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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/16/2025, has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/16/2025, were in compliance with the provisions of 37 CFR 1.97 and 37 CFR 1.98. The IDS document was considered. A signed copy of Form PTO-1449 is enclosed herewith.
Status of the Claims
Claims 1 and 3-20 are pending.
Applicants’ arguments filed on 10/16/2025, have been fully considered. Rejections and/or objections not reiterated from previous Office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Applicants’ amendments filed on 10/16/2025, have been fully considered. Applicants have amended claims 10-11. Applicants have cancelled claim 2. Claims 12-15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected invention. Therefore, claims 1, 3-11 and 16-20 are subject of the Office action below.
Maintained Rejections:
Claim Rejections - 35 USC § 103-Maintained
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 rejection of claims 1, 3, 6-11 and 18-20 under 35 U.S.C. 103 as being unpatentable over Cyrenne of record (Blood, 2017), as evidenced by: i) Zheng of record (J. Hematology & Oncology, 2014); and ii) PubChem CID 5311 of record (created 03/25/2005), and in view of Nicolay of record (Blood, 2016, 128(6), 805-815), is maintained for the reasons of record set forth in the previous Office action, of which said reasons are herein reiterated.
By way of a background, Applicants (e.g., see pages 1-5 of the specification), disclose a combination therapy for treating a lymphoma with: i) an NF-кB inhibitor1 and ii) an apoptosis activator, which includes Bcl-2 protein inhibitors. The specification (see pages 22-29 and Figures 4-6), provides working examples of inhibiting the growth of cutaneous T-cell lymphoma (CTCL) cell lines with dimethyl fumarate (DMF, an NF-кB inhibitor) and venetoclax (ABT-199, a Bcl-2 inhibitor).
Independent claims 10-11 are directed towards a method for treating a CTCL in a patient known or suspected to be suffering from the lymphoma, with a combination therapy comprising:
an inhibitor of NF-кB translocation, which is a bis-C1-C5 alkyl ester of fumarate; and
at least one apoptosis activator (e.g., ABT-199/venetoclax).
Regarding claims 10-11, Cyrenne teaches a method of inhibiting the growth of leukemic cells from CTCL patients, with a combination therapy comprising:
vorinostat, a histone deacetylase (HDAC) inhibitor, also known as SAHA2; and
ABT-199(venetoclax).
The combination therapy leads to efficient killing of CTCL cells due to the synergistic activation of apoptosis, resulting in enhanced treatment, when compared to a monotherapy comprising vorinostat or a monotherapy comprising venetoclax. Please see abstract, Figures 3-4 and discussions therein.
Zheng provides evidence (see abstract and Figure 4) that SAHA inhibits T-lymphoma cell growth through NF-кB inhibition. SAHA is an inhibitor of NF-кB translocation (see page 3, right column, page 7, bottom ¶ and cited reference 22).
Accordingly, at the time of the instant invention, a person skilled in the art would have had a reasonable expectation that the administration of a therapy comprising an NF-кB inhibitor (e.g., vorinostat/SAHA) and ABT-199 to a patient known or suspected to be suffering from a T-cell lymphoma such as CTCL, would treat the CTLC in the patient.
Cyrenne differs from claims 10-11 only insofar as Cyrenne is not explicit in disclosing, wherein the NF-кB inhibitor is a bis-C1-C5 alkyl ester of fumarate. However, the claimed invention would have been obvious over Cyrenne as evidenced by Zheng and PubChem CID 5311.
This is because at the time of the instant invention, it was known in the art an NF-кB inhibitor such as DMF, which is a bis-C1-C5 alkyl ester of fumarate, can treat a CTCL. For example, Nicolay teaches a method for inhibiting CTCL tumor growth and metastasis with DMF. Similar to Cyrenne as evidenced by Zheng and PubChem CID 5311, Nicolay teaches that DMF inhibits CTCL tumor growth and metastasis by targeting NF-кB (emphasis added). Please see abstract and discussions therein. DMF is an inhibitor of NF-кB translocation (see page 808, right column, page 811 under the “Discussion” section and cited references 51-52).
Therefore, at the time of the instant invention, one skilled in the art would have found it obvious to modify Cyrenne as evidenced by Zheng and PubChem CID 5311 with Nicolay, in order to administer a combination therapy comprising: i) an NF-кB inhibitor (e.g., DMF); and ii) ABT-199, to a patient known or suspected to be suffering from a T-cell lymphoma such as CTCL. The skilled artisan would have had a reasonable expectation that the combination therapy would: i) lead to efficient killing of CTCL cells due to the synergistic of the combination therapy; and ii) result in enhanced treatment, when compared to a monotherapy.
The use of simple substitution of one known element for another to obtain predictable results as a requirement of a prima facie case of obviousness has been deemed as proper (please see MPEP § 2143). In the instant case, the one known element is an NF-кB inhibitor and the predictable results is treating disease conditions such as CTCL, in which the therapeutic intervention is at an NF-кB inhibition + apoptosis induction.
Obviousness requires only a reasonable expectation of success, not complete confidence in a given outcome; "at least some degree of predictability" is all that is required. M.P.E.P. § 2143.02.
The prior art can be modified or combined to reject claims as prima facie obvious as long as there is a reasonable expectation of success. See In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (see MPEP § 2143.02).
Therefore, claims 10 and 11 are obvious over Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay.
Regarding 1, the cited references combine to teach treating lymphoma cells with an NF-кB inhibitor and at least one apoptosis activator (see discussions above).
Regarding claim 3, Nicolay teaches DMF (see discussions above).
Regarding claims 6-7 and 18, Cyrenne teaches ABT-199 (see discussions above).
Regarding claims 8-9 and 18-20, each of the dosing ratio of Bcl-2 inhibitor (e.g., ABT-199) to NF-кB inhibitor (e.g., DMF), and the dosing schedule in the combination therapy, is a result effective variable that would have been routinely determined and optimized in the pharmaceutical art.
For example, Furthermore, MPEP § 2144.05(II)(B), states that “after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.”
MPEP 2143(e) states: The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Thus, the claims fail to patentably distinguish over the state of the art as represented by the cited references.
The rejection of claims 1, 4-5, 10 and 16-17 under 35 U.S.C. 103 as being unpatentable over Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay, as applied to claim 1 above and further in view of NCT02546440 of record (09/10/2015), is maintained for the reasons of record set forth in the previous Office action, of which said reasons are herein reiterated.
The limitations of claims 1 and 10 as well as the corresponding teachings of Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay, are described above, and hereby incorporated into the instant rejections.
The inventions of claims 4-5 and 16-17 are similar to claims 1 and 10, however, claims 4-5 and 16-17 differ slightly from claims 1 and 10 in that the claims require DMF dosing regimen.
Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay, differ from claims 4-5 and 16-17 only insofar as the cited references do not combine to explicitly teach the limitation of claims 4-5 and 16-17.
However, the claimed inventions would have been obvious over Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay, because the recited DMF dosing regimens are known in the art.
For example, NCT02546440 relates to a clinical trial study to evaluate the effect and safety of administering from 30 mg/day to 720 mg/day of DMF (dosage escalated weekly over 9 weeks), to CTLC patients. Please see pages 1-7.
Since each of the recited DMF dosing regimen in claims 4-5 and 16-17, is an art-recognized variable (see discussions above), the selection specific amount of DMF, would have been routinely determined and optimized in the pharmaceutical art.
A prima facie case of obviousness exists in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" (see MPEP § 2144.05). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close (see MPEP § 2144.05).
In the instant case, because each of the claimed DMF dosing regimen in claims 4-5, overlap or lie inside ranges disclosed by the prior art (see discussions above), a prima facie case of obviousness exists.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Thus, the claims fail to patentably distinguish over the state of the art as represented by the cited references.
Response to the Applicants’ Arguments and Declaration
Applicants raised several issues (see pages 6-10 of Remarks), argue alleging that the rejection is improper on the grounds that:
1) One skilled in the art would not have been motivated to combined Cyrenne as evidenced by Zheng and PubChem CID 5311, with Nicolay, because Cyrenne fails to teach vorinostat as an NF-кB inhibitor. Please see pages 6-8 of Remarks.
Response:
Cyrenne was cited for teaching a method of treating CTCL with vorinostat and venetoclax (ABT-199). The combination therapy leads to efficient killing of CTCL cells due to the synergistic activation of apoptosis, resulting in enhanced treatment, when compared to a monotherapy comprising vorinostat or venetoclax. Please see discussions above.
Zheng and PubChem CID 5311 (see discussions above), provides evidence that vorinostat (SAHA) inhibits T-lymphoma cell growth through NF-кB inhibition.
In response to the Applicants’ arguments alleging that there is no motivation for a person skilled in the art to combine the cited references, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, as set forth in the rejection above and in the previous Office action:
A) Cyrenne teaches a method of inhibiting the growth of leukemic cells from CTCL patients, with a combination therapy comprising: i) vorinostat (SAHA); and ii) ABT-199 (venetoclax). The combination therapy leads to efficient killing of CTCL cells due to the synergistic activation of apoptosis, resulting in enhanced treatment, when compared to a monotherapy comprising vorinostat or a monotherapy comprising venetoclax. Please discussions above.
Vorinostat (SAHA) inhibits T-lymphoma cell growth through NF-кB inhibition. Vorinostat (SAHA) is an inhibitor of NF-кB translocation. Please discussions above.
Accordingly, at the time of the instant invention, a person skilled in the art would have had a reasonable expectation that the administration of a therapy comprising an NF-кB inhibitor (e.g., vorinostat/SAHA) and ABT-199 to a patient known or suspected to be suffering from a T-cell lymphoma such as CTCL, would treat the CTLC in the patient.
Cyrenne as evidenced by Zheng and PubChem CID 531 differs from the claimed invention only insofar as Cyrenne as evidenced by Zheng and PubChem CID 531, is not explicit in disclosing, wherein the NF-кB inhibitor is a bis-C1-C5 alkyl ester of fumarate.
However, the claimed invention would have been obvious over Cyrenne as evidenced by Zheng and PubChem CID 5311. This is because at the time of the instant invention, it was known in the art an NF-кB inhibitor such as DMF, which is a bis-C1-C5 alkyl ester of fumarate, can treat a CTCL.
B) For example, Nicolay teaches a method for inhibiting CTCL tumor growth and metastasis with DMF. Similar to Cyrenne as evidenced by Zheng and PubChem CID 5311, Nicolay teaches that DMF inhibits CTCL tumor growth and metastasis by targeting NF-кB (emphasis added). DMF is an inhibitor of NF-кB translocation. Please see discussions above.
This would form sufficient motivation for one of ordinary skill in the art to employ an NF-кB translocation inhibitor (e.g., DMF of Nicolay), in a combination therapy comprising DMF and ABT-199 (venetoclax). One skilled in the art would have had a reasonable expectation that the combination therapy would: i) lead to efficient killing of CTCL cells due to the synergistic of the combination therapy; and ii) result in enhanced treatment, when compared to a monotherapy.
The use of simple substitution of one known element for another to obtain predictable results as a requirement of a prima facie case of obviousness has been deemed as proper (please see MPEP § 2143). In the instant case, the one known element is an NF-кB inhibitor and the predictable results is treating disease conditions such as CTCL, in which the therapeutic intervention is at an NF-кB inhibition + apoptosis induction.
Obviousness requires only a reasonable expectation of success, not complete confidence in a given outcome; "at least some degree of predictability" is all that is required. M.P.E.P. § 2143.02.
The prior art can be modified or combined to reject claims as prima facie obvious as long as there is a reasonable expectation of success. See In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (see MPEP § 2143.02).
2) PubChem CID 5311 fails to present any effect of vorinostat on NF-кB (see page 7 of Remarks).
Response:
PubChem CID 5311 was cited for disclosing that SAHA is another name for vorinostat. Please see discussions above.
3) Applicants reiterate the declaration of Professor Jan Nicolay, alleging that Zheng: i) relates to peripheral TCL (pTCL), not cutaneous CTL (cTCL); and ii) teach indirect inhibition of NF-кB with SAHA. Applicants cite the declaration of Professor Jan Nicolay, in support of the Applicants’ allegation. Please see pages 7-8 of Remarks and ¶s 1-9 of the declaration of Professor Jan Nicolay, filed on 02/10/2025.
Response:
The claimed invention requires an inhibitor of NF-кB. There is no requirement in the instant claims that: i) an inhibitor of NF-кB must inhibit NF-кB only in CTCL or ii) the inhibition of NF-кB must be a direct inhibition. Applicants and the declarant have not provided any evidence on the record which would support what appears to be the Applicants’ and the declarant’s arguments alleging that a person skilled in the art would not have expected an inhibitor of NF-кB discovered an NF-кB inhibition assay, to inhibit NF-кB in CTCL.
Furthermore, in response to the Applicants’ arguments against the references individually (e.g., Cyrenne fails to teach vorinostat as an NF-кB inhibitor, see page 6 of Remarks; or PubChem CID 5311 fails to present any effect of vorinostat on NF-кB, see page 7 of Remarks), one cannot show nonobviousness by attacking references individually where the rejections are based on combination of references. In obviousness rejection a combination of references is used, and the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references that make up the state of the art with regard to the claimed invention. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co.; 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
4) Cyrenne clearly establishes that NF-кB is not involved in the synergistic mechanism of CTCL (see page 8 of Remarks).
Response:
Zheng provides evidence that Vorinostat (SAHA) inhibits T-lymphoma cell growth through NF-кB inhibition. Vorinostat (SAHA) is an inhibitor of NF-кB translocation. Please see discussions above. The Office did not take a position that Cyrenne clearly establishes that NF-кB is involved in the synergistic mechanism of CTCL.
5) Vorinostat is not an inhibitor of NF-кB translocation (see page 9 of Remarks).
Response:
Vorinostat (SAHA) is an inhibitor of NF-кB translocation (see discussions above).
6) Duvic et al (Biologics: Targets & Therapy, 2007 1(4), 377-392), supports Applicants’ assertion that Cyrenne clearly establishes that NF-кB is not involved in the synergistic mechanism of CTCL (see page 9 of Remarks).
Response:
Zheng provides evidence that Vorinostat (SAHA) inhibits T-lymphoma cell growth through NF-кB inhibition. Vorinostat (SAHA) is an inhibitor of NF-кB translocation. Please see discussions above. The Office did not take a position that Cyrenne clearly establishes that NF-кB is involved in the synergistic mechanism of CTCL. Furthermore, the Office did not rely on Duvic et al for the rejection of instant claims.
7) NCT02546440 fails to suggest or teach combining DMF with venetoclax (see page 10 of Remarks).
Response:
NCT02546440 was cited for teaching the effect and safety of administering from 30 mg/day to 720 mg/day of DMF to CTLC patients. The limitation of combining DMF with venetoclax, was addressed by Cyrenne as evidenced by Zheng and PubChem CID 5311, and in view of Nicolay (see discussions above).
Furthermore, in response to the Applicants’ arguments against the references individually (e.g., NCT02546440 fails to suggest or teach combining DMF with venetoclax, see page 10 of Remarks), one cannot show nonobviousness by attacking references individually where the rejections are based on combination of references. In obviousness rejection a combination of references is used, and the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references that make up the state of the art with regard to the claimed invention. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co.; 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
For the reasons above, and those made of record in the previous Office action, the rejections are maintained.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IBRAHIM D BORI whose telephone number is (571)270-7020. The examiner can normally be reached on Monday through Friday 8:00AM-5:00PM(EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S LUNDGREN can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IBRAHIM D BORI/
Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 defined (see page 5, lines 27-30 of the specification), as any compound that inhibit: i) NF-кB downstream signaling; ii) NF-кB translocation and/or; iii) NF-кB interaction with upstream or downstream signaling components of the cell.
2 see PubChem CID 5311, page 1.