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 .
Response to Amendment
The amendments filed 2 October 2025 is acknowledged. Claims 2, 3, 10, and 19 are amended. Claims 5, 9, and 11-15 are canceled. Claims 2-3, 10, 16-20, 23, 28-30, and 32 are pending.
Election/Restrictions
As previously noted, the response to the restriction/election requirement filed 5/2/2025 is acknowledged. Applicant elects, without traverse, Group I (claims 2, 3, 5, and 9-15), directed to a method of treating cancer comprising administering a therapeutically effective amount of an agent that modifies the neoantigen profile of the cancer by increasing intron retention or the stability of a retained intron.
Claims 16-20, 23, 28-30, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.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 5/2/2025.
Claim Status
Claims 1, 4-9, 11-15, 21-22, 24-27, and 31 are cancelled. Claims 2-3, 10, 16-20, 23, 28-30, and 32 are pending. Claims 16-20, 23, 28-30, and 32 are withdrawn as being directed to a non-elected invention as described above. Claims 2, 3, and 10 are under examination in the instant office action.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). However, claims 2, 3, and 10 do not properly benefit under §119 and/or 120 by the earlier filing dates of the priority documents claimed, since those claims are rejected under 35 U.S.C. 112(a) as lacking adequate description and a sufficiently enabling disclosure.
To receive benefit of the earlier filing date under §§ 119 and/or 120, 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 the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). See M.P.E.P. § 201.11.
Accordingly, the effective filing date of the claims is deemed the filing date of the instant application, namely 22 October 2021.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawal of Objections
The objections to the drawings are withdrawn in view of the amendments to the drawings and the specification.
The objection to the specification for informalities is withdrawn in view of the amendments to the specification.
The objection to the specification for improperly demarcated trademarks or tradenames is withdrawn in view of the amendment to the specification.
Withdrawal of Rejections
The rejection of claims 2, 3, 5, and 9-15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as being indefinite is withdrawn in view of the amendment to the claims and applicant’s arguments (Remarks 10/2/2025 p. 9).
The rejection of claims 2-3, 5, and 11-13 under 35 U.S.C. 102(a)(1) as being anticipated by Barbash et. al. as evidenced by Lee MKC, et. al. (Of Record, PTO-892 dated 3/19/2025) is withdrawn in view of the amendment to the claims.
The rejection of claims 14 and 15 under 35 U.S.C. 103 as being unpatentable over Barbash et. al. as evidenced by Lee et. al. (Of Record) is withdrawn in view of the amendment to the claims.
The rejection of claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over WO2018100535 to Barbash et. al (cited in IDS dated 10/22/2021) as evidenced by Lee et. al., and further in view of WO2019232449 to Pazolli et. al is withdrawn in view of the amendment to the claims.
The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over WO2018100535 to Barbash et. al. published 07 June 2018 (cited in IDS dated) as evidenced by Lee et. al. and WO2019232449 to Pazolli et. al. (effectively filed 01 June 2018), and further in view of Lauss M, et. al., Seliktar-Ofir S, et. al. and Keskin DB, et. al. is withdrawn in view of the amendment to the claims.
Specification- Maintained, changes necessitated by amendment
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Hyperlinks are found at: p. 22 line 14 (amended p. 22 line 25) , p. 51 line 19 (amended p. 53 line 1), p. 56 line 9 (amended p. 59 line 13). The examiner recommends deleting the browser executable code “http://” or “https://”.
Claim Rejections - 35 USC § 112(a)- Written Description- Maintained, changes necessitated by amendment
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 2, 3, and 10 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Scope of the claimed genus
Claim 2, 3, and 10 recite a method of treatment comprising a genus of agents, wherein the agents are only defined by function and the designation of being a small molecule. The agent “modifies the neoantigen profile of [a cancer] […] by increasing intron retention in a cancer cell or increasing stability of one or more retained introns in a cancer cell” and the agent “is a small molecule protein arginine N-methyltransferase 5 (PRMT5) inhibitor” (claim 2). Claim 3 recites broadly that the agent modifies the neoantigen profile by increasing the number of neoantigens present on the cancer cell. The claims do not require that the small molecule inhibitor of PRMT5 directly or specifically inhibit PRMT5. For example, PRMT5 is regulated by growth factors and modulates ERK1/2 signal amplitude in response to specific growth factors via interaction with CRAF (Pedro Andreu-Pérez et al. ,Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF. Sci. Signal.4,ra58-ra58(2011).DOI:10.1126/scisignal.2001936); therefore, a small molecule EGFR inhibitor would also be expected to inhibit PRMT5.
Additionally, claims 2 and 10 are directed towards identifying one or more neoantigens expressed by the retained introns; and administering to the patient one or more of the identified neoantigens. Regarding claim 10, the claim is further directed towards a method comprising expanding in vitro isolated T cells that have affinity.
State of the Relevant Art
Regarding methods of treatment using agents that modify the intron retention to increase the neoantigen expression of a cancer, there are examples in the art. For example, WO2020157760 to Levanon et. al. (effectively filed 31 January 2019, PTO-892 dated 06/02/2025) teaches a method of treating cancer comprising administering splicing modulating agents, specifically antisense oligonucleotides (ASOs) and gene editing compounds design to induce aberrant splicing events, including intron retention, resulting in immunogenic protein products and methods of enhancing immunotherapy (Abstract, p. 18 para. 2, p. 62-63, p. 72 para. 2, p. 82 last para). WO2019232449 to Pazolli et. al. (effectively filed 01 June 2018, PTO-892 dated 06/02/2025) teaches antibody-drug conjugates comprising a pladienolide or pladienolide derivate payload, which acts as a splicing modulator to a tumor and results in novel mRNA splicing including intron retention, resulting in novel neoantigens (Abstract, [769-773]). The nucleic acids of Levanon et. al. and the ADC comprising the small molecule pladienolide payload represent vastly different inventions with different mechanisms of action that are all included in the instant scope of the agent that increases neoantigen expression by increasing intron retention.
Regarding PRMT5 inhibitors, methods of treating cancer with PRMT5 inhibitors are known in the art. For example, U.S. Patent No. 11485731 (PTO-892 dated 06/02/2025) teaches a compound of Formula I or salts, solvate, or hydrates thereof that inhibits PRMT5 and methods of treating cancer by administering Formula I (Abstract, claim 1, [16-18]). Although not prior art, Tang, Yixuan, et al. "Design, synthesis and biological evaluation of novel and potent protein arginine methyltransferases 5 inhibitors for cancer therapy." Molecules 27.19 (2022): 6637 teaches design and synthesis of small molecule inhibitors or PRMT5 and discloses representative structures of known PRMT5 inhibitors (Fig. 1). It is clear from the dissimilarities between the structures (GSK-3326595 and JNJ-6419718, for example) that many disparate structures could perform the function of PRTM5 inhibitor, and that an artisan would not be able to envision the entirety of the genus just from the instant functional description.
Regarding identifying and administering neoantigens identified after administering the neoantigen-inducing agent of claim 2, the neoantigens themselves created by these vastly different agents and how they are identified as such would itself be a different genus of peptides for each agent, cancer, and patient combination. For example, WO2018183544 to Van Allen et. al. (Of Record, cited in IDS dated 10/22/2021) teaches a method of identifying neoantigens by performing RNA sequencing on tumor tissue to identify retained intron transcripts, selecting the transcripts based on expression level, then translating the retained intron into retained intron peptides using open reading frame orientation obtained from a genomic database. Additionally, subject specific HLA-alleles are analyzed, and then binding affinities of the retained intron peptides are predicted by a binding affinity threshold (Abstract, entire document). Further, the reference Kreiter et al (Nature (2015) 520(7549): 692-696, PTO-892 dated 06/02/2025) teaches a subpopulation of known cancer antigen epitopes but also teaches that less than half of the cancer-associated mutations tested are immunogenic. Specifically, 66% of 50 B16F10 mutations immunized with peptide were non-immunogenic (see Figure 1b), 79% of 96 CT26 mutations immunized with RNA were non-immunogenic (see Figure 1c), and 55% of 38 4T1 mutations immunized with RNA were non-immunogenic (see Figure 1d). Therefore, merely identifying cancer-associated gene mutations does not mean the mutation will be an effective immunogenic antigen for a claimed neoepitope administered in a method of treating cancer.
Additionally, Guo Y, Lei K, Tang L. Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy. Front Immunol. 2018 Jul 2;9:1499. doi: 10.3389/fimmu.2018.01499. PMID: 30013560; PMCID: PMC6036114 (PTO-892 dated 06/02/2025) teaches that cancer neoantigens are an attractive target for cancer immunotherapies (Abstract). However, Guo et. al. teaches “Many efforts are currently focused on addressing two key challenges in the development of neoantigen-based cancer vaccines for wide clinical applications. First, immunogenic neoantigens are rare and difficult to predict. Current predictive algorithm and validation tools need to be optimized for accurate prediction of major histocompatibility complex (MHC)-binding peptides and reliable selection of highly immunogenic neoepitopes (18)” (Introduction, p. 2 Col. 1 para. 2). Guo et. al. teaches that the reliability of predictive algorithms needs to been improves and that they are not able to account for every factor such as peptide processing and MHC binding stability (“Identification and Selection of Neoantigens” section, p. 2 Col 1 para. 3-Col. 2 para. 2).
Summary of Species disclosed in the original specification
In support of the claimed genera of agents that modify neoantigen or expression the specification discloses methods of increasing intron retention in cancer cell lines by contacting with the PRMT5 inhibitor EPZ015666 (alternatively named GSK3235025 and CAS Number 1616391-65-1)(Specification p. 22 lines 32-38, Examples “Chromatin-associated E2F1 binds to components of the splicing machinery” section p. 49). This inhibitor is contacted with three types of cancer cell lines, HCT116, U2OS, and MCF7 (p. 29 lines 24-26). However, there are no other working examples from Applicant’s disclosures in which any other agents, small molecules were tested. The specification also prophetically recites the PRMT5 inhibitors of WO 2018167276 of the general structure of formula (I) (p. 30-37).
Regarding neoantigens caused by intron retention, Fig 1B panel D demonstrates a number of neoantigens identified without reciting the gene names or sequences of the identified neoantigens. The specification also identifies a few candidates in the genes SENP7 and MECOM (Fig. 4; Fig. 5; Fig. 11); however, there is no data in the specification to suggest that these particular transcripts with retained introns 1) are translated into peptides; 2) bind to MHC; or 3) are expressed on the surface of a cancer cell. There are no methods disclosed comprising administering any agent as described to any subject, or any working examples of methods of treatment. One of ordinary skill in the art would not immediately recognize that the claimed expansive genera of agents and co-administered neoantigens would be able to perform the claimed function of treating cancer based on the specification.
The data generated as described in the specification cannot be reasonably extrapolated and applied to support possession of the entire claimed genus of neoantigen modifying agents or co-administered neoantigens, because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that: The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed derivatives, analogs, etc., regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only the above structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 USC § 112, first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for PRTM5 inhibitors that modify the neoantigen profile of a cancer by increasing intron retention, and therefore the applicant is not in possession of the full scope of a method of treating comprising administering an agent wherein the agent is a PRMT5 inhibitor that modifies the neoantigen profile of a cancer. There is a lack of an appropriate number of species shown to perform the function of increasing intron retention and methods of treatment comprising administering those agents. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of neoantigen modifying agents of claim 2. Regarding claims 3 and 10 the claims are ultimately dependent on the rejected claim 2 without sufficiently narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement- Maintained, changes necessitated by amendment
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(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.
The following is an analysis of these factors in relationship to this application.
Claim 2, 3, and 10 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 a method of treating cancer comprising administering particular small molecule inhibitors of PRMT5, does not reasonably provide enablement for a method of treating cancer comprising any generic PRMT5 inhibitor that modifies the neoantigen profile of a cancer by increasing intron retention or stabilizing a retained intron and administering any neoantigen identified therefrom. 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.
Scope of the claimed genus and nature of the invention
As described in the written description rejection above, claims 2, 3, and 10 recite a method of treatment comprising a genus of agents, wherein the agents are only defined by function and the designation of being a small molecule. The agent “modifies the neoantigen profile of [a cancer] […] by increasing intron retention in a cancer cell or increasing stability of one or more retained introns in a cancer cell” and the agent “is a small molecule protein arginine N-methyltransferase 5 (PRMT5) inhibitor” (claim 2). Claim 3 recites broadly that the agent modifies the neoantigen profile by increasing the number of neoantigens present on the cancer cell. The claims do not require that the small molecule inhibitor of PRMT5 directly or specifically inhibit PRMT5. For example, PRMT5 is regulated by growth factors and modulates ERK1/2 signal amplitude in response to specific growth factors via interaction with CRAF (Pedro Andreu-Pérez et al. ,Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF. Sci. Signal.4,ra58-ra58(2011).DOI:10.1126/scisignal.2001936); therefore, a small molecule EGFR inhibitor would also be expected to inhibit PRMT5.
Additionally, claims 2 and 10 are directed towards identifying one or more neoantigens expressed by the retained introns; and administering to the patient one or more of the identified neoantigens. Regarding claim 10, the claim is further directed towards a method comprising expanding in vitro isolated T cells that have affinity.
State of the Relevant Art; the level of one of ordinary skill; and the level of predictability in the art
Regarding agents that modify the neoantigen expression in cancer by increasing intron retention in cancer, this is a prophetic genus defined by function. Some examples of agents that increase intron retention are known in the art to be of use to treat cancer. For example, WO2020157760 to Levanon et. al. (effectively filed 31 January 2019) teaches a method of treating cancer comprising administering splicing modulating agents, specifically antisense oligonucleotides (ASOs) and gene editing compounds design to induce aberrant splicing events, including intron retention, resulting in immunogenic protein products and methods of enhancing immunotherapy (Abstract, p. 18 para. 2, p. 62-63, p. 72 para. 2, p. 82 last para). WO2019232449 to Pazolli et. al. (effectively filed 01 June 2018) teaches antibody-drug conjugates comprising a pladienolide or pladienolide derivate payload, which acts as a splicing modulator to a tumor and results in novel mRNA splicing including intron retention, resulting in novel neoantigens (Abstract, [769-773]). The nucleic acids of Levanon et. al. and the ADC comprising the small molecule pladienolide payload represent vastly different inventions with different mechanisms of action that are all included in the instant scope of the agent that increases neoantigen expression by increasing intron retention. Thus, the scope of the claims includes agents that have not yet been invented that may modify the neoantigen profile cancer by unknown mechanisms of increasing or stabilizing retained introns.
Regarding the PRMT5 inhibitors of claim 2, methods of treating cancer with PRMT5 inhibitors are known in the art. For example, U.S. Patent NO. 11485731 teaches a compound of Formula I or salts, solvate, or hydrates thereof that inhibits PRMT5 and methods of treating cancer by administering Formula I (Abstract, claim 1, [16-18]). Although not prior art, Tang, Yixuan, et al. "Design, synthesis and biological evaluation of novel and potent protein arginine methyltransferases 5 inhibitors for cancer therapy." Molecules 27.19 (2022): 6637 teaches design and synthesis of small molecule inhibitors or PRMT5 and discloses representative structures of known PRMT5 inhibitors (Fig. 1). It is clear from the dissimilarities between the structures (GSK-3326595 and JNJ-6419718, for example) that many disparate structures could perform the function of PRTM5 inhibitor. Thus, the claimed genus of methods includes administering PRMT5 inhibitors with disparate structures that have yet to be invented.
Regarding identifying and administering neoantigens identified after administering the neoantigen-inducing agent of claim 2, the neoantigens themselves created by these vastly different agents and how they are identified as such would itself be a different genus of peptides for each agent, cancer, and patient combination. Additionally, intron retention was known in the art to modify the neoantigen profile of cancer. Smart AC, et. al. Intron retention is a source of neoepitopes in cancer. Nat Biotechnol. 2018 Dec;36(11):1056-1058. doi: 10.1038/nbt.4239. Epub 2018 Aug 16. PMID: 30114007; PMCID: PMC6226333 (PTO-892 dated 06/02/2025) teaches an in silico approach to identify retained intron (RI) neoepitopes derived from intron retention events in tumor transcriptomes (Abstract) and that a representative cancer cell lines displayed a subset of the predicted RI neoepitopes as detected by mass spectrometry (Fig. 2).
WO2018183544 teaches a method of identifying neoantigens by performing RNA sequencing on tumor tissue to identify retained intron transcripts, selecting the transcripts based on expression level, then translating the retained intron into retained intron peptides using open reading frame orientation obtained from a genomic database. Additionally, subject specific HLA-alleles are analyzed, and then binding affinities of the retained intron peptides are predicted by a binding affinity threshold (Abstract, entire document). Further, the reference of Kreiter et al (Nature (2015) 520(7549): 692-696) teaches a subpopulation of known cancer antigen epitopes but also teaches that less than half of the cancer-associated mutations tested are immunogenic. Specifically, 66% of 50 B16F10 mutations immunized with peptide were non-immunogenic (see Figure 1b), 79% of 96 CT26 mutations immunized with RNA were non-immunogenic (see Figure 1c), and 55% of 38 4T1 mutations immunized with RNA were non-immunogenic (see Figure 1d). Therefore, merely identifying cancer-associated gene mutations does not mean the mutation will be an effective immunogenic antigen for a claimed method of treating cancer comprising administering the neoantigen.
Additionally, Guo Y, Lei K, Tang L. Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy. Front Immunol. 2018 Jul 2;9:1499. doi: 10.3389/fimmu.2018.01499. PMID: 30013560; PMCID: PMC6036114 teaches that cancer neoantigens are an attractive target for cancer immunotherapies (Abstract). However, Guo et. al. teaches “Many efforts are currently focused on addressing two key challenges in the development of neoantigen-based cancer vaccines for wide clinical applications. First, immunogenic neoantigens are rare and difficult to predict. Current predictive algorithm and validation tools need to be optimized for accurate prediction of major histocompatibility complex (MHC)-binding peptides and reliable selection of highly immunogenic neoepitopes (18)” (Introduction, p. 2 Col. 1 para. 2). Guo et. al. teaches that the reliability of predictive algorithms needs to been improves and that they are not able to account for every factor such as peptide processing and MHC binding stability (“Identification and Selection of Neoantigens” section, p. 2 Col 1 para. 3-Col. 2 para. 2).
Conclusion
It would take undue experimentation for a person of ordinary skill in the art to perform a method of treatment comprising any generic or undefined PRMT5 inhibitor that modifies the neoantigen profile of a cancer by increasing intron retention or by stabilizing a retained intron. Additionally, it would take undue experimentation for a person of ordinary skill in the art to perform a method of treatment of cancer further comprising administering any one or more neoantigens caused by RI. Thus, the methods of treatment of cancer comprising any agent as described as not enabled.
Response to arguments (112a Written Description and Enablement)
Applicant argues that as amended, the claims are sufficiently described and enabled. This is unpersuasive as described in the written description and scope of enablement rejections above. To summarize briefly, applicant claims a genus of methods of treating where the PRMT5 inhibitor is described by function with only one species disclosed and no structure/function relationship described and method of treating comprising administering a neoantigen where no neoantigens have been described structurally and there is unpredictability in whether or not administering a neoantigen is sufficient to induce an immune response against cancer. Regarding scope of enablement, each compound would have to be tested for the method of treating cancer because it would have been unpredictable which members of the genus of compounds would cause increased intron retention and expression of neoantigens as described, and of these each neoantigen would have to be tested individually as a therapy for cancer to determine whether it can stimulate an anti-tumor immune response. Therefore, as described in the rejections above, the amended claims 2, 3, and 10 are not described or enabled.
Claim Rejections - 35 USC § 103- New, necessitated by amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over WO2018100535 to Barbash et. al. published 07 June 2018 (cited in IDS dated 10/22/2021) as evidenced by Lee et. al. PRMT5: An Emerging Target for Pancreatic Adenocarcinoma. Cancers (Basel). 2021 Oct 13;13(20):5136. doi: 10.3390/cancers13205136. PMID: 34680285; PMCID: PMC8534199 (Of Record, PTO-892 dated 3/19/2025), and further in view of WO2019232449 to Pazolli et. al. (effectively filed 01 June 2018) (Of Record, PTO-892 dated 06/02/2025).
Regarding claims 2 and 3, Barbash et. al. teaches a method of treating cancer in a patient comprising administering a Type II PRMT inhibitor such as a PRMT5 inhibitor and an immuno-modulatory agent (Abstract, p. 13 lines 7-12 and lines 20-25). Barbash et. al. teaches a method of treating a colon carcinoma and lymphoma mouse model mice with a combination of Compound C, a PRMT5 inhibitor, and an OX-40 antibody. Barbash et. al. teaches “Treatment of A20 xenograft tumors with the combination of anti-OX-40 antibody and Compound C resulted in moderate survival advantage, highlighting the potential synergistic interaction between two agents” (Example 2 p. 111 and Fig. 28 and 29). Barbash further teaches that the PRMT5 inhibitors resulted in a retention of introns (p. 100 lines 1-24, Fig. 14). As evidenced by Lee et. al., the method of Barbash et. al. comprising treatment with a PRMT5 inhibitor would inherently increase neoantigen expression in cancer cells because PRMT5 inhibition increases neoantigen expression via perturbation of alternative splicing and increased MHC class I expression (See “PRMT5 Inhibition and Its Implications for Tumour Microenvironment” section, para 3).
Barbash et. al. teaches a method of treating with a small molecule PRMT5 inhibitor (reads on a), d), and e)).
Barbash et. al. teaches the method of treating in combination comprising administering the PRMT5 inhibitor and an OX-40 antibody (Example 2 p. 111 and Fig. 28 and 29), which is a checkpoint inhibitor (reads on claims 12-13).
Barbash et. al. does not teach a method of claim 2 wherein said method comprises administering the agent to the patient, identifying retained introns in RNA transcripts from one or more cancer cells from the cancer patient to whom the agent has been administered, identifying one more neo-antigens expressed by the retained introns, and administering to the patient one or more of the identified neo-antigens.
This deficiency is resolved by Pazolli et. al.
Regarding claims 2 and 3, Pazolli et. al. teaches a method of treating neoplastic disorders (reads on the instant cancer) comprising administering antibody-drug conjugates comprising a splicing modulator in order to induce a neoantigen-based immune response by increasing neoantigens in the cancer (Abstract, [02-06], [767-768]). The increased neoantigens are caused by modulation of splicing causing intron retention ([05-06], [769], [809], [1215]). The method also includes administering at least one additional therapy, including a combination of the splicing modulator and one or more checkpoint inhibitors [773]. In some embodiments, neoantigens can be used to monitor the effectiveness of treatment with a splicing modulator: “For instance, after administration of a splicing modulator, ADC, or composition, a patient sample (e.g., a tumor biopsy) can be obtained and screened for neoantigens or for identifiers of an immune or inflammatory response. Further treatment can be provided, e.g., at reduced dosage, if a neoantigen and/or immune response is detected” [774]. Explicitly, Pazolli teaches a method comprising administering ADCs comprising a splicing modulator to an NCI-N87 xenograft model of gastric carcinoma and subsequent detection of TAOK1 (neojunction transcript) via isolation of tumors and RNA extraction followed by RT-qPCR ([1252], Fig. 24). Pazolli et. al. also teaches “Patients may be evaluated for the levels of target antigen in a given sample (e.g. the levels of target antigen expressing cells) in order to assist in determining the most effective dosing regimen, etc. An exemplary embodiment is a method of determining whether a patient will be responsive to treatment with an ADC of the present disclosure, comprising providing a biological sample from the patient and contacting the biological sample with the ADC. Exemplary biological samples include tissue or body fluid, such as an inflammatory exudate, blood, serum, bowel fluid, stool sample, or tumor biopsy (e.g., a tumor biopsy derived from a patient having or at risk of a target antigen expressing cancer, e.g., a HER2-expressing cancer, a CD138-expressing cancer, an EPHA2-expressing cancer). In some embodiments, a sample (e.g., a tissue and/or body fluid) can be obtained from a subject, and a suitable immunological method can be used to detect and/or measure protein expression of the target antigen […] Such evaluations are also used for monitoring purposes throughout therapy, and are useful to gauge therapeutic success in combination with the evaluation of other parameters” [760]. Pazolli teaches “In some embodiments, treatment can comprise a combination of administering the splicing modulator, ADC, or composition to induce a neoantigen-based immune response and one or more neoantigen vaccines” [773] … “In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide […] In some embodiments, the at least one neoantigen peptide comprises one or more than one neoantigen sequence” [803]. “The term “personalized” when used to describe a neoantigen vaccine refers to a vaccine created by identifying one or more neoantigens produced in a patient, preferably one identified in the patient after an exposure to a splicing modulator, ADC, or composition, and then using one or more of those neoantigens as the basis of the vaccine for the same patient. Accordingly, in some embodiments, a patient is given a splicing modulator, ADC, or composition and screened for neoantigens produced by the treatment. In some embodiments, the selected neoantigen vaccine comprises a neoantigen peptide or mRNA disclosed herein and confirmed to be present in the patient after exposure to the splicing modulator, ADC, or composition. In some embodiments, the splicing modulator, ADC, or composition and/or peptide or mRNA vaccine may be administered to the patient once or repeatedly. Subsequently, in some embodiments, one or more of those neoantigens are used to create a personalized vaccine that is given to the patient. In some embodiments, the one or more neoantigens used to create a personalized vaccine possess binding affinity for one or more patient-specific HLA alleles. In some embodiments, the patient expresses one or more MHC1 alleles that bind to the one or more neoantigens. The prediction of whether a given neoantigen will bind to a specific MHC1 allele can be determined using any computational prediction method known in the art. Exemplary computational prediction methods are disclosed, e.g., in Meydan et al. (2013) BMC Bioinformatics 14(Suppl. 2):S13, which is incorporated herein by reference for such methods” ([812], also see [816]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to practice the method of administering a splicing modulator to a patient that induces intron retention and neoantigen expressing; identifying neoantigen transcripts from a patient sample obtained from the patient to whom the splicing modulator has been administered; identifying one or more neoantigens expressed by the retained introns; and administering to the patient the one or more identified neo-antigens as taught by Pazolli et. al. using the PRMT5 inhibitor effective for the treatment of cancer via splice site modulation (including induction of intron retention) as taught by Barbash et. al. This would have a predictable effect because an artisan reading Barbash et. al. in view of Pazolli et. al. would expect a splicing modulator used for the treatment of cancer that modifies intron retention (the PRMT5 inhibitor of Barbash et. al.) to increase neoantigen expression as taught by Pazolli et. al. and be useful in the method of Pazolli et. al.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over WO2018100535 to Barbash et. al. published 07 June 2018 (cited in IDS dated) as evidenced by Lee et. al. and in view of WO2019232449 to Pazolli et. al. (effectively filed 01 June 2018) as applied to claim 2 above, and further in view of Lauss M, et. al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat Commun. 2017 Nov 23;8(1):1738. doi: 10.1038/s41467-017-01460-0. PMID: 29170503; PMCID: PMC5701046 (published 23 November 2017, PTO-892 dated 06/02/2025), Seliktar-Ofir S, et. al. Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation. Front Immunol. 2017 Oct 10;8:1211. doi: 10.3389/fimmu.2017.01211. PMID: 29067023; PMCID: PMC5641376 (published 10 October 2017, PTO-892 dated 06/02/2025) and Keskin DB, et. al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019 Jan;565(7738):234-239. doi: 10.1038/s41586-018-0792-9. Epub 2018 Dec 19. PMID: 30568305; PMCID: PMC6546179 (published 19 December 2018, PTO-892 dated 06/02/2025).
Regarding claim 10, Pazolli et. al. discloses embodiments wherein: “treatment can comprise a combination of administering the splicing modulator, ADC, or composition to induce a neoantigen-based immune response and one or more neoantigen vaccines. In some other embodiments, treatment can comprise a combination of administering the splicing modulator, ADC, or composition to induce a neoantigen-based immune response and one or more engineered tumor-targeting T-cells (e.g., CAR-T)” [773] and “administration of a splicing modulator, ADC, or composition comprising a splicing modulator can be combined with […] treatment with cytokines or cytokine analogs, vaccination with tumor-associated vaccines, and engineering tumor-targeting T-cells (e.g., expansion of tumor-infiltrating lymphocytes or CAR-T)” [777]. Pazolli et. al. also teaches that the neoantigens primed CD8+ T-cell activation resulting in IFNγ production (Fig. 17).
The examiner would like to note that because the term “isolating T cells” is used in step (e), the broadest reasonable interpretation (BRI) of the claim is that the “isolated T cells” in (f) means the entire population of T cells isolated in step (e) rather than a population that is further purified for only neoantigen-specific T cells. The total population of the tumor-infiltrating T cells may necessarily be interpreted to comprise T cells that have affinity for one or more of the administered neoantigens.
Barbash et. al. as evidenced by Lee et. al. in view of Pazolli et. al. does not explicitly teach the method further comprising isolating T cells from a tumour microenvironment in the patient; expanding in vitro isolated T cells that have affinity for the one or more administered neoantigens; and administering to the patient the expanded T cells.
This deficiency is resolved by Lauss et. al., Seliktar-Ofir S, et. al., and Keskin et. al.
Lauss et. al. teaches a method of treating cancer comprising administering adoptive T-cell therapy (ACT) using tumor infiltrating lymphocytes (p. 2 column 1 Introduction and Results “Patient cohort and tumor biopsies”). Lauss et. al. teaches that neoantigen load of the tumor is associated with benefit from ACT in patients with melanoma. Specifically, Lauss et. al. teaches that “patients with the lowest predicted neoantigen load (median 8, range 4–18) had worse survival as compared to patients with the highest (median 85, range 57–183) predicted neoantigen load and intermediate (median 31, range 19–56) amount of predicted neoantigens” (p. 5 Col. 2, Fig. 5d) and “Our data provide compelling evidence that a high mutational and predicted neoantigen tumor load is associated with improved clinical outcome following ACT. The same phenomenon was previously reported to associate with the outcome of patients with melanoma or lung cancer, following treatment with immune checkpoints inhibitors7–10, highlighting the importance of neoantigens in response to immunotherapy” (p. 6 Col. 2 para. 2).
Seliktar-Ofir et. al. teaches a method of treating cancer comprising autologous tumor infiltrating lymphocytes by isolating and expanding CD137+ tumor-reactive T cells (Abstract), wherein the TILs were isolated from tumor biopsies and subsequently expanded by a “large-scale expansion procedure […] Within 14 days, cultures expanded by about 1,000 fold. Day 14 is the potential day of infusion” (reads on isolated from tumor microenvironment, see p. 2 “Generation of TIL and Autologous Melanoma lines). Seliktar-Ofir et. al. teaches “Importantly, this fraction of cells demonstrated enhanced in vitro and in vivo antitumor reactivity. Recently, Parkhurst et al. isolated CD137+ TIL by FACS sorting after stimulation with dendritic cells transfected with mutated TMG RNA and could show that expanded CD137+ cells are enriched for neoantigen-specific T cells” (p. 2 right column, first para.).
Keskin et. al. teaches that a neoantigen vaccine generated intratumoral T cell responses, and specifically that tumour-associated T cells and neo-antigen-reactive T cells in PBMCs shared TCRɑβ clonotypes specific for neoantigens targeted by the vaccine (Fig. 4). Keski