DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed December 4, 2025 is pending.
Claims 1-51 are pending.
Claims 1-4, 31, 37, and 42 are independent claims.
Applicant’s election of Group I (claims 1, 5, 8-11, 13-18, 26, and 27, drawn to a method of reactivating a latent Epstein-Barr virus (EBV) in a cell infected with the EBV); and the species of (a) chidamide as the benzamide-based HDAC inhibitor as recited in claim 9, (b) epirubicin as the topoisomerase inhibitor as recited in claim 14, and (c) nutlin-3a as the Mdm2 inhibitor as recited in claim 17 in the reply filed on December 4, 2025 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
It is noted that claims 26 and 27 were inadvertently included in Group I in the Office Action mailed on December 2, 2025. However, claims 26 and 26 are dependent on claim 2 which is a nonelected invention. Therefore, claims 26 and 27 have been withdrawn from further consideration as being drawn to a nonelected invention.
Claims 2-4, 6, 7, 12, 19-24, 26, 27, and 28-51 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1, 5, 8-11, and 13-18 are currently under consideration.
Priority
The instant Application is a 371 of PCT/EP21/79137 filed 10/20/2021 which claims domestic benefit to provisional applications 63/094,104 filed 10/20/2020.
Claim Objections
Claim 1, 5, 8-11, and 13-18 are objected to because of the following informalities:
Claim 1, 5, 8-11, and 13-18 recite “EBY” but the term should instead be “EBV.”
Claim 1 recites “A method of reactivating a latent Epstein-Barr virus (EBY) in a cell infected with the EBY, comprising…” in lines 1 and 2 but the phrase should recite “A method of reactivating latent Epstein-Barr virus (EBV) in a cell infected with EBV comprising…” without the “a” before the term “latent,” without the term “the” before the term “EBV,” and without the comma before the term “comprising” in line 2.
Claim Rejections - 35 USC § 112
Indefinite Language
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, 5, 8-11, and 13-18 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 recites the limitation "the EBV-positive cancer cell" in line 4. There is insufficient antecedent basis for this limitation in the claim. While claim 1 recites “a cell infected with the EBV” in lines 1 and 2, it does not recite that the cell is a cancer cell. Therefore, it is unclear what the phrase "the EBV-positive cancer cell" is referring to.
Written Description
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, 5, 8-11, and 13-18 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 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.
Independent claim 1 is drawn to a in a cell infected with the EBV, comprising contacting the cell with a benzamide-based histone deacetylase (HDAC) inhibitor, wherein the benzamide-based HDAC inhibitor increases a level of expression or activity of an EBV-associated protein in the EBV-positive cancer cell.
The specification discloses that the benzamide-based HDACi chidamide, CXD101, entinostat, and mocetinostat showed a strong dose-dependent effect on Zta expression, and chidamide and CXD101 did so with low toxicity (e.g. see Example 2, page 62, lines 18-21, and Figures 1B and 9C). It is noted that figures 1B also discloses that the benzamide-based HDACis CI-994 and Dinaline do not have an effect on Zta expression.
The specification also discloses that none of the tested HDACi were able to reactivate EBV in
naturally- or ex vivo-infected B cell lines. Together, these results indicate that HDACi, such as benzamide-based HDACi, predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells (e.g. see page 63, lines 28-31).
The species of benzamide-based HDACi disclosed by the Applicant are encompassed by the genus recited in claim 1. However, the Applicant clearly discloses that not all benzamide-based HDACis are suitable for reactivating latent EBV by increasing the level of expression or activity of an EBV-associated protein in the EBV-positive cell. For example, the benzamide-based HDACis dinaline did not have an effect on Zta expression, a key regulator of EBV reactivation.
Furthermore, claim 1 recites a genus of EBV-positive cells which encompass any cell including gastric epithelial cancer cells and B cells. However, the Applicant clearly discloses benzamide-based HDACis predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells.
When given the broadest reasonable interpretation in light of specification, the method of reactivating latent EBV in an EBV-positive cell of the instant invention is done broadly by contacting the cell with any benzamide-based HDACi, wherein the HDACi increases a level of expression or activity of an EBV-associated protein in any EBV-positive cell.
It is noted that the broadest claim (claim 1) does not recite sufficient structural elements for the benzamide-based HDAC inhibitor or EBV-positive cells encompassed in the method of reactivating latent EBV in a cell infected with the EBV.
Claim 5 limits the EBV-positive cell to an EBY-positive cancer cell.
Claims 9 limits the benzamide-based HDAC inhibitor to any one of chidamide, CXD 101, entinostat, mocetinostat, and combinations thereof.
Claim 10 limits the benzamide-based HDAC inhibitor to chidamide.
It is noted that claim 5 recites sufficient structure for the EBV-positive cells and claims 9 and 10 recite sufficient structure for the benzamide-based HDAC inhibitor.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Zentelis 2018 (Investigating mechanisms of Epstein-Barr virus reactivation in epithelial cells [PhD thesis]. University of Oxford) teaches that Zebra (or Zta) is a key regulator of EBV reactivation (e.g. see Abstract). Zentelis also teaches potential novel therapeutic compound combinations for the treatment of EBV-associated epithelial cancers. Benzamide-based HDACis were the most potent group of reactivating agents and induced the expression of lytic cycle genes as well as targeted cell killing in combination with antiviral agents (e.g. see Abstract).
Zentelis teaches several benzamide-based HDACis for their ability to induce Zebra expression, and therefore reactivation of latent EBV, in a gastric carcinoma cell line that is characterized by the presence of EBV (e.g. see page 87, second paragraph). Zentelis showed that control treatment with DMSO induced Zebra expression in less than 2% of cells, representing the low level of background in this experimental set-up. The HDACi dinaline, the deacetylated derivate of CI-994, did not induce Zebra expression, while CI-994 induced Zebra expression in less than 5% of cells. Chidamide, CXD101, entinostat and mocetinostat showed strong dose responses. Increased concentrations of compounds led to a significant increase in the percentage of Zebra-positive cells (e.g. see page 87, second paragraph).
Therefore, the art teaches that not all benzamide-based HDACis are suitable for reactivating latent EBV by increasing the level of expression or activity of an EBV-associated protein in the EBV-positive cell. It is noted that the instant claims recite a genus of benzamide-based HDACis which encompasses dinaline which does not induce Zebra expression, a key regulator of EBV reactivation.
As noted above, the Applicant discloses that chidamide, CXD101, entinostat, and mocetinostat show a strong dose-dependent effect on Zta expression and, therefore, EBV reactivation, while the benzamide-based HDACis CI-994 and Dinaline do not. The specification also discloses that benzamide-based HDACis predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells.
Such a disclosure does not serve to provide sufficient written description of the claimed method of reactivating latent EBV in an EBV-positive cell of the instant invention broadly by contacting the cell with any benzamide-based HDACi, wherein the HDACi increases a level of expression or activity of an EBV-associated protein in any EBV-positive cell.
The disclosure does not identify any specific structural features or combination of features which give rise to (1) a benzamide-based HDACi that increases a level of expression or activity of an EBV-associated protein or (2) a EBV-positive cell that has reactivated EBV with an increased level of expression or activity of an EBV-associated protein. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited benzamide-based HDACis or EBV-positive cells which gives rise to their functional activity. Ultimately, identifying: (1) benzamide-based HDACis simply on the basis of being of being able to increase a level of expression or activity of an EBV-associated protein or (2) an EBV-positive cell simply on the basis of having reactivated EBV with an increased level of expression or activity of an EBV-associated protein; rather than by identifying the structure of the benzamide-based HDACi and the EBV-positive cell in question is generally insufficient to provide written description.
Thus, there is insufficient written description for the breadth of a method of reactivating latent EBV in an EBV-positive cell of the instant invention by contacting the cell with any benzamide-based HDACi, wherein the HDACi increases a level of expression or activity of an EBV-associated protein in any EBV-positive cell.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of benzamide-based HDACis and EBV-positive cells encompassed by the claims at the time the instant application was filed.
Enablement
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, 5, 8-11, and 13-18 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 reactivating latent Epstein-Barr virus (EBV) in a cancer cell infected with the EBV comprising contacting the cell with chidamide, CXD101, entinostat, or mocetinostat; does not reasonably provide enablement for a method of reactivating latent Epstein-Barr virus (EBV) in any cell infected with the EBV comprising contacting the cell with any benzamide-based histone deacetylase (HDAC) inhibitor (HDACi).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(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.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Independent claim 1 is drawn to a method of reactivating latent Epstein-Barr virus (EBV) in any cell infected with the EBV comprising contacting the cell with any benzamide-based HDACi, wherein the HDACi increases a level of expression or activity of an EBV-associated protein in the EBV-positive cancer cell.
The claims do not recite sufficient structural elements for the HDAC inhibitor encompassed in the method of reactivating a latent EBV in a cell infected with the EBV.
State of the prior art/Predictability of the art
Zentelis 2018 (Investigating mechanisms of Epstein-Barr virus reactivation in epithelial cells [PhD thesis]. University of Oxford) teaches that Zebra (or Zta) is a key regulator of EBV reactivation (e.g. see Abstract). Zentelis also teaches potential novel therapeutic compound combinations for the treatment of EBV-associated epithelial cancers. Benzamide-based HDACis were the most potent group of reactivating agents and induced the expression of lytic cycle genes as well as targeted cell killing in combination with antiviral agents (e.g. see Abstract).
Zentelis teaches several benzamide-based HDACis for their ability to induce Zebra expression, and therefore reactivation of latent EBV, in a gastric carcinoma cell line that is characterized by the presence of EBV (e.g. see page 87, second paragraph). Zentelis showed that control treatment with DMSO induced Zebra expression in less than 2% of cells, representing the low level of background in this experimental set-up. The HDACi dinaline, the deacetylated derivate of CI-994, did not induce Zebra expression, while CI-994 induced Zebra expression in less than 5% of cells. Chidamide, CXD101, entinostat and mocetinostat showed strong dose responses. Increased concentrations of compounds led to a significant increase in the percentage of Zebra-positive cells (e.g. see page 87, second paragraph).
Therefore, the art teaches that not all benzamide-based HDACis are suitable for reactivating latent EBV by increasing the level of expression or activity of an EBV-associated protein in the EBV-positive cell. It is noted that the instant claims recite a genus of benzamide-based HDACis which encompasses dinaline which does not induce Zebra expression, a key regulator of EBV reactivation.
Working examples/Guidance in the specification
The specification discloses that the benzamide-based HDACi chidamide, CXD101, entinostat, and mocetinostat showed a strong dose-dependent effect on Zta expression, and chidamide and CXD101 did so with low toxicity (e.g. see Example 2, page 62, lines 18-21, and Figures 1B and 9C). It is noted that figures 1B also discloses that the benzamide-based HDACis CI-994 and Dinaline do not have an effect on Zta expression.
The specification also discloses that none of the tested HDACi were able to reactivate EBV in
naturally- or ex vivo-infected B cell lines. Together, these results indicate that HDACi, such as benzamide-based HDACi, predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells (e.g. see page 63, lines 28-31).
The species of benzamide-based HDACi disclosed by the Applicant are encompassed by the genus recited in claim 1. However, the Applicant clearly discloses that not all benzamide-based HDACis are suitable for reactivating latent EBV by increasing the level of expression or activity of an EBV-associated protein in the EBV-positive cell. For example, the benzamide-based HDACis dinaline did not have an effect on Zta expression, a key regulator of EBV reactivation.
Furthermore, claim 1 recites a genus of EBV-positive cells which encompass any cell including gastric epithelial cancer cells and B cells. However, the Applicant clearly discloses benzamide-based HDACis predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells.
Therefore, the disclosed species of benzamide-based HDACis and EBV-positive cells do not enable one of ordinary skill in the art to make and/or use the claimed method of reactivating EBV commensurate in scope with the breadth of the claims.
Amount of experimentation necessary
The instant specification discloses that chidamide, CXD101, entinostat, and mocetinostat show a strong dose-dependent effect on Zta expression and, therefore, EBV reactivation, while the benzamide-based HDACis CI-994 and Dinaline do not. The specification also discloses that benzamide-based HDACis predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells.
The claimed methods encompass methods of reactivating latent Epstein-Barr virus (EBV) in any cell infected with the EBV comprising contacting the cell with any benzamide-based HDACi. There is insufficient objective evidence that the disclosed methods of reactivating latent EBV with chidamide, CXD101, entinostat, or mocetinostat in cancer cells can be extrapolated to provide guidance and direction for the claimed method of reactivating latent EBV in any cell infected with the EBV comprising contacting the cell with any benzamide-based HDACi.
Thus, based on the content of the disclosure in view of the prior art regarding dinaline not inducing Zebra expression, a skilled artisan, through extensive trial-and-error experimentation, would have to identify benzamide-based HDACis and cells infected with EBV and then use the benzamide-based HDACis to reactivate latent EBV in the infected EBV cells with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Given that that chidamide, CXD101, entinostat, and mocetinostat show a strong dose-dependent effect on Zta expression and, therefore, EBV reactivation, while the benzamide-based HDACis CI-994 and Dinaline do not, and that benzamide-based HDACis predominantly induce EBV reactivation in gastric epithelial cancer cells but not in B cells; a person of ordinary skill in the art would have to perform undue experimentation in order to use any benzamide-based HDACi to reactivate EBV in any EBV infected cell commensurate in scope with the breadth of the claims.
Thus, the specification does not enable one of ordinary skill in the art to use what is claimed and therefore claims 1, 5, 8-11, and 13-18 are rejected under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 102
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 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, 5, 8-11, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Faller 2016 (WO2016205695, an IDS reference filed 04/20/2023).
Faller teaches a virus-inducing drug such as a histone deacetylase inhibitor (HDAC inhibitor - HDACi) can be used to re-induce the expression of viral thymidine kinase or protein kinase in virus infected cells in the subject; the subject can then be treated with antiviral drugs to eliminate latent viral infections (e.g. see [0019]). In certain instances, HDAC inhibitors, including some new, highly-potent compounds, induce EBV lytic phase gene expression and kill Epstein-Barr virus (EBV)-infected cells in combination with antiviral drugs (e.g. see [0038]).
Faller also teaches an experiment to measure whether Chidamide, a benzamide-based HDAC inhibitor, could induce EBV associated transcripts (e.g. see [00145]). The induction of mRNA for the protein kinases TK (Figure 1A) and BGLF4 (Figure IB) in an EBV-positive lymphoma cell lines was measured after contacting the cell line with different concentrations of chidamide (chid) for 24 hrs (e.g. see [00145]). Chidamide had synergistic activity with the anti-viral agent ganciclovir, a second agent, in killing EBV+ lymphoma cells (e.g. see [00154]).
Faller also teaches inducing agents (agents that induce expression) may act directly on the viral genome or indirectly through a cellular factor required for viral expression (e.g. see [0058]). For example, viral gene expression can be regulated through the regulation of the expression of viral transcription factors such as ZTA (e.g. see [0058]).
Faller also teaches that the methods of the provided invention can comprise contacting a subject with a viral inducing agent, and antiviral agent, and one or more additional active agents, wherein the additional agent can comprise an anticancer agent (e.g. see [0074]).
Therefore the reference teachings anticipate the instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 11, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Faller 2016 (WO2016205695, an IDS reference filed 04/20/2023) in view of Zentelis 2018 (Investigating mechanisms of Epstein-Barr virus reactivation in epithelial cells [PhD thesis]. University of Oxford).
The teachings of Faller are outlined in the 102 rejection above.
Faller does not teach that the second agent comprises a topoisomerase inhibitor or an Mdm2 inhibitor, wherein the topoisomerase inhibitor comprises epirubicin and the Mdm2 inhibitor comprises nutlin-3a.
Zentelis teaches that Zebra is a key regulator of EBV reactivation (e.g. see Abstract). Zentelis teaches potential novel therapeutic compound combinations for the treatment of EBV-associated epithelial cancers. Benzamide-based HDACis were the most potent group of reactivating agents and induced the expression of lytic cycle genes as well as targeted cell killing in combination with antiviral agents. Additionally, topoisomerase inhibitors and other chemotherapeutic agents showed synergistic effects on Zebra expression together with HDACis, which was linked to the induction of p53 expression through those compounds (e.g. see Abstract).
Zentelis also teaches that topoisomerase inhibitors such as epirubicin and doxorubicin are used as chemotherapeutic agents for different cancer types (e.g. see page 135, first paragraph). Furthermore, nutlin-3a is a compound that specifically inhibits the interaction of p53 with its negative regulator mouse double minute 2 homolog (MDM2) and the EBV leads to stabilization of p53 at the protein level (e.g. see page 135, first paragraph).
In an attempt to identify drug combinations that are able to synergize with chidamide in the induction of Zebra expression, Zentelis teaches that topoisomerase inhibitors as a class of
compounds with potential synergistic effects on Zebra expression together with chidamide (e.g. see page 182, third paragraph). The combinations of chidamide with epirubicin and chidamide with Nutlin-3a treatment have been shown to result in high levels of Zebra expression (e.g. sere page 183, first paragraph). In contrast to chidamide and Nutlin-3a treatment, which induced stronger cell death in EBV-positive cells, epirubicin led to cell death independently of the EBV-status of the cell line (e.g. sere page 183, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Faller to incorporate the teachings of Zentelis to include that the second agent comprises a topoisomerase inhibitor or an Mdm2 inhibitor, wherein the topoisomerase inhibitor comprises epirubicin and the Mdm2 inhibitor comprises nutlin-3a. This is because topoisomerase inhibitors and other chemotherapeutic agents, such as epirubicin and nutlin-3a, show potential synergistic effects on Zebra expression together with HDACis.
Given that combinations of chidamide with epirubicin and chidamide with Nutlin-3a treatment have been shown to result in high levels of Zebra expression, a key regulator of EBV reactivation, and these combinations are able to induce cell death; it would have been obvious to a skilled artisan, with the goal of inducing EBV reactivation and cytotoxicity, to include epirubicin or Nutlin-3a in combination with chidamide in Faller’s method with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641