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 .
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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/22/2025 has been entered.
Claims 1-74 are cancelled and claims 75-81 are new. Claims 75-81 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 05 June 2020, claims domestic benefit to US provisional application 62/858,317, filed 06 June 2019.
Withdrawn Objections and Rejections
In the office action of 02/04/2025, claims 48, 52, 54-55, 57, 63, 66, and 71 were rejected under 35 USC 103 and on the grounds of nonstatutory double patenting. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following rejections rely on the same grounds of rejection and rationale as the rejections of 02/04/2025, as the new claims are the same in scope as the previously presented 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 75-81 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017 (herein “Bissonnette”) in view of Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
Bissonnette teaches combinations that include an HDAC Inhibitor (HDACi) and a PD-1 inhibitor that are useful for treating cancer, including reducing and/or preventing cancer metastasis (abstract). Bissonnette teaches that cancers that are treatable with the disclosed methods include solid tumors, including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma and hepatocellular carcinoma (page 12, [0157]).
Bissonnette teaches a combination therapy comprising an HDACi and a PD-1 inhibitor, such as a PD-1 antibody (page 1, [004]), and a method of treating cancer by administering a therapeutically effective amount of the combination to a patient in need thereof (page 1, [0013]). Bissonnette teaches that the HDACi can be selected from a group containing belinostat (page 34, claim 12) or the HDACi inhibitor can have the following structure, which is HBI-8000 (page 2, [0021]):
PNG
media_image1.png
167
404
media_image1.png
Greyscale
Bissonnette teaches that HBI-8000 is reported to inhibit HDAC 1, 2, 3, and 10 at low nanomolar concentrations and has an activity that is more active than Entinostat at HDAC 1, 2, 3, 8, 10, and 11. Bissonnette also teaches that HBI-8000 has a favorable pharmacokinetic profile and safety profile that allows for continuous dosing-oral administration (pages 18-19, [0200]). Bissonnette further teaches that HBI-8000 is administered 2 to 3 times per week (page 21, [0225]).
Bissonnette teaches that the inhibitor antibody comprises a human antibody, a mouse antibody a chimeric antibody, a humanized antibody, or a chimeric humanized antibody (page 9, [0108]). Bissonnette teaches that the inhibitor antibody is administered at an amount of about 0.1 mg/kg to about 30 mg/kg (page 10, [0121]) and teaches exemplary dosages including about 5 mg/kg (page 2, [0023]).
Bissonnette further teaches that the HDACi and antibody can be administered simultaneously or sequentially in either order (page 21, [0222]) and are administered as a treatment regimen (page 25, [0248]). Bissonnette teaches that HBI-8000 is administered orally, for example as a tablet or capsule, and the antibody is formulated for intravenous administration (page 11, [0134]).
Bissonnette teaches that the combinations disclosed can be administered to a cancer patient at any time following diagnosis, for example, the cancer patient can be treatment naïve, i.e., has not received a cancer therapy for the diagnosed cancer. Bissonnette also teaches that the combinations can be administered as a first line of therapy (page 18, [0198]).
Bissonnette teaches that the combination therapy can be used to reduce the level of myeloid-derived suppressor cells (MDSC) and Tregs in a patient and that the reduction can benefit the treatment of cancer (page 20, [0218] and [0219]).
Bissonnette further teaches that the clinical use of immune-oncology agents targeting CTLA-4 and PD-1, and its ligand PD-L1, have resulted in improvements over the standard of care in the treatment of many types of cancer. Bissonnette teaches that while these checkpoint inhibitors have improved clinical responses in certain cancers, durable clinical responses only occur in approximately 10-45% of patients and that a significant number of tumors are either become resistant or refractory. Bissonnette teaches that epigenetic modifiers such as HDACi have been successful in the treatment of some hematologic malignancies, but despite clinical data demonstrating activity against solid tumors, the result has not translated into the clinic as a monotherapy. Accordingly, Bissonnette teaches examples of combination therapies for the treatment of cancer (page 1, [0003]).
Bissonnette, however, does not disclose the addition of an anti-CTLA-4 antibody to the HBI-8000 and PD-1 antibody combination therapy.
Llopiz teaches that epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunomodulatory drugs. Llopiz studied the therapeutic efficacy of checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1 antibodies, in combination with the histone deacetylase inhibitor (HDACi), belinostat. Llopiz teaches that in subcutaneous murine HCC models, belinostat was shown to improve the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy, an effect which correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Llopiz further teaches that the combination of the HDACi and anti-CTLA-4 induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Llopiz then studied a combination of belinostat with the simultaneous blockade of CTLA-4 and PD-1 and teaches that it led to complete tumor rejection (abstract).
Llopiz teaches that epigenetic drugs targeting modifications at the DNA histone level are a group of antitumor agents and that while the presumed mechanism of action of the compounds was a direct antitumor effect, they can simultaneously modify antitumor immunity. Llopiz teaches that because of this, they may not only act at the level of tumor cells by modulating antigen expression and the machinery responsible for their presentation and recognition by T-cells, but they may also directly act on the immune system, activating effector cells, and inhibiting immunosuppressive mechanisms. Llopiz teaches that, accordingly, some of these compounds increase the efficacy of checkpoint inhibiting antibodies in different murine tumor models and that HDACi have demonstrated promising effects by improving the antitumor efficacy of immunotherapies based on anti-CTLA-4, anti-PD-1, or their combination (page 380, left column, paragraph 2).
Llopiz further teaches that epigenetic drugs may modulate tumor cell antigenicity/ immunogenicity leading to improved antitumor responses but that the in vitro results regarding expression of molecules involved in antigen presentation, co-stimulation, co-inhibition as well as T-cell recognition of tumor cells treated with belinostat do not point to this effect as the mechanism responsible for the enhanced antitumor efficacy. Llopiz teaches that, rather, it suggests that the increased efficacy of the combination therapy may be related to its effect on immune cells. Llopiz teaches that Belinostat is an HDACi that, according to its profile, can be considered a pan-inhibitor (page 380, left column, paragraph 2).
Chae teaches that recent evidence from pre-clinical studies evaluating immune checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-PD-1/PD-L1 plus anti CTLA-4 monoclonal antibodies is being evaluated in a wide range of tumor histologies as well as in combination with additional treatments such as chemotherapy, surgery, and radiation. Chae provides a review summarizing the current landscape of combination therapies with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC) (abstract).
Chae teaches that, at the time of publication, there was 44 ongoing clinical trials evaluating the combination of anti-PD-1/PD-L1 plus anti-CTLA-4 antibodies for patients with NSCLC and melanoma (page 4, right column, paragraph 2). Chae also discloses that there were 11 trials evaluating PD-1/PD-L1 blockade in combination with anti-CTLA-4 blockade in the treatment of renal cell carcinoma (page 16, Fig. 2a).
Chae teaches dosages of anti-PD-1/PD-L1 plus anti-CTLA-4 antibodies used in the trials that are in the range disclosed by Bissonnette including 1-10 mg/kg of anti-PD-1 antibody and 3-10 mg/kg of anti-CTLA4 antibody (page 17, left column, paragraph 3) and teaches that the combination therapy has demonstrated superior outcomes over single-agent regimens (page 19, right column, paragraph 2). For instance, Chae teaches that combination therapy in advanced melanoma has demonstrated better survival outcomes including a PFS and OS of 11.5 months and 58%, respectively, compared to anti-CTLA-4 monotherapy PFS and OS of 2.9 months and 19%, respectively, and anti-PD-1 antibody monotherapy PFS and OS of 6.9 months and 44%, respectively.
Chae further teaches a trial evaluating the combination of nivolumab (an anti-PD-1 antibody) and ipilimumab (an anti-CTLA-4 antibody) in combination with ACY241, an HDAC inhibitor (page 16, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the method of treating melanoma, renal cell carcinoma, and NSCLC with HBI-8000 and an anti-PD-1 antibody taught by Bissonnette to further include an anti-CTLA-4 antibody as taught by Llopiz and Chae. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma, NSCLC, or renal cell carcinoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma, NSCLC, and renal cell carcinoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
Response to Arguments
Applicant’s arguments in the response filed 12/22/2025 have been fully considered, but are not persuasive.
With regards to the rejection of the claims under 35 USC 103, applicant argues that, while the rejection articulates a basis for combining the cited references, the articulated reason would not have motivated a person of ordinary skill in the art to substitute HBI-8000 for belinostat (as taught by Llopiz) in a combination treatment with an anti-CTLA-4 antibody or to add an anti-CTLA-4 inhibitor to Bissonnette’s double combination (HBI-8000 plus anti-PD-1 antibody). Applicant argues that the approach applied in the rejection is essentially an “obvious to try” approach, but that the office action does not identify a finite number of identified, predictable solutions. Applicant argues that the rejection uses applicant’s own disclosure to piece together the prior art, which is not proper.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, specifically the use of applicant’s own disclosure to piece together the prior art, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Additionally, the rejection does not rely on KSR (E), obvious to try and; therefore, the rejection is not required to identify a finite number of identified predictable solutions in the art to meet the criteria of KSR(E). The rejection also does not propose the substitution of belinostat for HBI-8000 and, as such, is not required to provide any motivation for said substitution. It is noted, however, that Bissonnette does teach that the HDACi used in the combination can be belinostat or HBI-8000, suggesting analogous properties. Rather, the rejection relies on motivation and support from within the combination of applied references for the addition of the anti-CTLA-4 antibody to the combination of HBI-8000 and an anti-PD-1 antibody taught by Bissonnette. Specifically, as discussed in the rejection, Llopiz demonstrates that when an anti-CTLA-4 antibody is added to the combination of a HDACi and anti-PD-1 antibody, complete tumor rejection and enhanced activity is achieved compared to the HDACi combined with the anti-PD-1 antibody alone. It is also noted that conclusive proof of efficacy is not required in order to establish a prima facie case of obviousness, rather, the requirement is a reasonable expectation of success. See MPEP 2143.02 (I).
Applicant further argues that the previous response to arguments, in the office action of 02/04/2025, burden of proof regarding the complexity of the art was misplaced to applicant. Applicant argues that the office fails to articulate a finite number of identified, predictable solutions to the problem of treating renal cell carcinoma or small cell lung cancer and; thus, the rejection fails to establish a prima facie case of obviousness. Applicant argues that; therefore, the rejection fails to shift the burden of production to applicant to prove that cancer treatment is complex. Applicant further argues that the art demonstrates complexity, for instance, Bissonnette and Llopiz note failures with monotherapy with anti-checkpoint inhibitory antibodies often fails because of either inherent or acquired resistance to immunotherapy.
As discussed in detail above, the rejection does not rely on the KSR(E) rationale of obvious to try and; therefore, does not need to articulate a finite number of identified, predictable solutions to the claimed problem. Furthermore, a demonstration that monotherapy with checkpoint inhibiting antibodies may fail does not demonstrate that the addition of an anti-CTLA-4 antibody to the combination of HBI-8000 and anti-PD-1 for the treatment of the cancers disclosed by Bissonnette would have been unpredictable. This is particularly the case as the prior art is teaching combinations of HDACi and immune checkpoint inhibitors in order to overcome potential resistances and effectively treat the cancers. Reasonable expectation of success is addressed in the rejection, specifically that Llopiz teaches the triplet combination for the treatment of HCC which is an alternative cancer to melanoma, NSCLC, or renal cell carcinoma taught by Bissonnette. Additionally, Chae demonstrates that the combination of anti-CTLA-4 and anti-PD-1 antibodies were in studies for all three of the claimed cancers and had demonstrated superior results compared to monotherapies. Applicant does not provide any evidence to counter this reasonable expectation of success or to suggest that the specific modification of the rejection would have been unpredictable.
Applicant further argues that the showing of unexpected results in Example 1 and FIG. 1-3 should be reconsidered.
In example 1, applicant tested the efficacy of HBI-8000 in combination with anti-CTLA-4 and anti-PD-1 inhibitor antibodies in MC38 colon adenocarcinoma models. HBI-8000 was administered at a dosage of 50 mg/kg orally, once daily for twenty-one days (qdx21). Anti-CTLA-4 was administered at a dose of 2.5 mg/kg on days 1, 4, and 7 and anti-PD-1 was administered intraperitoneally at 5 mg/kg, twice a week for two weeks (page 59, [0195]). The anti-CTLA-4 antibody used was hybridoma clone 9H10 and the PD-1 mAb used was hybridoma clone RMPI-14 (page 60, footnote at the bottom of the table). Applicant tested 7 different treatments including a vehicle, HBI-8000 alone, CTLA-4 mAb alone, PD-1 mAb alone, CTLA-4 mAb in combination with HBI-8000, CTLA-4 mAb in combination with PD-1 mAb, and CTLA-4 mAb in combination with PD-1 mAb and HBI-8000 (pages 59-60, Table 2) and the study was continued until tumor volumes reached 3000 mm3 or the last day of the study, day 43 (page 60, [0196]). From this study, applicant concludes that the triple combination therapy resulted in significant tumor volume reduction (Fig. 1) and a 40-50% survival rate at the conclusion of the study (Fig. 2) demonstrating that HBI-8000 enhanced the activity of the triplet combination therapy (page 60, [0197]).
While applicant does demonstrate improved survival when the triple combination is used, the observed increase in activity and survival rate using the combination of the HDACi, anti-PD-1 inhibitor, and anti-CTLA-4 inhibitor would have been expected based on the teachings of the prior art.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
In this case, the applied reference Llopiz, demonstrates that the addition of anti-CTLA-4 to HDACi and anti-PD-1 combination therapy can lead to complete tumor rejection and provides synergistic outcomes (abstract). As Llopiz teaches an HDACi and a cancer that are taught by Bissonnette as alternatives in the disclosed methods, an ordinarily skilled artisan would have reasonably expected that similar synergistic responses would be observed when an anti-CTLA-4 antibody is added to the methods of Bissonnette where HBI-8000 and anti-PD-1 are used in combination to treat cancers.
With regard to this response, which was also provided in the office action of 02/04/2025, applicant argues that the office action does not provide objective evidence and instead suggests that one of ordinary skill in the art would have expected the difference to appear through normal variation. This, however, is not the case. As discussed above, Llopiz provides results, and objective evidence, demonstrating that the triple combination of an HDACi with anti-PD-1 and anti-CTLA-4 antibodies results in synergistic outcomes and complete tumor rejection. Results which suggest that the addition of an anti-CTLA-4 antibody to the combination of HBI-8000 and anti-PD-1 of Bissonnette would result in synergistic outcomes and improved survival.
In so far as applicant may argue the degree to which the survival is improved in the instant examples, applicant does not provide a comparison to the closest prior art in order to demonstrate that the results are unexpected compared to the teachings of the prior art.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (E) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).“ MPEP 716.02 II also states that when there is two equally close prior art references, “[s]howing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other. “
The closest prior art to examples discussed by applicant is the triplet combination taught by Llopiz. For instance, while applicant argues that the Kaplan-Meier plot of Fig. 2 shows that the triple combination group was the only group that achieved “any survival” among the several arms compared, including double combination arms, it is not established or demonstrated that this survival is surprising compared to the teachings of Llopiz, which suggests synergistic outcomes and complete tumor rejection when a triplet combination comprising an HDACi, anti-PD-1 antibody, and anti-CTLA-4 antibody combination is used. Rather, applicant compares the triplet combination to monotherapies, HBI-8000 + CTLA-4 antibody and CTLA-4 + PD-1 antibodies, all of which would be expected to result in less survival based on the teachings of the combination of applied art.
Applicant further argues that the outcomes are especially surprising when compared to the teachings of Bissonnette. Applicant argues that, while there is not a head-to-head comparison between the triple combination and Bissonnette’s double combination, Bissonnette shows, in Fig. 3, that HBI-8000 plus anti-PD-1 antibody achieved a positive 50 day survival rate; however, the rate was far lower than the 40-50% achieved with the instant triple combination. It is noted that, based on Fig. 3 of Bissonnette, the survival rate appears to be approximately 25% at 50 days. While applicant’s results, and the comparison to the results in Bissonnette, does demonstrate that the addition of an anti-CTLA-4 antibody to the HBI-8000 + PD-1 antibody combination does provide enhanced survival, this would have been expected in view of the teachings of Llopiz as discussed in detail above. Applicant does not provide any evidence to suggest that this increase is to a degree that would have been unexpected in view of the teachings of the prior art. Furthermore, it is noted that MPEP 716.02 states that “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
With this regard, applicant argues that while there is not a comparison against the belinostat-containing triple combination, Llopiz was not identified as the closest prior art, citing portions of the office action in which Bissonnette is modified by Llopiz. However, the required comparison to the prior art does not need to be limited to only a single art, nor is there is a requirement that the closest prior art used in comparison for unexpected results be the primary reference used in the rejection. For instance, as discussed above, MPEP 716.02 (e) discusses comparisons to closest prior art and provides details for comparison to art that is closer than that applied in the rejection as well as two equally close prior art references. The purpose of the comparison is to demonstrate that the results obtained by the applicant are unexpected over what would have been expected based on the prior art. While applicant’s results do demonstrate that the triple combination is superior to double combinations, this would have been expected based on the teachings of Llopiz. Applicant does not provide a comparison to Llopiz to demonstrate that the result is unexpected. For instance, a comparison of the claimed triple combination to the triple combination disclosed by Llopiz which comprises an anti-PD-1 antibody, anti-CTLA-4 antibody, and belinostat.
As discussed in detail above, applicant has not provided sufficient evidence of an unexpected result compared to the closest prior art references. In the case that unexpected results were identified, the results provided by applicant are also not commensurate in scope with the instantly claimed invention. MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
In this case, the independent claim is drawn to a method of treating melanoma, renal cell carcinoma, or NSCLC using HBI-8000, any PD-1 antibody, and any CTLA-4 antibody, where each of the two antibodies are administered at an amount of between 3 mg/kg to 10 mg/kg.
In the example of the instant disclosure referenced by applicant in the response, and discussed in detail above, only a single model of cancer was demonstrated, colon adenocarcinoma, in which a higher survival rate was observed when the triplet combination was used in comparison to the HDACi and anti-CTLA-4 combination. As such, applicant’s arguments of unexpected results is not commensurate in scope with the instantly claimed invention which is drawn to the treatment of alternative cancers including melanoma, renal cell carcinoma, and NSCLC. Additionally, the example demonstrates HBI-8000 in combination with a single anti-PD-1 and a single anti-CTLA-4 inhibitor, all at single, specific, dosages (see instant specification, [0195]). Therefore, the results presented in the example not commensurate with the scope of the claim in which any anti-PD-1 and any anti-CTLA-4 inhibitor are used at any concentration ranging from 3-10 mg/kg and in combination with any amount of HBI-8000.
In response to this response, which was presented in the office action of 02/04/2025, applicant argues that the MC38 tumor model is a syngeneic preclinical tumor model that is commonly used to demonstrate in vivo efficacy of immunoreactive anti-cancer drugs. Applicant notes that it is the same model used by Bissonnette and that Llopiz also uses an animal model, albeit one based on Hepa129 tumor cells. Applicant argues that, therefore, the MC38 model is a fair comparison of the claims with the prior art. Applicant further argues that a narrow range of dosages, 3-10 mg/kg is claimed narrowly bracketing the demonstrated dosage of 5 mg/kg. Applicant argues that the office action articulates no reasonable basis to which to criticize the tested range, other than an unsupported assertion that a head-to-head comparison against the prior art over the full range of the claims is needed.
As discussed in detail above, the results presented by applicant would have been reasonably expected in view of the prior art and applicant does not provide sufficient comparison to the closest prior art to demonstrate that the results are unexpected. Furthermore, even if applicant did demonstrate unexpected results, applicant does not provide a sufficient number of tests to demonstrate that the results are obtained over the entire scope of the claims. For instance, applicant does not demonstrate the outcomes that are supposedly unexpected with any other type of cancer, including those recited in the claim, nor does applicant provide a sufficient comparison of antibodies/dosages that are both inside and outside of the claimed range to demonstrate that the results span the entire scope of the claim. MPEP 716.02 (d) states “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).”
Additionally, it is noted that applicant’s arguments concerning the MC38 tumor model are contradictory to arguments made concerning the unpredictability and complex nature of the art. Here, applicant suggests a predictability between the MC38 (colon adenocarcinoma) tumor models studied and the claimed melanoma, renal cell carcinoma, and NSCLC; however, with regards to the applied prior art rejection, applicant argues that the art is not predictable.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Copending application 17/410,459
Claims 75-81 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 76-80 and 89 of copending Application No. 17/410,459 (herein “App’459”) in view of Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017.
App’459 claims a method of treating melanoma in a patient who was previously treated with a PD-1 inhibitor comprising administering a therapeutically effective amount of HBI-8000 and an anti-CTLA-4 inhibitor antibody. App’459 further claims that the HBI-8000 is administered once a day, twice a day, once a week, or twice weekly as a regimen.
While App’459 does not claim that HBI-8000 is administered with anti-PD-1 and anti-CTLA-4 antibodies as claimed in the instant claims, this addition would have been obvious in view of the prior art.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of App’459 to include the methods disclosed by Bissonnette and to further include anti-PD-1 and anti-CTLA-4 antibodies as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 12,122,833 B2
Claims 75-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of US 12,122,833 B2 (herein “US’833”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
US’833 claims a method for treating melanoma in a immune checkpoint inhibitor naïve subject in which 20 mg to 40 mg of HBI-8000 is orally administered to the subject in combination with intravenous infusion of a composition comprising a PD-1 antibody (claims 1-2, 8-11, and 16-18). US’833 further claims species of PD-1 antibody that include human antibodies such as nivolumab (claims 3-4 and 12-13). US’833 claims that the HBI-8000 is administered 2 times per week (claims 5-6 and 14-15).
The claims of US’833 differ from the instantly claimed invention in that US’833 does not claim the addition of anti-CTLA-4 to the combination of HBI-8000 and anti-PD-1.
The teachings of Bissonnette, Llopiz, and Chae and are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to have modified the method of treating melanoma with HBI-8000 and an anti-PD-1 antibody as claimed by US’833 to include the methods disclosed by Bissonnette and to further include an anti-CTLA-4 antibody as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is also teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
Copending application 17/993,567
Claims 75-81 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, and 14-21 of copending Application No. 17/993,567 (herein “App’567”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
App’567 claims a method for treating cancer comprising administering a therapeutically effective amount of a combination of HBI-8000 and a PD-L1 inhibitor antibody to a subject, wherein the cancer is one including NSCLC, melanoma, and renal cell carcinoma. App’567 further claims that the PD-L1 inhibitor is an antibody including species of human antibodies such as avelumab.
App’567 differs from the instant application in that the instant application claims the HDAC inhibitor HBI-8000 in combination with both anti-PD-1 and anti-CTLA-4 antibodies.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of App’567 to include the methods disclosed by Bissonnette and to further include an anti-CTLA-4 antibody as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 11,535,670 B2; Issued 12/27/2022
Claims 75-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, and 9-12 of U.S. Patent No. 11,535,670 B2; Issued 12/27/2022 (herein “US’670”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
US’670 claims a method of treating a colorectal cancer in a subject comprising administering to the subject a therapeutically effective amount of an HDAC inhibitor with a structure matching HBI-8000 in combination with an anti-PD-L1 antibody (US’670, claim 1). US’670 further claims that the subject is treatment naïve (US’670, claims 2-3) and that the combination is administered as a first, second, third, fourth, fifth, or sixth line of treatment (US’670, claims 4-5). US’670 claims that the subject has been treated with at least one anti-cancer therapy or anti-cancer agent (US’670, claims 6-7). US’670 further claims that the PD-L1 antibody is selected from antibodies which include human antibodies such as avelumab (US’670, claims 9 and 10). US’670 claims pharmaceutical compositions and kits of the active ingredients (US’670, claims 11 and 12).
While US’670 does not claim that the HBI-8000 is used in combination with anti-PD-1 and anti-CTLA-4 antibodies for the treatment of melanoma, NSCLC, or renal cell carcinoma.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of US’670 to include the methods disclosed by Bissonnette and to further include anti-PD-1 and anti-CTLA-4 antibodies as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
US 10,385,131 B2; Issued 08/20/2019
Claims 75-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 6-8 of U.S. Patent No. 10,385,131 B2; Issued 08/20/2019 (herein “US’131”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
US’131 claims a method of treating a solid cancer comprising administering an HDAC inhibitor in combination with an anti-PD-L1 inhibitor antibody and claims a genus structure of HDAC inhibitor that encompasses HBI-8000, as well as a structure matching HBI-8000 (US’131, claims 1 and 7-8). US’131 further claims that the subject has been previously treated with at least one prior line of anti-cancer therapy (US’131, claim 1). US’131 further claims that the PD-L1 inhibitor is an antibody including human antibodies, such as avelumab (US’131, claim 6). US’670 further claims that the cancer is melanoma, NSCLC, or renal cell cancer (US’670, claim 8).
The claims of US’131 differ from the instant claims in that US’131 does not claim that the HBI-8000 is used in combination with anti-PD-1 and anti-CTLA-4 antibodies.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of US’131 to include the methods disclosed by Bissonnette and to further include anti-PD-1 and anti-CTLA-4 antibodies as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
US 10,385,130 B2; Issued 08/20/2019
Claims 75-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-16 of U.S. Patent No. 10,385,130 B2; Issued 08/20/2019 (herein “US’130”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
US’130 claims a method of treating cancer comprising administering an HDAC inhibitor in combination with a PD-1 inhibitor antibody and claims a genus structure of HDAC inhibitor that encompasses HBI-8000, as well as a structure matching HBI-8000 (US’130, claims 1, 7-11, and 14-16). US’131 further claims that the subject has been previously treated with at least one prior line of anti-cancer therapy (US’130, claim 1). US’130 further claims that the PD-1 inhibitor is an antibody including human antibodies, such as nivolumab (US’130, claim 6). US’130 further claims that the HDAC inhibitor is administered alone for a period of time before administration of the HDAC inhibitor and the PD-1 inhibitor indicating sequential and simultaneous administration (US’130, claim 13). US’130 further claims that the cancer is melanoma, NSCLC, or renal cell cancer (US’130, claim 8)
The claims of US’130 differ from the instant claims in that US’130 does not claim that the HBI-8000 is used in combination with anti-PD-1 and anti-CTLA-4 antibodies.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of US’130 to include the methods disclosed by Bissonnette and to further include anti-PD-1 and anti-CTLA-4 antibodies as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
US 10,287,353 B2; Issued 05/14/2019
Claims 75-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-6 of U.S. Patent No. 10,287,353 B2; Issued 05/14/2019 (herein “US’353”) in view of US 2017/0327582 A1 (Bissonnette, R.P., et al) 16 November 2017, Llopiz, D., et al (2019) Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model Cancer Immunology, Immunotherapy 68; 379-393 and Chae, Y.K., et al (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) Journal for ImmunoTherapy of Cancer 6(39); 1-27.
US’353 claims a method of treating melanoma in a subject comprising administration of a compound matching instant HBI-8000 (US’353, claims 1 and 4-6) where HBI-8000 is administered via intravenous infusion at a dosage of about 30 mg BIW, indicating biweekly or 2 times per week (US’353, claim 2).
The claims of US’353 differ from the instant claims in that US’353 does not claim that the HBI-8000 is used in combination with anti-PD-1 and anti-CTLA-4 antibodies.
The teachings of Bissonnette, Llopiz, and Chae are as discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the claims of US’353 to include the methods disclosed by Bissonnette and to further include anti-PD-1 and anti-CTLA-4 antibodies as taught by Llopiz and Chae. It would have been obvious to incorporate the methods of Bissonnette as Bissonnette is teaching HBI-8000 in combination with an anti-PD-1 antibody for the treatment of melanoma. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as Llopiz demonstrates that HDAC inhibition combined with simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection and enhanced activity compared to an HDACi combined with anti-PD-1 antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as Llopiz demonstrates the treatment of HCC which is a cancer that Bissonnette teaches can be treated by the disclosed methods as an alternative to melanoma. Additionally, Bissonnette teaches belinostat as an alternative HDACi to HBI-8000 in the disclosed methods suggesting analogous properties. An ordinarily skilled artisan would have further had a reasonable expectation of success based on the teachings of Chae, which demonstrate that the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies had been considered for the treatment of melanoma and had demonstrated superior results compared to monotherapy, indicating that the addition of anti-CTLA-4 increases the efficacy of anti-PD-1 therapy.
Response to Arguments
Applicant’s arguments in the response filed 12/22/2025 have been fully considered, but were not persuasive.
With regards to the nonstatutory double patenting rejections, applicant argues that a prima facie case of obviousness type double patenting does not exist, even applying a two-way test of ODP. Applicant references MPEP 804, subparagraph 5.
A two-way test of ODP, however, is not required in the instant application.
MPEP 804, subparagraph 5 states that “A two-way test is to be applied only when the applicant could not have filed the claims in a single application and the Office is solely responsible for any delays.”
MPEP 804, subparagraph 4 states that “if the patent term filing date of an application under examination is the same or later than that of a reference application or patent, only a one-way determination of distinctness is needed in resolving the issue of double patenting, i.e., whether the invention claimed in the application would have been anticipated by, or an obvious variation of, the invention claimed in the reference application or patent.”
This section of the MPEP goes on to state that “even if the application under examination has the earlier patent term filing date, only a one-way determination of distinctness is needed to support a double patenting rejection in the absence of a finding: (A) that "the PTO is solely responsible for any delays" in prosecution of that application… and (B) that the applicant could not have filed the conflicting claims in a single (i.e., the earlier-filed) application.”
As these criteria are not met for the instant application, two-way analysis for ODP is not required.
Applicant further argues that the claims are non-obvious over the cited US patents and co-pending applications for reasons analogous to those articulated regarding the rejection under 103. Applicant further argues that the claims of the cited patents and applications would not have been obvious over the pending claims, at least because each could be practiced without practicing the claimed method. Applicant argues that each of the cited patents and applications claim combination therapy with HBI-8000 and either a PD-1 inhibitor or a PD-L1 inhibitor. Applicant argues that one could practice those methods, all or which do not require the use of a CTLA-4 inhibitor without practicing the claimed method, which does require a CTLA-4 antibody.
Applicant’s arguments pertaining to the rejection under 103 were not persuasive for the reasons discussed above. Therefore, the arguments are also not persuasive in regards to the double patenting rejections.
Additionally, while the claims of the cited patents could be practiced without practicing the claimed method, this is inconsequential to the double patenting rejections of record. MPEP 804 II.B. states that “A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s).”
In this case, as described in the rejections of the instant office action, while the claims of the issued patents or the copending applications are drawn to the combination of HBI-8000 with either a PD-1 or a PD-L1 inhibitor, it would have been obvious to modify the claims in view of the prior art to arrive at the instantly claimed invention. Therefore, the claims of the instant application are obvious over the claims of the cited patents and applications.
Applicant further argues that if the claims of the instant application had been presented in the same application as the cited applications and patents, it is altogether likely that the examiner would have required a restriction. This speculation alone, however, is not sufficient to demonstrate that the claims of the instant application and those of the cited patents/co-pending applications are not obvious variants of one another.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693