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 . 1
Status of Claims
Claims 1-6 and 20-31 are pending.
Election/Restrictions
Applicant’s election without traverse of prostate cancer in the reply filed on Sept. 30, 2025 is acknowledged. Previously withdrawn claim 22 directed to lung cancer is rejoined. The election of species has been modified to include cancers such as leukemias and lymphomas, such as MZL (Marginal Zone Lymphoma) as detailed in the rejections below.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on Dec. 5, 2022; Oct. 17, 2023; Mar. 11, 2024; and Oct. 29, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered.
Claim Rejections - 35 USC § 112, 2nd paragraph
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.
Claims 1-6 and 20-27 are 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 1’s preamble recites the prevention of cancer in a subject in need, where in line 3, where the subject treated is “a subject suffering from cancer.” Claim 1, and the balance of claim which are dependent upon claim 1, are indefinite, as the plain language meaning of “prevention” of a disease such as cancer, implies a healthy subject not afflicted with cancer, whereas claim 1 further claims the subject administered daclatasvir (DCV) is “suffering from cancer”. By definition, the prevention aspect of claim 1, must preclude those subjects already suffering from cancer. As such, it is unclear what patient population is required by the claims.
Given the indefiniteness regarding the patient population of claim 1, the broadest reasonable interpretation includes both those subjects in need suffering from cancer to be treated and those subjects not suffering from cancer and in need of cancer prevention. It is noted that all subjects are in need of prevention of cancer.
Claim 4 recites the limitation "the ADT" in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim, as claim 4 depends from claim 2, and claim 2 does not recite or otherwise introduce the term “ADT.”
Claim Rejections - 35 USC § 112(a)
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.
Claims 1, 3-5, 20, 23, 24, 25, 26, 27, 28, and 29 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 treatment of TRIB2 associated prostate and TRIB2 lung cancer with daclatasvir (DCV), does not reasonably provide enablement for treatment of any cancer whether TRIB2 associated or not, or prevention of any cancers, whether TRIB2 associated or not. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth factors to consider when assessing if a disclosure would have required undue experimentation. The applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (Balls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The predictability or unpredictability of the art:
The instant claimed invention is unpredictable since a person having ordinary skill in the art (PHOSITA) recognizes the difficulty in treating all cancers with method claimed. Further, per the specification, the claimed invention is based on the treatment of cancer, specifically only lung and prostate cancers, in subjects in need where the cancer expresses higher levels of Tribbles homolog 2 (TRIB2), relative to non-cancer cells. See paragraph 2 of the specification. Note also the working examples detailed below taking place solely ONLY in vitro in lung and prostate cancer cell models.
As of January 2025, in a comprehensive review of the role of TRIB2 in cell proliferation, Zhang teaches while TRIB2 plays a role in physiological proliferation of a variety of cancer cells, see Abstract, it questions the effectiveness of targeting TRIB2 in treating cancer as follows.
Although research on TRIB2 in cell proliferation has advanced our understanding of its potential mechanisms, a comprehensive understanding of its role remains incomplete. . . . Firstly, while TRIB2 mainly promotes cell proliferation and is primarily defined as an oncogene, it has also exhibited inhibitory effects in certain contexts. This dual regulatory function may depend on the specific tissue and cell type it targets. Therefore, we must give sufficient attention and conduct in-depth explorations to its inhibitory effect. Secondly, the impact of TRIB2 regulating intercellular interactions on cell proliferation should be further investigated. For instance, how TRIB2 regulates the interactions between stromal cells, immune cells, endothelial cells, and cancer cells within the cancer microenvironment, and how it modulates the interaction between endothelial cells, inflammatory cells, and VSMCs after vascular injury, promoting the proliferation of cancer cells and VSMCs, respectively. Additionally, research on the involvement of TRIB2 in non-cancer cell proliferation is still relatively limited, and further exploration of its physiological and pathological functions in non-cancer cell proliferation needs to be strengthened.
While early progress has been made in developing small molecule inhibitors, natural products, and nanomaterials targeting TRIB2, this area remains in its infancy. See page 12, column 2, bridging to page 14 column 1.
It is noted that Zhang teaches the role of Daclatasvir (DCV) in the context of treating enzalutamide resistant prostate cancer, see page 10 of 17, column 1),
While Zhang teaches the role that TRIB2 plays with inhibitory effects of oncogenic cell proliferation as detailed pages 12-14 above, this teaching serves as lack of enablement for the prevention of all cancers, including all TRIB2 associated cancers. The prevention of all these cancers lack enablement, as Zhang states the impact of TRIB2 regulating intercellular interactions on cell proliferation should be further investigated, and where Zhang2 teaches the involvement of TRIB2 in non-cancer proliferation is still limited at this late stage post filing. These questions regarding TRIB2 in the context of both healthy and cancerous cell proliferation establishes the uncertainty of prevention of any and all cancers, including TRIB2 associated ones.
As readily apparent from Zhang, the unpredictability in the art not only weighs against the full scope of treating ALL cancers (except those otherwise recognized in the art such as prostate associated with TRIB2 and lung associated with TRIB2, as supported by Applicant’s working examples below) and the prevention of ALL cancers.
Note that prior art reference, Sultanik3 teaches a method of treating a patient population in need, with a specific DCV combination, suffering from a single type of rare non-Hodgkin’s-type lymphoma, MZL, where Sultanik does not make reference to TRIB2. However, the fact the specificity of Sultanik being limited solely to a combination of a daclatasvir (DCV) and sofosbuvir to treat MZL in a female subject, fails to enable the invention as broadly as claimed. This is due to the fact that as detailed below in the working examples section of the enablement rejection, any inventiveness of the claimed invention is based solely on DCV’s ability to modulate/inhibit TRIB2 in prostate and lung cancer demonstrated in vivo cell models.
The unpredictability of the art is a Wands factor against enablement of the full scope of claimed invention.
The breadth of the claims
The instant claims are deemed very broad since these claims read on treatment and prevention of any cancer, whether TRIB2 associated or not, and in part with claim 28 and those claims dependent, treatment of ANY TRIB2 associated cancer with DCV. Thus breadth of claims is a Wands factor against enablement of the full scope of the invention.
The amount of direction or guidance presented, and the presence or absence of working examples: It has been established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970).
It is pointed out Applicant fails to provide an in vivo to enable the full scope of the invention. A non-enabling reference to a prophetic Phase I dose escalation trial of DCV in patients with metastatic, enzalutamide resistant prostate cancer is noted. See Example 7, paragraph 222.
Example 1 of the specification notes that via high throughput screening identifies the HCV antiviral drug, daclatasvir (DCV) and NOT the HCV antiviral ledipasvir drug does not work to inhibit TRIB2. See starting at paragraph 162. See also Example 2 starting at paragraph 166. The in vitro cell model working examples of the specification are only all directed to the anti-tumor effects of DCV treatment in a prostate cancer cell model in terms of TRIB2 inhibition, (see Examples 3-6 starting at paragraph 170) and TRIB2 lung cancer model (Example 6, paragraph 220).
Also noted are the statements from the Written Opinion of the corresponding International Application (PCT/US2021/036038) this case takes priority from. It is clear Applicant’s working examples are limited specifically to TRIB2 with regard prostate cancer and lunger cancer in vitro. No vitro experiments are provided.
The Written Opinion notes coadministration of daclatasvir (DCV) and enzalutamide is contraindicated due to decreased daclatasvir exposure resulting in
potential loss of virologic control. See Item VIII I.4 “The data in the application as filed demonstrate the successful treatment ERPC [enzalutamide resistant prostate cancer] and lung cancer by daclatasvir. In both cancers, TRIB2 protein is overexpressed. There appears to be no data for the treatment of cancers in which TRIB2 is not overexpressed.”
Because of this and based off the limited in vitro working examples, the Written Opinion concludes the working examples clearly are limited to those cancers that overexpress TRIB2. See Viv (c) of the Written Opinion.
Therefore, in view of the Wands factors as discussed above, particularly the breadth of the claims to treat and/or prevent any cancer (outside of those associated with TRIB2, like prostate and lung); the state of the art and lack of amount of direction or guidance presented (no actual working examples directed to prevention of cancer in vivo in a clinical setting, or clinical examples to treat subjects and only in vitro examples directed to TRIB2 associated prostate and lung cancer), Applicant fails to provide information sufficient to practice the claimed invention as broadly claimed.
To be clear, in summary, Applicant’s invention is enabled solely to treatment of TRIB2 associated prostate and lung cancers with DCV.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sultanik et al. "Regression or an HGV-associated disseminated marginal zone lymphoma under IFN-free antiviral treatment", BLOOD, 9 April 20i 5 (20i 5-04-09), pages 2446-2447. Sultanik is cited as NPL Ref. 8 on the IDS dated Dec 5 2022.
Claim 1 is a method of preventing or treating cancer in a subject in need thereof, said method comprising administering a therapeutically effective amount of daclatasvir (DCV) to a subject suffering from cancer.
In terms of claim interpretation, this novelty rejection is limited to the subject matter of treating a specific cancer, MZL [Marginal Zone Lymphoma, a type of non-Hodgkin’s lymphoma, a cancer of the lymphatic system] with DCV in combination with sofosbuvir.5
With regard to the subject in need, Sultanik discloses a 57 year old woman presented with right breast swelling. See page 2, first column, first paragraph. ”A biopsy specimen of the [patient’s] breast revealed an extranodal MZL [Marginal Zone Lymphoma].” Id.
Sultanik teaches given the link between hepatitis C virus (HCV) infection and the indolent cause of lymphoma, the authors chose to initiate an antiviral treatment aiming for a possible hemato-oncologic improvement with HCV clearance. Id. A combination of sofosbuvir (400 mg per day) and ribavirin (1000 mg per day) was started, where at week 4 ribavirin was replaced with daclatasvir (DCV), i.e., a 12-week therapy of sofosbuvir and daclatasvir was conducted. Id. Sultanik notes this clinical case was first report of direct-acting antivirals, such as DCV in inducing cancer, lymphoma (MZL), remission. Id.
Regarding claim 3 where the subject is either treatment naïve or previously treated, as a patient can only be one or another, the subject of Sultanik anticipates claim 2.
Regarding claim 26 and the limitation where DCV is part of a combination therapy, Sultanik teaches DCV in combination with sofosbuvir. See page 2, col 1.
Regarding claim 27 where the treatment comprises (I) reducing tumor volume/burden in the subject; (ii) inhibiting tumor growth in a subject, as detailed by Sultanik, the treated subject was noted to undergo a complete clinical and radiological regression of breast, cervical ganglionic and humeral shaft lesions, where the patient remained in complete remission 6 months after the end of treatment. See page 2, col 1.
Claim Objections
Claim 3 is objected to for being both original and twice cancelled in the pending claim set. Examiner requests that Applicant’s delete the “cancelled” claim 3s.
Claims 30-31 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. NOTE: Upon future review of claims 30-31 as they presently stand, or as amended in the future, the Examiner reserves the right re-examine and re-evaluate their allowability through prosecution.
Conclusion and Correspondence
In summary, claims 1-6 and 21-29 are rejected, claims 30-31 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/US2021/036038 06/04/2021
PCT/US2021/036038 has PRO 63/035,353 06/05/2020
2 Zhang et al. The role of tribbles homolog 2 in cell proliferation. Cell Commun Signal 23, 5 (2025). https://doi.org/10.1186/s12964-024-01985-0
3 See below novelty rejection of claims 1, 3 and 26-27.
4 The post-published document D1 [“Enzalutamide - Drug Summary”] discloses that coadministration of daclatasvir and enzalutamide is contraindicated due to decreased daclatasvir exposure resulting in
potential loss of virologic control. Daclatasvir is a CYP3A4 substrate; enzalutamide is a
strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer reduced the
daclatasvir AUC by 79% (page 7, paragraph 18).
A similar analysis is made with the European Search Report of corresponding application EP 21 736 129, see Section 2.1. However, while the ESR requires a showing of in vivo data, the conclusion drawn here is that limiting the claims here to TRIB2 associated prostate and lung cancer is sufficient to demonstrate the claims are enabled.
Reference D1 is Anonymous: "enzalutamide - Drug Summary", Prescribers' digital reference, 29
September 2021 (2021-09-29), pages 1-21, XP055845917, Retrieved from the Internet:
URL:https://www.pdr.net/drug-summary/Xtandi-enzalutamide-2590
[retrieved on 2021-09-29]
5 As detailed above in the scope of enablement rejection, Sultanik cannot fully enable the treatment of cancers beyond TRIB2 associated prostate or lung cancer, or enable the prevention of any cancers, see above.