DETAILED ACTION
This office action is in response to applicant’s filing dated November 25, 2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 25, 2025 has been entered.
Status of Claims
Claims 1, 7-14, 17, 19, 20, 22, 27, and 28 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed November 25, 2025. Claims 2-6, 15, 16, 18, 21, and 23-26 were previously canceled.
Applicants elected without traverse Group I, drawn to a pharmaceutical combination comprising at least one immunomodulatory compound and belinostat or a pharmaceutically acceptable salt thereof as the elected invention and a pharmaceutical combination comprising ipilimumab and nivolumab as the elected species in the reply filed on August 4, 2020. The requirement is still deemed proper.
The instant claims no longer read on the elected species, combination comprising ipilimumab and nivolumab. Examination has expanded to encompass the species tremelimumab. Claims 11-14, 17, 19, 20, and 22 remain withdrawn.
Claims 1, 7-10, 27, and 28 are presently under examination as they relate to the expanded species: tremelimumab.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Priority
The present application is a 371 of PCT/EP2017/054081 filed on February 22, 2017, which claims benefit of US Provisional Application Nos. 62/298,445, and 62/298,445, filed on February 22, 2016 and US Provisional Application No. 62/409,708 filed October 18, 2016. The effective filing date of the instant application is February 22, 2016.
Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 103
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 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.
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, 8-10, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Salem et al (WO 2016/187122 A1, effective filing date May 15, 2015, cited in a previous Office Action).
Regarding claim 1, Salem teaches cytotoxic particles comprising a biodegradable polymer and a cytotoxic agent for use in a method of treating a tumor (claim 1), further comprising an immune checkpoint inhibitor (claim 2), wherein the cytotoxic agent is belinostat (claim 5); and the immune checkpoint inhibitor is an anti-CTLA-4 antibody, tremelimumab (claim 6). Moreover, Salem teaches the immune checkpoint inhibitor is administered before, concurrently with, or after the tumor is injected with cytotoxic particles (claim 2). Thus, Salem teaches administering the immune checkpoint inhibitor concurrently with the cytotoxic agent. Moreover, Salem teaches the disclosed compositions may include immune checkpoint inhibitors [0010]. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to formulate a composition comprising the cytotoxic particles comprising belinostat to further contain tremelimumab to formulate a composition to administer belinostat and tremelimumab concurrently.
Regarding claim 28, Salem teaches a kit comprising as components (a) cytotoxic particles comprising (i) a biodegradable polymer and (ii) a cytotoxic agent and (b) an immune checkpoint inhibitor (claim 21). The Examiner acknowledges that Salem teaches the cytotoxic particles may optionally comprise (iii) a T-cell stimulatory agent and the kit may optionally comprise (c) a T-cell stimulatory agent, these components are optional and not required. Salem further teaches the cytotoxic agent is belinostat (claim 22) and the immune checkpoint inhibitor is an anti-CTLA-4 antibody, tremelimumab (claim 23).
While the reference may not be anticipatory insofar as one must select belinostat from various cytotoxic agent compounds and tremelimumab from various immune checkpoint inhibitors as taught in Salem, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected belinostat detailed supra from the list of cytotoxic agents and tremelimumab from the list of immune checkpoint inhibitors that may be therapeutically effective in order to arrive composition useful for treating a tumor. The skilled person would have been motivated to do so by the unambiguous disclosure of each particular species of cytotoxic agents and immune checkpoint inhibitors individually and alternatively as equally useful in a method of treating a tumor. This conclusion is supported by the fact that it has long been held in patent prosecution that a reference should be considered as expansively as is reasonably possible in determining the full scope of the contents within its four corners.
Thus, one of ordinary skill in the art before the effective filing date of the invention would have readily envisaged a composition and/or kit consisting of belinostat and tremelimumab from the disclosure of Salem. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the pharmaceutical composition consisting of belinostat and tremelimumab to administer in concurrently in combination. Moreover, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to produce a kit consisting of the composition consisting of belinostat and tremelimumab to administer the compositions concurrently or sequentially.
Regarding claims 8-10, which are directed to the use of the claimed pharmaceutical combination for the treatment of cancer, hepatocellular carcinoma, and breast cancer, respectively, such a limitation of the instant claims fail to patentably distinguish the instant claims over the cited prior art because such a limitation is an intended use of the composition (i.e. an intent to use the disclosed pharmaceutical combination as treatment for cancer, hepatocellular carcinoma, or breast cancer), which does not impart any physical or material characteristics to the composition that is not already present in the cited prior art. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See Ptiney Bowes Inc. v. Hewlett-Packard Co., 182 F.2d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 378, 42 USPQ2d 1550, 1554 and MPEP 2112.02(II). In the instant case, the claims are directed to a pharmaceutical combination and, thus, would be reasonably expected to be capable of performing the intended use as instantly claimed, absent factual evidence to the contrary and further absent any apparent structural difference between the composition of the prior art and that of the instant claims.
With regard to the limitation of instant claim 8, wherein the pharmaceutical composition comprises a therapeutically effective amount of belinostat and a therapeutically effective amount of the immunomodulatory compound, in a review of the instant specification, disclosure of therapeutically effective amounts was not identified. As set forth above, Salem teaches the composition comprises a cytotoxic agent, including belinostat, further comprising administering an immune checkpoint inhibitor is useful for treating a tumor. Salem further teaches the cytotoxic particles comprise the cytotoxic concentration value of at least 0.01 -50.0 µg/mg [0044]. Salem does not explicitly teach amounts of immune checkpoint inhibitor. However, Salem teaches the cytotoxic particles may comprise a cytotoxic agent and further comprise an additional agent wherein the concentration ratio of the cytotoxic agent and additional agent includes 1:1 [0051]. It would be obvious to utilize the amounts of cytotoxic agent and concentration ratio of cytotoxic agent to additional agent as a starting point for optimizing the amount of belinostat and tremelimumab for producing cytotoxic particles for treating a tumor. The amounts taught by Salem are construed as therapeutically amounts of belinostat and a therapeutically effective amount of the immunomodulatory compound.
Regarding claim 27, Salem teaches the compositions disclosed herein may be delivered via a variety of routes; typical administration include parenteral administration (e.g., intravenous) [0061].
Taken together, all this would result in the practice of the method of claims 1, 8-10, 27, and 28 with a reasonable expectation of success.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Salem et al (WO 2016/187122 A1, effective filing date May 15, 2015, cited in a previous Office Action) as applied to claims 1, 8-10, 27, and 28 above, and further in view of Sehested et al (WO 2009/109861 A1, cited in a previous Office Action).
Salem teaches all the limitations of claim 7 (see above 103 rejection), except wherein the belinostat is formulated with arginine.
However, Sehested teaches liquid formulations of Belinostat™ further comprising L-arginine, wherein the Belinostat™ is freely soluble, and which are suitable for administration by injection, infusion, intravenous infusion (page 2, lines 18-20).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the belinostat with arginine for use in a pharmaceutical combination consisting of belinostat and with a reasonable expectation of success, since the prior art establishes that compositions of belinostat are known to be formulated with arginine, thus resulting in the combination of claim 7 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
The Examiner's analysis of Salem is based on improper hindsight and a reasonable expectation of success for the claimed composition to be effective at cancer treatment is not present. Salem provides no more than hope that its "endless number of permutations" may be effective (based on a "three-part design" regimen) and "hope that a potentially promising drug will treat a particular cancer is not enough to create a reasonable expectation of success in a highly unpredictable art such as this.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2145. X. A. states, "Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Applicants may also argue that the combination of two or more references is “hindsight” because “express” motivation to combine the references is lacking. However, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See MPEP § 2141 and § 2143 for guidance regarding establishment of a prima facie case of obviousness.”
In the instant case, the obviousness rejection is based on the combined teachings of Salem and Sehested. As set forth above, Salem teaches cytotoxic particles comprising a biodegradable polymer and a cytotoxic agent for use in a method of treating a tumor, further comprising an immune checkpoint inhibitor, wherein the cytotoxic agent is belinostat and the immune checkpoint inhibitor is an anti-CTLA-4 antibody, tremelimumab. As set forth above, It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to formulate a composition comprising the cytotoxic particles comprising belinostat to further contain tremelimumab to formulate a composition to administer belinostat and tremelimumab concurrently. As set forth above, while the reference may not be anticipatory insofar as one must select belinostat from various cytotoxic agent compounds and tremelimumab from various immune checkpoint inhibitors as taught in Salem, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected belinostat detailed supra from the list of cytotoxic agents and tremelimumab from the list of immune checkpoint inhibitors that may be therapeutically effective in order to arrive composition useful for treating a tumor. The skilled person would have been motivated to do so by the unambiguous disclosure of each particular species of cytotoxic agents and immune checkpoint inhibitors individually and alternatively as equally useful in a method of treating a tumor.
With regard to the argument that Salem’s teachings are based on a "three-part design" regimen, the examiner notes that Salem explicitly teaches optionally including a T-cell stimulatory agent. Thus, the T-cell stimulatory agent is not required. As set forth above, one of ordinary skill in the art before the effective filing date of the invention would have readily envisaged a composition and/or kit consisting of belinostat and tremelimumab from the disclosure of Salem. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the pharmaceutical composition consisting of belinostat and tremelimumab to administer in concurrently in combination. Moreover, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to produce a kit consisting of the composition consisting of belinostat and tremelimumab to administer the compositions concurrently or sequentially.
Applicant argues:
Salem does not include unambiguous disclosure that each agent could be used individually as "equally useful in a method of treating cancer." If anything, Salem demonstrates that a two part administration as claimed would have no efficacy in cancer treatment. A person of ordinary skill in the art would not have expected the claimed compositions to have been useful for treatment of cancer. The efficacy associated with the claimed combinations, demonstrated only in the present application, was unexpected.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2143.02 states:
Conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018). Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that "[g]ood science and useful contributions do not necessarily result in patentability." Id. at 1364, 83 USPQ2d at 1304. Moreover, MPEP 2123 states:
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, as set forth above, Salem teaches a kit comprising as components (a) cytotoxic particles comprising (i) a biodegradable polymer and (ii) a cytotoxic agent and (b) an immune checkpoint inhibitor (claim 21). Salem further teaches the cytotoxic agent is belinostat (claim 22) and the immune checkpoint inhibitor is an anti-CTLA-4 antibody, tremelimumab (claim 23). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to formulate a composition comprising the cytotoxic particles comprising belinostat to further contain tremelimumab to formulate a composition to administer belinostat and tremelimumab concurrently with a reasonable expectation of success in view of the teachings of Salem.
Moreover, MPEP 2144.07 states that “[T]he selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination.” Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Applicant is also reminded that “[l]t is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985). In the instant case, as set forth above, Salem teaches a kit comprising as components (a) cytotoxic particles comprising (i) a biodegradable polymer and (ii) a cytotoxic agent and (b) an immune checkpoint inhibitor (claim 21). Salem further teaches the cytotoxic agent is belinostat (claim 22) and the immune checkpoint inhibitor is an anti-CTLA-4 antibody, tremelimumab (claim 23). As set forth above, while the reference may not be anticipatory insofar as one must select belinostat from various cytotoxic agent compounds and tremelimumab from various immune checkpoint inhibitors as taught in Salem, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected belinostat detailed supra from the list of cytotoxic agents and tremelimumab from the list of immune checkpoint inhibitors that may be therapeutically effective in order to arrive composition useful for treating a tumor. The skilled person would have been motivated to do so by the unambiguous disclosure of each particular species of cytotoxic agents and immune checkpoint inhibitors individually and alternatively as equally useful in a method of treating a tumor. This conclusion is supported by the fact that it has long been held in patent prosecution that a reference should be considered as expansively as is reasonably possible in determining the full scope of the contents within its four corners.
Furthermore, MPEP 2123 states:
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). In the instant case, the Examiner acknowledges that Salem exemplifies a three-step approach, a cytotoxic agent, an anti-CTLA-4 and anti-OX40 combination. However, Salem also teaches a kit comprising a cytotoxic agent and an immune checkpoint inhibitor where a T-cell stimulatory agent is optional. Thus, the anti-OX40 is not required in the compositions or methods taught by Salem.
Conclusion
Claims 1, 7-10, 27, and 28 are rejected.
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/Primary Examiner, Art Unit 1628