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.
Priority
The instant application, filed 05 June 2020, claims domestic benefit to US provisional application 62/858,317, filed 06 June 2019.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 07/21/2026 is acknowledged. Claims 79-80 are amended and claims 1-74 are cancelled. Claims 75-81 are currently pending and are examined on the merits herein
Withdrawn Objections and Rejections
The claims were rejected on the grounds of nonstatutory double patenting provisionally over copending applications 17/410,459 and 17/993,567; and over US 12,122,833 B2; US 11,535,670 B2; US 10,385,131 B2; US 10,385,130 B2; and US 10,287,353 B2; Applicant’s filing and the approval of a terminal disclaimer has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are maintained.
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]):
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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 07/21/2026 have been fully considered, but are not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that one of ordinary skill in the art would not have been motivated to select the specific combination of elements claimed from the myriad of possible combinations of oncology drugs. Applicant argues that Bissonnette does not present data related to the combination of belinostat plus anti-PD-1 antibody. Applicant further argues that Bissonnette broadly stating that HDAC can be combined with other active agents is not sufficiently specific to suggest the instantly claimed triple combination for the treatment of melanoma, RCC, or NSCLC.
These arguments are not persuasive.
The rejection of the claims does not rely on the selection of the claimed combination from all possible combinations of oncology drugs as suggested by applicant in the response, nor does the rejection rely on the teachings of Bissonnette alone, rather the rejection relies on specific motivation and reasonable expectation of success identified in the prior art for combining a HDACi, which HBI-8000 is, with anti-PD-1 and anti-CTLA-4 antibodies. As discussed in the rejection, Bissonnette teaches the treatment of melanoma, RCC, or NSCLC with HBI-8000 and an anti-PD-1 antibody. The teachings of Llopiz and Chae further motivate and provide a reasonable expectation of success for including an anti-CTLA-4 antibody in the methods of Bissonnette teaching that HDACi combined with anti-CTLA-4 and PD-1 simultaneously can lead to complete tumor rejection and enhanced activity compared to a HDACi combined with anti-PD-1 antibody alone (Llopiz) and that anti-CTLA-4 and anti-PD-1 antibodies had been combined for the treatment of melanoma RCC, and NSCLC and had demonstrated superior results compared to monotherapy (Chae). The rejection is based on the combination of these references and what the references would have suggested to an ordinarily skilled artisan prior to the effective filing date of the claimed invention. See MPEP 2145 (IV).
Regarding applicant’s arguments that Bissonnette does not present data concerning belinostat plus anti-PD-1 antibody; Bissonnette does provide data for the treatment of tumors using a combination of HBI-8000, which is the instantly claimed HDACi, and anti-PD-1 compared to each of the treatments alone and vehicle controls. Reference to belinostat in Bissonnette is recited in the instant rejections in order to demonstrate that Bissonnette had considered belinostat as an alternative HDACi for the methods disclosed, which indicates that Bissonnette considered that the HDACi would have analogous properties.
Furthermore, none of the applied references are required to provide experimental data in order to establish a prima facie case of obviousness as the standard for obviousness is a reasonable expectation of success. See MPEP MPEP 2143.02 (I) which 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) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
Applicant further argues that the instant application is the first to provide evidence of outstanding activity of the triple combination of HBI-8000, anti-PD-1 antibody, and anti-CTLA-4 antibody in a relevant syngeneic immunologically active tumor model, i.e., MC38 tumor in C57BL/6 mice. Applicant argues that Llopiz teaches that in only one particular type of cancer model, HEPA129 in a CH3 mouse, the triple combination of belinostat, PD-1 antibody, and CTLA-4 antibody was especially effective. Applicant argues that HEPA129 is not a well-established model for studying the effects of immunotherapy and that it is not relevant to the narrow range of cancers recited in the claims (melanoma, RCC, NSCLC). Applicant argues that, in contrast, MC38 tumor model in C57BL/6 mice, which applicant exemplifies, is a well established syngeneic mouse model considered the gold standard for validating immune therapy potential.
This argument is not persuasive.
While it is appreciated that applicant provides experimental data demonstrating the claimed triple combination in MC38 tumor models in C57BL/6 mice, conclusive proof of efficacy is not required in order to establish a prima facie obviousness as discussed above.
As discussed by applicant in the response, the instant disclosure studied the claimed combination in MC38 tumor models, which is a colon adenocarcinoma model. Applicant argues that the HEPA129 cell line used in Llopiz, which is hepatocellular carcinoma, is not reflective of the instantly claimed cancers; however, even applicant does not experimentally demonstrate the claimed combination in the instantly claimed cancers. Additionally, while applicant argues that the model used in the instant examples provides a better standard for validating immune therapy potential compared to the model used by Llopez, applicant does not provide any support for such speculative statements nor does applicant provide any evidence that the model used by Llopiz is insufficient to demonstrate the benefits of the combination of an HDACi, anti-PD-1 and anti-CTLA-4. This is particularly the case in view of the teachings of Bissonnette, which suggests HCC as an alternative to melanoma, RCC, and NSCLC as a cancer that can be treated and Chae which demonstrates anti-PD-1 and anti-CTLA-4 in combination to treat the claimed cancers demonstrating a nexus among the art with regards to the cancers that can be treated with HDACi, PD-1 antibodies and CTLA-4 antibodies.
Applicant continues to maintain that the art is unpredictable; however, if it was established that the art is indeed unpredictable, which it is not, such unpredictability would also raise questions regarding applicant’s own claims as applicant does not provide any evidence of the claimed triple combination treating the claimed cancers to any unexpected degree.
Applicant further argues that the art is replete with possible combination therapies of which applicant’s is only one. Applicant cites Chae as disclosing summaries of combination therapies known in the art at the time of the effective filing date. Applicant argues that one of ordinary skill in the art would have to read applicant’s disclosure to find motivation for the specifically claimed combination. Applicant also argues that, while the rejection does not rely on KSR (E), KSR (E) speaks directly to the type of combination of references set forth in the instant office action. Applicant argues that KSR (E) makes it clear that where the standard is obvious-to-try, the number of options should be finite, small, and predictable.
Although the art discloses alternative cancer treatment methods and there were alternative treatment methods known, the disclosure of alternative methods does not criticize, discredit, or otherwise discourage the claimed method and; therefore, the knowledge of alternatives does not teach away from the claimed invention. See MPEP 2123 (II).
With regards to applicant’s argument that one of ordinary skill in the art would have to read the instant disclosure to find motivation for the claimed combination, motivation for the combination is also found in the prior art as discussed in the rejection. For instance, Llopiz demonstrates that by adding a CTLA-4 inhibitor to the combination of an HDACi and anti-PD-1, complete tumor rejection and enhanced activity is observed compared to the HDACi and anti-PD-1 alone. Chae also supports the addition of the anti-CTLA-4 antibody to the methods of Bissonnette, teaching that anti-CTLA-4 antibodies in combination with anti-PD-1 antibodies has demonstrated superior results compared to monotherapy and had been considered for use in the claimed cancers.
Furthermore, 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).
With regards to KSR(E), as stated by applicant in the response, the rejection does not rely on KSR(E). Even if KSR(E) could have been applied in the rejections, as the claimed treatments were known, the rejection does not rely on KSR(E), but rather, relies on specific teachings, suggestions, and motivation from the art that would have led one of ordinary skill in the art to arrive at the instantly claimed invention. It is noted that this is the basis of KSR rationale (G). MPEP 2143 I.G. states “[t]he rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006)… The courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649.”
Applicant further argues that the disclosure demonstrates unexpected superiority of the combination in an art-recognized, immunologically relevant tumor model (MC38/C57BL/6) over the closest prior art, represented by the double combination of Bissonnette. Applicant argues that attempting to substitute Llopiz as the closest prior art does not strengthen the rejection because of the tumor model used in Llopiz, which applicant argues is not relevant to immunologically active melanoma, RCC, or NSCLC. Applicant argues that the instant application also compares those results to all three double combinations, including the double combination taught and exemplified by Bissonnette and demonstrates superior activity over the closest prior art.
It is first noted that applicant’s arguments concerning the tumor model used in Llopiz is not persuasive for the reasons discussed in detail above.
That said, while applicant does demonstrate improved survival when the triple combination is used, for instance in Example 1 and Figs. 1-3 of the instant disclosure, 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.
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. “
As discussed in detail in the rejection, the art suggests combinations including HBI-8000 + anti-PD-1; belinostat (an HDACi) + anti-PD-1 + anti-CTLA-4; and anti-PD-1 + anti-CTLA4. While applicant does compare the claimed combination to double combinations (in the previous response using results from Bissonnette for HBI-8000 + anti-PD-1), applicant does not provide a comparison to the triple combination that is taught by Llopiz in order to establish that the claimed method results in unexpected outcomes compared to the closest prior art.
While applicant argues that Bissonnette is the closest prior art, and that this comparison was provided, MPEP 716.02 (II) states that if there are two equally close prior art references, a comparison to one will not rebut obviousness unless the prior art is sufficiently similar to each other that the comparison of one would provide the same information as a comparison to the other. In this case, a comparison to Bissonnette alone, or even anti-PD-1 and anti-CTLA-4 in combination, is not sufficient as the prior art applied teaches a combination of HDACi, anti-PD-1, and anti-CTLA-4. 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, 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 this regard, 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; however, applicant does not demonstrate the outcomes that are supposedly unexpected with any other type of cancer, including those recited in the claim. Applicant also does not provide any evidence that the MC38 tumor model results would be the same in the claimed cancers if unexpected results were identified. Additionally, applicant does not 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).”
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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