cultured cells for mouse models to a subject having a HIV infection for administering a NEDD8 E1 inhibitor with a reasonable expectation of success because MLN has been successfully tested in in vivo models.
19. Since claims 3-6 and 9-13 recite only consequences after administering NAE1 inhibitor (i.e., MLN) to a subject and do not recite any further structural limitation of the claims from which they depend they are also unpatentable in view of Stanley et al. (see MPEP 2111.02(II)). In the instant claims, the administration of an NEA1 inhibitor (i.e., MLN) will necessarily decrease any “production of infectious HIV from latent HIV provirus or other HIV latency components in T cells” (as required by claim 3), increase APOBEC3G within reactivated HIV (as required by claim 4), decrease “infectivity of reactivated HIV” (as required by claim 5), reduce “HIV provirus transcription and HIV viral protein production” (as required by claim 6), and prevent or limit “immune cell activation and systemic inflammation from HIV during viremia-suppressing ART” (as required by claim 9), during the process of administration and treatment of HIV with an NEA1 inhibitor as taught by Stanley et al. Since the claims are directed to a method, these consequences are interpreted as intended results, and would also be obvious in view of Stanley et al. as applied to claims 1-2.
20. Claims 7, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Stanley et al. as applied to claims 1-6 and 9-13 above, and further in view of Mann, J. F.S., et al. “A targeted reactivation of latent HIV-1 using an activator vector in patient samples from acute infection” EBioMed 2020 July, 59:102853 (“Mann et al.”).
Regarding claim 7, Stanley et al. differs from the instantly claimed invention in that it does not teach the administration of the NEA1 inhibitor of claim 1 “prior to and during short-term exposure to a latency reactivating agent (LRA)” required by claim 7 and “before and for a defined time period after stopping antiretroviral therapy” required by claims 8 and 14. However, in the same field of endeavor of HIV disease research and need for novel and improved therapeutic strategies for clinical manifestations of HIV infection, Mann et al. teaches the ability of HIV-1 to establish latent provirus within the CD4 T cell reservoir is a major reason for virus recrudescence upon cessation of cART. Identifying novel mechanisms to deplete this reservoir are of great research priority, (page 2, left col., para. 3) and ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments (page 1, Abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing of the instant application to combine the use of an NEA1 inhibitor of Stanley et al. with LRA and/or ART in the method of Mann et al. to inhibit the ability of HIV-1 to establish latent provirus within the CD4 T cell reservoir, a major reason for virus recrudescence upon cessation of cART.
Conclusion
21. No claims are allowed in this action.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN JEROME FOWLER whose telephone number is (571)272-0195. The examiner can normally be reached Monday - Friday 9-4PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALAN J FOWLER/Examiner, Art Unit 1691
/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691