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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on December 18, 2025 are acknowledged. Claims 2, 11, and 17-33 have been canceled. Claims 1, 3-10, 12-16, and 34 are pending.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology ("e.g." stands for "exempli gratia", and should be removed or replaced with a non-Latin version, such as "for example"). In addition, the abstract is less than 50 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112
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.
Enablement
Claims 1, 3-10, 12-16, and 34 are 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.
Breadth of claims and nature of the invention:
Claims 1, 3-10, 12-16, and 34 are drawn to a method of treating a human subject comprising administering an isolated inhibitory nucleic acid targeting INCA1 wherein the isolated inhibitory nucleic acid is an antisense oligonucleotide and comprises SEQ ID NO: 8 wherein the subject has melanoma, breast cancer, or brain cancer (emphasis added).
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Noch et al. (World Neurosurgery 2018) discloses that the blood brain barrier has long been a source of difficulty for the delivery of therapeutic agents to treat glioblastoma and other central nervous system (CNS) malignancies [page 505, right column, last paragraph bridging to page 506, left column]. Noch et al. also discloses that glioblastoma is an extremely complex disease that resists therapeutic agents through a highly evolved mechanism to recognize and adapt to ongoing threats. Further, Noch et al. discloses that glioblastoma stem cells are highly therapy-resistant [page 512, right column, last paragraph].
Tong et al. (Frontiers in Oncology 2018) discloses that breast cancer is the most common malignancy in women and is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. The emergence of drug resistance poses a threat to the successful development of targeted therapy in various molecular subtypes of breast cancer [abstract]. Further, Tong et al. discloses that one of the major challenges for breast cancer treatment is its heterogeneous nature which determines the therapeutic options [page 1, first paragraph].
Merlino et al. (Pigment Cell & Melanoma Research 2016) discloses that there still remains the need for high quality clinical and translational research because little is known about how best to match patients to therapies with the greatest probability of promoting long term disease control in addition to overcoming resistance to existing therapies [page 413, right column, last paragraph]. Merlino et al. also discloses that clinical therapy for melanoma is ripe with challenges. One low-hanging fruit is the need for clinical interrogation of alternative dosing strategies for currently available agents [page 415, left column, first full paragraph]. Further, heterogeneity within and between tumors presents a significant challenge for overcoming resistance to therapies [page 415, right column, second full paragraph].
Jue et al. (Journal of Neuro-Oncology 2016) discloses that glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. The specific challenges for establishing a personalized molecular targeted medicine program for GBM patients include overcoming the blood brain barrier, unravelling the intra-and inter-heterogeneity that exists and the importance of developing more relevant animal models that recapitulate a patient’s GBM tumor [abstract]. Jue et al. also discloses the need for pre-clinical models to validate the efficacy of novel/repurposed drugs and drug combinations is critical. Further, the use of patient-derived cell lines to produce orthotopic xenograft models is highly advisable to give the most accurate prediction of how a drug will affect a patient’s tumor [page 432, left column, first full paragraph].
Dobrolecki et al. (Cancer Metastasis Review 2016) discloses that with respect to basic and translational research, the existence of disease heterogeneity, both within and among breast cancers, there are significant challenges to the generation and use of relevant preclinical models that represent the full spectrum of breast disease [page 549, left column, first full paragraph].
Mak et al. (Am J Transl Res 2014) discloses that although animal models play a large role in the evaluation of efficacy and safety of new cancer interventions, genetic, molecular, and physiological limita-tions often hinder their utility. Despite success-ful pre-clinical testing, 85% of early clinical tri-als for novel drugs fail; of those that survive through to phase III, only half become approved for clinical use [page 114, left column, last paragraph bridging to right column]. Mak et al. also discloses that the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is generally not translated to human trials [abstract].
Therefore, there is insufficient reason to believe that one of skill could treat melanoma, breast cancer, or brain cancer by targeting INCA1. Furthermore, as evidenced by Mak et al., there is unpredictability in translating the results obtained from animal models to clinical trials in cancer treatment.
Amount of direction provided by the inventor and existence of working
examples:
The specification as filed discloses that cancers evaluated or treated by the methods described include epithelial cancers, such as lung cancer, breast cancer, colorectal cancer, kidney cancer, head and neck cancer, prostate cancer, pancreatic cancer, or ovarian cancer [page 13, second full paragraph].
The instant specification discloses that shRNAs were used to generate stable knockdown of INCA1 in the U251 GBM cell line [page 65, lines 6-7]. Furthermore, silencing INCA1 expression in PDGCLs using gapmers resulted in a 5 to 7-fold reduction in PD-L1 expression [page 65, lines 24-25].
The instant specification discloses using an antisense oligonucleotide with 2’-O-methoxyethyl modifications targeting the HNRNPH1 binding site (ASO H1B; SEQ ID NO: 8) to reduce the interaction of INCA1 with HNRNPH1 in cells in vitro. Further, to study the effect of ASO H1B in vivo, A375 melanoma cells were transfected with ASO H1B. The instant specification also discloses that although changes in INCA1 and PD-L1 RNA levels were not observed, ASO H1B significantly reduced INFƔ-stimulated PD-L1 protein expression. Significant change of JAK2 was also observed at mRNA and protein levels. Therefore, the results indicate that INCA1 specifically interacts with HNRNPH1 and blocking the interaction affects PD-L1 and JAK2 expression [page 69, lines 10-21].
The working example discloses using a mouse model to determine whether INCA1 knockdown improves CAR T cell function in vivo. The results show that INCA1 plays a functional role in controlling tumor IFNƔ signaling and its knockdown leads to increased susceptibility of human tumor cells to T cell-mediated killing [page 66, last paragraph bridging to page 67].
Quantity of experimentation:
In view of the nature of the invention, the state and level of predictability in the art, the lack of working examples to show treatment of any cancer, and the failure to provide adequate guidance to overcome the state and level of predictability in the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
In In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Response to Arguments
Applicant's arguments filed December 18, 2025 have been fully considered but they are not persuasive.
Applicant asserts that in view of the data in the application, the claimed ASO comprising SEQ ID NO: 8 would be expected to have a therapeutic effect in the treatment of a cancer that is associated with modulation of PD-L1 and JAK2 expression. Applicant also asserts that Example 1 demonstrates that INCA1 knockdown in U251 glioblastoma cells with short hairpin RNAs resulted in reduced expression of JAK2 and PD-L1 and downregulation of PD-L1 and JAK2 protein levels. Applicant also asserts that Example 1 demonstrates knockdown of INCA1 in melanoma cells with SEQ ID NO: 8 significantly changed the expression of PD-L1 and JAK2 proteins. Therefore, Applicant asserts that this provides evidence that targeting INCA1 with an inhibitory nucleic acid comprising SEQ ID NO: 8 can provide a therapeutic effect by resulting in reduction of the protein levels of JAK2 and PD-L1. Applicant asserts that the specification discloses that the shRNAs and gapmers target INCA1 by hybridizing to INCA1 and activating an RNase H pathway in the cell thereby inducing substantial cleavage or degradation of the INCA1 RNA in the cell. Therefore, the claimed ASO H1B targets INCA1 and reduces protein levels of JAK2 and PD-L1 like the shRNA and gapmers albeit by a slightly different mechanism. Thus, one skilled in the art would expect the ASO H1B to provide a therapeutic effect in other cancers that are also characterized by upregulation of PD-L1 and JAK2.
These arguments are not found persuasive. The claims are drawn to a method of treating a human subject in need thereof comprising administering an isolated inhibitory nucleic acid targeting INCA1 wherein the isolated inhibitory nucleic acid is an antisense oligonucleotide and comprises SEQ ID NO: 8. However, the instant specification discloses that shRNAs were used to generate stable knockdown of INCA1 in the U251 GBM cell line [page 65, lines 6-7] and gapmers were used to silence INCA1 expression in PDGCLs [page 65, lines 24-25]. Page 69, lines 16-17 discloses that changes in INCA1 and PD-L1 RNA levels were not observed. Thus, suggesting a different mechanism than the shRNA and gapmer discussed above and that the same effect would not be obtained with the antisense oligonucleotide as with the shRNA or gapmer. Furthermore, the state of the art in translating pre-clinical results to actual therapy at the time was such that challenges existed for the treatment of melanoma, breast cancer, and brain cancer.
Applicant asserts that the specification provides ample description relating to pharmaceutical compositions comprising inhibitory nucleic acids targeting INCA1 as well as suitable dosages. Thus, a person of ordinary skill in the art would have sufficient direction to determine effective dosages without undue experimentation.
This argument is not found persuasive. The specification discloses the following
PNG
media_image1.png
252
682
media_image1.png
Greyscale
PNG
media_image2.png
614
678
media_image2.png
Greyscale
[page 47, first, second, and third full paragraphs]. The specification further discloses the following
PNG
media_image3.png
196
646
media_image3.png
Greyscale
[page 48, first full paragraph]. However, the specification does not provide sufficient guidance for one of skill to know what level of inhibition is required in order to obtain a therapeutic effect given the uncertainty in the art.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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, Jennifer Dunston can be reached on (571) 272-2916. 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.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637