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 05/12/2021 claims domestic benefit to US provisional application 63/023,554, filed 05/12/2020.
Status of Application, Amendments, and/or Claims
Applicant’s amendment filed 11/18/2025 is acknowledged. Claim 1 is amended and claims 2-7 and 10-36 are cancelled. Claims 1 and 8-9 are currently pending and are under examination herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/04/2025, 09/25/2025, 10/01/2025, and 12/23/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
The following grounds of rejections are new or maintained as necessitated by applicant’s amendment to the claim.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 8-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “significant”, as added in claim 1, is a relative term which renders the claim indefinite. The term “significant” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
As amended, the claim recites a “significant” increase in one or more of OS, PFS, or SR at the recited time points. However, none of the claims, or the specification, define what the increase would have to be to meet the limitation of significant, rendering the metes and bounds of the claim indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Okusaka, T. and M. Ikeda (2018) Immunotherapy for hepatocellular carcinoma: current status and future perspective ESMO Open 3(e000455); 1-6 in view of NCT03638141 v8 (sponsor: Sidney Kimmel Comprehensive Cancer Center at John Hopkins) posted 01 MAY 2019 (herein “John Hopkins”), NCT02938793 (v3) (Sponsor: Prisma Health-Upstate) posted 22 FEB 2018 (herein “Prisma”), Tai, D., et al (2019) Rationale of Immunotherapy in Hepatocellular Carcinoma and Its potential biomarkers Cancers 11; 1-27, Yau, T., et al (2019) Abstract 4012: Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040 Journal of Clinical Oncology 37(15); 2 pages and Wolchok, J.D., et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma N. Engl J Med. 377(14); 1345-1356.
Okusaka teaches that numerous clinical studies were underway to evaluate the efficacy of immune checkpoint inhibitor for patients with many kinds of cancer, including hepatocellular carcinoma (HCC). Synergistic effects of immune checkpoint inhibitors used in combination with molecular targeted agents or local therapy have also been suggested, resulting in expectations regarding the use of these drugs in combination with existing standard treatment methods for HCC (abstract). Okusaka teaches that the PD-L1/PD-1 pathway that constitutes the immune checkpoint mechanism is now considered to serve as the most important treatment and current efforts focused on anti-PD-1 antibodies or anti-PD-L1 antibodies for HCC (page 1, right column, monotherapy with an immune checkpoint inhibitor). Okusaka discusses HCC studies using PD-1/PD-L1 antibodies including nivolumab, pembrolizumab, tislelizumab, camrelizumab, spartalizumab, durvalumab, atezolizumab, and avelumab, as well as anti-CTLA-4 antibodies including tremelimumab and ipilimumab (page 2, table 1).
Okusaka further teaches that anti-CTLA-4 antibodies bind to CTLA-4 molecules expressed on the surface of cytotoxic T cells and regulatory T cells and thus reinforce the antitumor activity of cytotoxic T cells, thereby enhancing the immune responses induced by PD-1/PD-L1 inhibitors (paragraph bridging pages 3 and 4). Okusaka teaches that combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab was being assessed in a phase I/II clinical trial for patients with HCC. The phase 1 study enrolled 40 patients and had a response rate of 25%, suggesting that the combination therapy might be more effective than durvalumab monotherapy. The study also showed that the combination had a manageable toxicity profile. At the time of publication, a global phase III trial was underway to compare the efficacy of different regimens as a first line treatment; the four arms consist of durvalumab monotherapy, two regimens of durvalumab + tremelimumab combination therapies, and sorafenib monotherapy (page 4, left column, paragraph 2).
Okusaka teaches durvalumab plus tremelimumab as a first-line therapy (page 4, left column, paragraph 2; page 2, Table 2, First-line therapy), indicating that, prior to treatment, the patient had not received any therapy for HCC, including systemic therapies.
Okusaka further teaches that local therapy for cancer is expected to affect the tumour microenvironment and to reinforce the efficacy of immune checkpoint inhibitors. In addition, it is expected to enhance therapeutic efficacy by stimulating the release of tumour-associated antigens and neoantigens from cancer cells into the blood. Furthermore, the combination of radiotherapy with chemotherapeutic agents is expected to increase neoantigen release through a DNA-disturbing activity, possibly resulting in a higher efficacy of immune checkpoint inhibitors, the induction of immunogenic cell death, and the reinforcement of therapeutic efficacy through a decrease in immunosuppressive cells such as Treg cells and myeloid-derived suppressor cells. In patients with HCC, in particular, local therapy such as radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE) has often been used as a standard therapy, and many clinical studies have been started with the expectation of synergistic effects when immune checkpoint inhibitors are combined with such local therapeutic approaches (page 5, left column, paragraph 2).
Okusaka teaches the combination of nivolumab with TACE using drug-eluting beads (DEB-TACE) and teaches that, in Germany, a trial of this combination compares two regimens in which TACE is applied repeatedly at 8-week intervals and nivolumab treatment is started either 1 day after TACE or 2 days after TACE (days 2-3) and subsequently at repeated at intervals of 2 weeks (page 5, left column, paragraph 3). Okusaka also teaches a study combining pembrolizumab and TACE in which pembrolizumab treatment is started 30 or 45 days after TACE (page 5, left column, paragraph 4).
Okusaka further teaches a pilot study regarding the combination of tremelimumab with local therapy including RFA or TACE. In the study, tremelimumab was administered at 4-week intervals and local therapy was applied on day 36 (page 5, paragraph bridging right and left columns).
Okusaka, however, does not disclose the claimed regimen of durvalumab and tremelimumab or that administration results in a significant increase in OS, ORR, PFS, and/or SR of the subject at 12 months and/or 18 months as compared to an untreated subject as claimed.
John Hopkins is a phase 2 clinical trial designed to determine the safety and efficacy of immunotherapy comprising durvalumab, an anti-PD-L1 antibody, also known as MEDI4736, and tremelimumab, an anti-CTLA-4 antibody, combined with Drug-eluting Bead Transarterial Chemoembolization (DEB-TACE) in patients with Hepatocellular Carcinoma (HCC) (page 3, Study Description, Brief Summary; page 4, Study design, Study Phase; page 2, Official title).
In John Hopkins, patients received 4 doses of durvalumab, 1500 mg by IV, every 4 weeks starting at week 2 and a single dose of tremelimumab, 300 mg by IV, starting at week 2. If patients demonstrated a complete response at week 15, patients were eligible to receive 9 additional doses of durvalumab, at the same dosage, every 4 weeks (page 5, Arms, Experimental: Cohort A- durvalumab and single-dose tremelimumab).
Prisma is a phase 2 clinical trial designed to study durvalumab in combination with tremelimumab in subjects with advanced rare solid tumors (page 2, official title). In the study, patients were intravenously administered durvalumab at 1500 mg, which is stated to be equivalent to 20 mg/kg. Patients would additionally be intravenously administered tremelimumab at 75 mg, which is stated to be equivalent to 1 mg/kg. Prisma discloses that tremelimumab will be administered first and the infusion duration would be approximately 1 hour. The durvalumab infusion would start approximately 1 hour after the end of the tremelimumab infusion and administered over approximately 1 hour (page 3, detailed description, paragraph 2). Teachings which demonstrate administration on the same day. The infusion regimen of Prisma also meets the instant claim 8 limitations of separate and sequential administration as the antibodies are administered separately one following the other.
As Prisma teaches that 75 mg of tremelimumab is equivalent to 1 mg/kg, an ordinarily skilled artisan would have reasonably concluded that 300 mg is equivalent to 4 mg/kg of tremelimumab, as 300 mg is 4 times the 75 mg dosage which would suggest 4 times the 1 mg/kg equivalent. Using these dose equivalents, the treatment regimens of John Hopkins for the combination of durvalumab and tremelimumab are equivalent to those of the instant claims.
Tai teaches that HCC is the most common type of liver cancer and is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly immune checkpoint blockade (ICB) (abstract). Tai teaches that it is known that anti-PD-1 and anti-CTLA-4 antibodies have differences in their underlying functional mechanisms. For instance, anti-PD-1 ICB was thought to act primarily at the interface of T cells and tumor cells within the local tumor microenvironment, while anti-CTLA4 ICB was shown to be able to act more upstream at the phase of T cells priming at the lymph nodes. Hence, the combination of anti-PD-1 and anti-CTLA-4 antibodies has been studied based on its potential synergistic antitumor activity (page 13, 2.4.1, paragraph 1). Tai teaches antibodies to the PD-1/PD-L1 pathway that were currently in trial for the treatment of HCC including nivolumab, pembrolizumab, avelumab, durvalumab, and atezolizumab (page 2, 2.1.1, paragraph 1; page 3, 2.1.2, paragraph 1). Tai further teaches anti-CTLA-4 antibodies including ipilimumab, and tremelimumab (page 3, 2.1.3, paragraph 1).
Tai teaches that a combination of nivolumab and Ipilimumab, which was first evaluated in a phase III trial for patients with advanced melanoma, demonstrated superior outcomes in terms of both progression-free survival and median survival compared to monotherapy with nivolumab or ipilimumab alone; providing impetus for other solid tumors including HCC. Tai discusses results from the CheckMate 040 clinical trial which evaluated combination nivolumab and ipilimumab in 148 sorafenib treated patients. Tai teaches that the overall response rate was 31% with 7 complete responses and that the 24-month overall survival rate was 40%. Tai further teaches that encouraging results promoted the commencement of CA209-9DW, a phase 3 trial comparing combination ipilimumab and nivolumab against sorafenib or lenvatinib in the treatment of naïve advanced HCC (page 13, 2.4.1., paragraph 1).
Tai further teaches median overall survival of subjects in HCC clinical trials including anti-PD-1/PD-L1 and anti-CTLA-4 monotherapies in which median overall survival is reported to range from 8.2-16.4 months. Median overall survival is also reported for studies with sorafenib as 14.7 months or in placebos as 10.6 months (page 4, Table 1).
Yau further details the CheckMate 040 study discussed by Tai and discloses that patients had a median overall survival as high as 23 months. Yau further discloses 12-month overall survival rates as high as 61% and 24-month survival rates as high as 48% (results; Table provided). Yau concludes that NIVO+IPI led to clinically meaningful responses and had an acceptable safety profile in SOR treated patients with an ORR twice that of NIVO monotherapy, specifically 31% and 14%, respectively (conclusions).
Wolchok discloses results from nivolumab and ipilimumab combination therapy used in the treatment of advance melanoma, results which Tai references as providing impetus for other solid tumors including HCC. Wolchok teaches that at a follow-up of more than 33 months in a phase 1 dose finding study, nivolumab plus ipilimumab resulted in an overall survival rate at least 3 years among 68% of patients, regardless of whether they had received previous treatment. Results from the randomized phase 2 CheckMate 069 trial involving previously untreated patients showed a rate of overall survival at 2 years of 64% in the group that received combination therapy and 54% in the group that received ipilimumab alone. Previously reported data from the phase 3 CheckMate 067 trial involving patients with previously untreated advanced melanoma showed significantly longer progression-free survival and higher rates of objective response with nivolumab plus ipilimumab and with nivolumab alone than with ipilimumab alone. Wolchok presents the analysis of 3-year overall survival from the CheckMate 067 trial (page 2, paragraph 2).
In figure 1, Wolchok shows PFS and OS for patients treated with nivolumab plus ipilimumab compared to nivolumab alone and ipilimumab alone from months 0-45 after treatment. In the figures, PFS is shown to be higher at both 12 and 18 months in the combination group compared to either monotherapy. At 12 months, overall survival is comparable between the nivolumab and ipilimumab combination group and the nivolumab monotherapy group, and both groups have higher overall survival than the ipilimumab treated group. At 18 months, overall survival is shown to be slightly higher in the group treated with the combination vs nivolumab monotherapy and much higher than the group treated with ipilimumab monotherapy. Wolchok teaches that median overall survival was not met at 2 years for the combination therapy but was met for the nivolumab and ipilimumab groups (page 6, paragraph 1). Wolchok also teaches that combination therapy has been shown to have a higher rate of objective response than nivolumab alone regardless of the tumor PD-L1 expression level (page 8, paragraph 4). Wolchok teaches that in the study, the objective response rate was 58% for the combination treatment compared to 44% and 19% for the nivolumab and ipilimumab monotherapies, respectively (Table 1, page 16).
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 disclosed by Okusaka, in which durvalumab and tremelimumab are administered as a first line therapy to treat HCC, by using the dosing regimens of John Hopkins in which druvalumab and tremelimumab are administered at dosages of 1500 mg and 300 mg, respectively, with durvalumab administered every 4 weeks and tremelimumab administered once. It would have further been obvious to administer the durvalumab and tremelimumab in weight bases dosages of 20 mg/kg and 4 mg/kg, respectively, according to the equivalence taught by Prisma, and separately and sequentially on the same day as taught by Prisma. An ordinarily skilled artisan would have reasonably expected that the treatment would significantly increase OS at 15, 18, and/or 21 months and/or PFS and/or SR of the subject at 12 months and/or 18 months as compared to a subject not receiving the treatment method, based on the teachings of Tai, Yau, and Wolchok.
It would have been obvious to one of ordinary skill in the art to administer durvalumab and tremelimumab according to the methods disclosed by John Hopkins and Prisma as John Hopkins and Prisma demonstrate that these were known administration regimens for durvalumab in combination with tremelimumab, which is the same antibody combination taught by Okusaka for the treatment of HCC. Additionally, John Hopkins is teaching the treatment of HCC with the disclosed dosages. The use of weight based mg/kg equivalent dosages compared to flat mg dosages is further supported by KSR(E). See MPEP 2143. In this case, the prior art demonstrates that administration of the antibodies in both mg and mg/kg dosages were known in the prior art. Therefore, it would have been obvious to an ordinarily skilled artisan to try either of these dosing methods with the reasonable expectation that the dosing would be equivalent based on the teachings of Prisma.
An ordinarily skilled artisan would have reasonably expected that the treatment would result in significant increases in OS at 15, 18, and/or 21 months and/or PFS and/or SR of the subject at 12 months and/or 18 months compared to a subject not treated, based on the teachings of Tai, Yau, and Wolchok.
As discussed in detail above, Tai provides an overview of anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy clinical trials in HCC and discloses overall median survival in the studies ranging from 8.2-16.4 months. Additionally, Tai teaches that for sorafenib and placebo, the median overall survival was 14.4 and 10.6 months, respectively (page 4, Table 1). Tai further teaches that in studies using a combination of anti-PD-1 and anti-CTL-4 antibodies, overall survival rates at 24 months were 40% (page 13, paragraph 1), referencing results from the CheckMate 040 study. The results from the study are further elaborated on by Yau, which teaches that the median overall survival with combination therapy was as high as 23 months with a 12-month overall survival rate as high as 61% (table). Based on these results, an ordinarily skilled artisan would have reasonably expected that subjects treated with the method taught by the combination of John Hopkins and Prisma would result in a significant increase in OS at 15, 18, and/or 21 months as Tai and Yau demonstrate significantly higher median overall survival rates with combination of PD-1/PD-L1 and CTLA-4 checkpoint blockade compared to controls and other therapies. As Tai and Yau demonstrate higher median overall survival using combination therapies, an ordinarily skilled artisan would also reasonably expect that survival rate would also be increased. This is particularly the case as Yau teaches overall survival rates at 12-months and 24-months to be as high as 61% and 40% while the median overall survival in monotherapies and alternative therapies suggest 50% survival by as low as 8.2 months.
An ordinarily skilled artisan would have also had a reasonable expectation that progression free survival would be increased through the use of combination therapy based on the teachings of Wolchok. Wolchok demonstrates that in clinical trials in melanoma, nivolumab and ipilimumab resulted in higher PFS at 12 and 18 months compared to studies using either as a monotherapy. Additionally, overall survival is higher for the combination at 18 months compared to either monotherapy and higher than ipilimumab monotherapy at 12 months. Wolchok also teaches that median overall survival was not met at 2 years for the combination therapy but was met for the nivolumab and ipilimumab groups. While Wolchok studied melanoma and not HCC, Tai teaches that results from melanoma provided impetus for other solid tumors, including HCC. As the results disclosed by Tai and Yau demonstrate that clinical responses in HCC, such as overall survival and overall response rates, are higher in subjects treated with a combination of PD-1/PD-L1 and CTLA-4 blockade, an ordinarily skilled artisan would also reasonably expect that progression free survival would also be increased such as is seen in the results of Wolchok in the treatment of melanoma.
It is noted that, while Tai, Yau, and Wolchok teach clinical trial results from the combination of nivolumab and ipilimumab, not durvalumab and tremelimumab, an ordinarily skilled artisan would nevertheless have expected similar results as nivolumab and ipilimumab are blocking the same pathways, specifically the PD-1/PD-L1 and CTLA4 pathways as demonstrated by the teachings of Tai. The comparison of PD-1/PD-L1 pathway blocking antibodies is further supported by Okusaka which teaches that the PD-L1/PD-1 pathway that constitutes the immune checkpoint mechanism is now considered to serve as the most important target of treatment and that antibodies to both PD-L1 and PD-1 had been considered in the treatment of HCC to inhibit the immune checkpoint.
It is also noted that, while the dosage regimens of the instant claims would have been obvious in view of the combination of John Hopkins, Prisma, Okusaka, Tai, Yau, and Wolchok as described above, the determination of an optimal treatment regimen is considered to be routine optimization where considerations were known in the prior art.
MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, dosage and administration frequency were known to be result-effective variables and an ordinarily skilled artisan would have been able to use the teachings of the prior art and optimization that is routine in the field to determine optimal dosage regimens for the combination therapy.
Response to Arguments
Applicant’s arguments in the response filed 11/18/2025 have been fully considered, but were not persuasive.
With regards to the rejection of the claims under 35 USC 103, applicant argues that John Hopkins teaches away from the claimed invention and the combination of Okusaka, John Hopkins, Prisma, Tai, Yau, and Wolchok. Applicant argues the office action misrepresents what Okusaka discloses. Applicant cites Okusaka page 4, left column, paragraph 2, which is cited in the rejection and states the following:
“At present, a global phase III trial is underway to compare the efficacy of different regimens as a first-line treatment; the four arms consist of durvalumab monotherapy, two types of durvalumab+tremelimumab combination therapies (regimens 1 and 2) and sorafenib monotherapy (NCT03298451).”
Applicant argues that, based on this statement, it is not clear which of the regimens are being investigated as first-line treatments. This argument, however, is not persuasive. Okusaka clearly states that the efficacy of the different regimens, which include all of durvalumab monotherapy, two types of durvalumab + tremelimumab combination therapies, and sorafenib monotherapy, were being tested as a first-line treatment. Teachings which clearly identify that the regimens recited were all being investigated as first-line treatments. Applicant does not provide sufficient evidence to suggest that this is not the case or that the referenced study, NCT03298451, does not include first-line therapies with durvalumab + tremelimumab as is clearly indicated by Okusaka.
Applicant further argues that the combination of applied references does not provide data or statements that demonstrate that the phase III NCT03298451 trial was, or would be successful. Applicant argues that the first report that the study was successful is the current application, which is the referenced phase III clinical HIMALAYA trial.
While the teachings of the applied references do not provide data concerning the outcomes of NCT03298451, conclusive proof of efficacy is not required as the standard for a prima facie case of obviousness is a reasonable expectation of success. MPEP 2143.02 (I) states that “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 John Hopkins teaches away from the cited combination of references. Applicant argues that John Hopkins was published after Okusaka and explicitly requires administration of DEB-TACE prior to the administration of the anti-PD-L1 and ant-CTLA-4 antibody, which is why the administration of the antibodies occurs in week 2 of the treatment cycle. Applicant argues that, in contrast, the instant claims require administration of the antibodies on day 1 of week 0 for the treatment of HCC in a patient with no prior systemic therapies for HCC. Applicant argues that John Hopkins teaches away and suggests that the trial referenced in Okusaka was either unsuccessful and/or that the trial referenced in Okusaka was not investigating the combined use of durvalumab and tremelimumab as the first line therapy.
John Hopkins does not teach away from the claimed invention because John Hopkins does not criticize, discredit, or otherwise discourage the claimed solution by teaching or studying an alternative HCC patient population.
MPEP 2123 (II) states “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). ‘A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.’ In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)… Furthermore, ‘[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”
Furthermore, the study of John Hopkins is NCT03638141, which is not the same trial as NCT03298451 referenced by Okusaka which teaches first line therapies, and in no way does this alternate study suggest that the treatments referenced by Okusaka were not first-line therapies. Additionally, the idea that other studies were performed on other patient groups does not in itself suggest that first line therapy was not effective or was not expected to be effective. This is further supported by the teachings of Okusaka in which alternative administration orders are discussed. For instance, in the rejections of record, teachings in Okusaka are cited in which DEB-TACE had been studied in combination with immunotherapy both before immunotherapy administration as well as after immunotherapy administration demonstrating that both sequences of administration were known in the art and were considered to be alternative treatment methods.
Applicant further argues that John Hopkins renders Okusaka unfit for its intended purpose. Applicant argues that if Okusaka did provide a disclosure on the use of durvalumab and tremelimumab as a first-line treatment for HCC, Okusaka could not be combined with John Hopkins because the disclosures of Okusaka and John Hopkins would each change the principle of operation of the other, rendering each other unfit for their intended purpose.
This argument is also not persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the rejections of record, John Hopkins is applied in the rejection in order to demonstrate, in combination with Prisma, that the claimed dosages would have been obvious to use in the methods disclosed by Okusaka as they had already been considered for treatment with the combination of durvalumab and tremelimumab. Applicant provides no evidence to suggest that using the durvalumab and tremelimumab dosages of John Hopkins in the method disclosed by Okusaka, as proposed by the rejection, would not be effective or that the dosages would render the treatment method disclosed by Okusaka inoperable.
Applicant further argues that, in direct contrast to the knowledge in the art at the time that the instant application was filed, the instant application demonstrates a significant increase in overall survival at both 15 and 18 months and a significant increase in PFS and survival rate at both 12 and 18 months as a result of the combined administration of tremelimumab in combination with 20 mg/kg (1500 mg) of durvalumab in a subject having HCC when the antibodies are administered on day 1 of week 0 and when the subject has not received any prior systemic therapy for HCC. Applicant cites Figs. 5-6, 7A, 8, and 11 for support.
While the instant disclosure does demonstrate that the claimed method results in a significant increase in overall survival at 15 and 18 months and a significant increase in PFS and survival rate at 12 and 18 months, such results would have been reasonably expected based on the combined teachings of the prior art as discussed in detail in the rejection of record; particularly the teachings of Tai, Yau, and Wolchok.
MPEP 716.02 states “[a]ny 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.” The MPEP chapter further states “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.”
Applicant further argues that the applied references do not provide data or evidence that the instantly claimed method would result in these outcomes and that the instant application provides the first evidence of these results. However, as discussed in detail above, the standard for obviousness is reasonable expectation of success and conclusive proof of efficacy is not required in order to establish a prima facie case of obviousness. As such, none of the applied references are required to conclusively, experimentally, demonstrate the claimed method leading to the claimed outcomes in order to establish obviousness. While applicant may be the first to conclusively demonstrate the claimed outcomes, this alone is not sufficient to overcome the prima facie case of obviousness as the outcomes would have been reasonably expected.
With regards to the reference Tai, which is applied in the rejection of record to demonstrate a reasonable expectation of success in arriving at the claimed outcomes, applicant argues that, while Tai discloses treating HCC with immune checkpoint blockade, the reference lists both tremelimumab and durvalumab as possible ICBs for future study. Applicant argues that Tai does not disclose that the combination and regimen claimed would result in the claimed outcomes and provides no data or evidence that tremelimumab and durvalumab effectively treat HCC as recited in the claims. Applicant provides a replicate of the summary table provided in Tai Table 3 which shows that the clinical trial NCT03298451, using the claimed antibodies to treat HCC, had results that were unknown and “To Be Announced”.
While the applied references do not provide conclusive proof that the combination of tremelimumab and durvalumab results in the claimed outcomes in the treatment of HCC, conclusive proof of efficacy is not required in order to establish obviousness, only a reasonable expectation of success. See MPEP 2143.02 (I). In this case, the combination of Tai, Yau, and Wolchok demonstrate that the combination of anti-PD-1/L1 and anti-CTLA4 antibodies was well known and studied in the prior art and that results, such as those claimed, had been observed in patient studies including in HCC as demonstrated by Tai and Yau. While these studies utilized different PD-1/PD-L1 and CTLA4 blocking antibodies, the antibodies were used to inhibit the same pathways as those of the instantly claimed invention. As such, an ordinarily skilled artisan would have reasonably expected that the combination of tremelimumab and durvalumab, which was a known combination in the art for treating HCC, would result in similar outcomes. Regarding the claimed outcomes, the results generated from these studies are considered to be the closest prior art and provide a reasonable expectation of success in reaching the claimed outcome using the method taught by the combination of applied references.
Applicant further argues that the Tai disclosure indicates that results from one clinical trial using one specific combination cannot be extrapolated to a different combination even if the agents target the same checkpoint. Applicant references the studies NCT03006926 (Table 3, row 9) and NCT03289533 (table 3, row 11), both of which studied anti-PD-1 antibody and mTKI combinations in HCC but used different agents and resulted in significantly different data for ORR, DCF, PFS, and OS.
While the clinical trials referenced by applicant demonstrate that the use of different anti-PD-1 antibody and mTKI agents can lead to different results, the trials referenced by applicant use PD-1/PD-L1 antibodies in combination with multitargeted Tyrosine Kinase Inhibitors (mTKI) which are not antibodies and do not act on the CTLA-4 pathway. These agents are not the same as anti-CTLA4 antibodies and; therefore, do not establish that the use of anti-PD-1/PD-L1 and anti-CTLA4 antibodies would have been unpredictable or that a person of ordinary skill in the art would not have had a reasonable expectation of success in arriving at the claimed results. Applicant provides no substantial evidence or comparison to the closest prior art in order to establish the specifically claimed anti-PD-L1 and anti-CTLA-4 antibodies provide unexpected outcomes over the use of any other anti-PD-1/PD-L1 and anti-CTLA-4 antibody combinations studied in the prior art. With regards to predictability, applicant does not provide any substantial evidence to demonstrate that the inhibition of the PD-1/PD-L1 or CTLA-4 pathway with anti- PD-1/PD-L1 or anti-CTLA-4 antibodies is unpredictable.
Applicant further argues that one of ordinary skill in the art would not be able to reasonably extrapolate the results of NCT01658878, which used nivolumab and ipilimumab, anti-PD1 and anti-CTLA-4 antibodies, to determine the efficacy of the instantly claimed method which uses different immunotherapies, namely durvalumab (an anti-PD-L1 antibody) and tremelimumab (an anti-CTLA-4 antibody).
While the study discussed in Tai uses nivolumab and ipilimumab, not durvalumab and tremelimumab, these agents target the same pathways. Specifically, nivolumab and durvalumab target the PD-1/PDL1 pathway and ipilimumab and tremelimumab target the CTLA-4 pathway. Therefore, one of ordinary skill in the art would reasonably expect similar outcomes through the use of either of the antibody combinations. Applicant does not provide any substantial data or comparison to demonstrate that the claimed durvalumab and tremelimumab combination provides unexpected results compared to the combination of nivolumab and ipilimumab.
Applicant further argues that Tai discloses that it is desirable to administer chemotherapy, including TACE with immunotherapy to increase the efficacy of immunotherapy. Applicant suggests that these teachings indicate that the results from NCT878 cannot be used in combination with John Hopkins to obviate the claimed method.
It is first noted that Tai and John Hopkins are not the only applied references used to establish obviousness of the instantly claimed method and, as discussed in detail above, conclusive proof of efficacy is not required. The references applied in the rejection demonstrate that the administration of anti-PD-1/PD-L1 antibodies in combination with anti-CTLA-4 antibodies without the addition of TACE therapy would be reasonably expected to result in the claimed outcomes. As cited by applicant in the response, Tai teaches that TACE can further improve the efficacy of these therapeutics. Teachings which are corroborated by Okusaka. Such teachings suggest that the outcomes demonstrated with anti-PD-1/PD-L1 antibodies in combination with anti-CTLA-4 antibodies would be even more efficacious. In the case that applicant’s argument is concerned with the timing of the TACE administration, none of the applied references teach that TACE must be administered prior to immunotherapy in order for such enhancement to occur. Rather, Okusaka demonstrates that administration both before and after immunotherapy had been considered.
Finally, applicant argues that Tai discloses that adverse effects or therapy-induced immune-related adverse events of different immunotherapies and agents can vary and significantly affect their ability to treat cancers. Applicant references Tai page 10 for support. Applicant argues that; therefore, one could not use the results of one combination to assert the safety profile of a different combination.
The teachings of Tai are applied to the rejections of the instant office action in order to demonstrate that treatment outcomes such as OS, PFS, and SR as claimed would have been expected in view of the teachings of the prior art. The claims do not require any adverse effect outcomes and, as such, the prior art applied is not required to teach adverse effects in order to render the claims obvious. With regards to the adverse events discussed in the instant disclosure, applicant does not provide a comparison to the closest prior art as per MPEP 716.02(e) in order to demonstrate that the claimed method results in unexpectedly different adverse events than the closest prior art. It is also noted that Okusaka teaches that a phase I/II trial for patients with HCC treated with durvalumab and tremelimumab in combination had manageable toxicity profile with the most common grade 3 or greater treatment-related adverse event being asymptomatic increase in aspartate aminotransferase (10%) (page 4, left column).
With regards to Yau, applicant’s arguments are analogous to those made concerning Tai. Specifically, applicant argues that Yau does not disclose data concerning durvalumab and tremelimumab combination outcomes in HCC and discloses an anti-PD-1 antibody not an anti-PD-L1 antibody. Applicant’s arguments were not persuasive for the reasons discussed in detail above concerning Tai.
With regards to Wolchok, applicant argues that the reference teaches anti-PD-1 and anti-CTLA-4 antibodies in the treatment of melanoma, not anti-PD-L1 antibodies or HCC.
The reference Wolchok is cited in the rejections of the instant office action in combination with the other references, which demonstrate that targeting the PD-1/PD-L1 and CTLA-4 pathways in combination result in the effective treatment of HCC and improved OS compared to other therapies. Wolchok teaches that, in melanoma, PFS was increased in addition to OS. Tai teaches that combination therapies using PD-1/PD-L1 and CTLA-4 antibodies in cancers such as HCC are motivated by results obtained in the treatment of melanoma. As Tai and Yau demonstrate increases in overall survival with the combination therapy, an ordinarily skilled artisan would have also reasonably expected that PFS would also be improved based on the teachings of Wolchok. Additionally, as discussed in detail in the rejections, the effects of anti-PD-1/PD-L1 and anti-CTLA-4 therapies are on the immune system, not specifically the cancer cells themselves, further suggesting that increases in overall survival could be expected based on the teachings of Wolchok.
Applicant further argues that the instant application demonstrates that the increase in OS, PFS, and SR was accompanied by no changes in safety profile of the antibodies and, as stated, the higher dose of tremelimumab provided the best benefit-risk profile compared with the other ICI regimens. These responses were observed regardless of PD-L1 expression level or viral status. Applicant references [00164] for support. Applicant argues that these results are unexpected over the prior art which suggests unpredictability of AEs and irAEs in immunotherapy treatment of HCC.
While applicant argues that the increase in OS, PFS, and SR at 12, 15, and 18 months was accompanied by no changes in the safety profiles of the antibodies, applicant does not provide sufficient evidence to support that this result was unexpected. For example, a comparison to the closest prior art or evidence to suggest that safety would have been expected to increase or change. In the specification, [00164] states that no new safety signals were identified beyond the established safety profile for each agent, alone or in combination. Across all arms, T300+D provided the best benefit-risk profile compared to the other ICI regimens. Based on this disclosure, the safety was the same as that established for the combination which suggests that the claimed method does not result in unexpected or superior safety.
Furthermore, Yau teaches that the combination of PD-1/PD-L1 and CTLA-4 blockade in HCC had clinically meaningful responses and acceptable safety profiles (abstract, conclusion). Wolchok teaches that the use of combination therapies in melanoma was consistent with previous results and no new types of events occurred. Most immune-mediated adverse events resolved within 3 to 4 weeks when well-established safety guidelines were followed. Wolchok goes on to teach that the discontinuation of therapy due to adverse events did not appear to compromise benefit with the combination therapy, because 67% of these patients were alive at 3 years, despite having received three courses of treatment (page 9, paragraph 1). Wolchok also teaches that a data and safety monitoring committee provided oversight to assess the risk-benefit profile (page 3, Trial oversight, paragraph 3), demonstrating that such risk-benefit profiling is common and routine in the art. While applicant argues that these results would not translate to other antibodies, applicant does not provide evidence to support such speculation. For instance, applicant does not provide a comparison to the closest prior art to demonstrate that the claimed method has unexpected properties or that the results would not have been expected in view of the teachings of the prior art as described in MPEP 716.02 (e).
Applicant does not provide a comparison to the closest prior art in order to demonstrate that the claimed method results in an unexpected outcome compared to what would have been expected.
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) further states that “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.”
Applicant does not provide a comparison to the closest prior art, for instance the studies disclosed by Tai, Yau, and Wolchok in which combinations of alternative anti-PD-1/PD-L1 and anti-CTLA-4 antibodies are used to treat cancers including HCC, in order to demonstrate that the claimed method results in any unexpected outcome(s). Alternatively, applicant does not provide a comparison to demonstrate that any portion of the claimed method, for instance, administration of the tremelimumab and daratumumab on day 1 of week 0 in patients who have not received any prior system therapies for HCC, is critical to achieve such outcomes.
In this regard, it is noted that MPEP 716.02 further 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.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1 and 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 47, 51-57 of copending Application No. 17/765,585 in view of NCT02938793 (v3) (Sponsor: Prisma Health-Upstate) posted 22 FEB 2018 (herein “Prisma”), Okusaka, T. and M. Ikeda (2018) Immunotherapy for hepatocellular carcinoma: current status and future perspective ESMO Open 3(e000455); 1-6, Tai, D., et al (2019) Rationale of Immunotherapy in Hepatocellular Carcinoma and Its potential biomarkers Cancers 11; 1-27, Yau, T., et al (2019) Abstract 4012: Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040 Journal of Clinical Oncology 37(15); 2 pages and Wolchok, J.D., et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma N. Engl J Med. 377(14); 1345-1356.
App’585 claims a combination for the treatment of hepatocellular carcinoma (HCC) in a subject comprising a therapeutically effective amount of an anti-PD-L1 antibody or an antigen binding fragment thereof; and an anti-CTLA-4 antibody or an antigen binding fragment thereof at dosages of 1500 mg and 300 mg, respectively (claim 1). App’585 claims that the anti-CTLA-4 antibody is tremelimumab (claim 51) and the anti-PD-L1 antibody is durvalumab (claim 52). App’585 claims that the anti-PD-L1 and anti-CTLA-4 antibodies are administered every four weeks (claim 53) which is further limited to four doses followed by administration of the anti-PD-L1 antibody every four weeks (claim 54). App’585 further claims that the anti-PD-L1 antibody and the anti-CTLA-4 antibody are administered for one dose followed by administration of the anti-PD-L1 antibody every four weeks (claim 55). App’585 claims that the administration is simultaneous, separately, or sequentially (claim 56) and that the method further comprises administration of TACE (claim 57).
The instant claims differ from those of App’585 in that App’585 claims flat doses for the combination of the anti-PD-L1 and anti-CTLA-4 antibodies. Additionally, App’585 does not claim that the antibodies are administered on the same day, that the subject has not received any prior systemic therapy for HCC, or the outcomes of the instant claims.
The teachings of Prisma, Okusaka, Tai, Yau, and Wolchok are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’585 to arrive at the claimed regimen based on the teachings of Prisma, and to apply the combination therapy to HCC as a first-line treatment and to administer TACE following initiation of durvalumab and tremelimumab based on the teachings of Okusaka. An ordinarily skilled artisan would have reasonably expected that the treatment would increase OS at 15, 18, and/or 21 months and/or PFS and/or SR of the subject at 12 months and/or 18 months as compared to a subject not receiving the treatment method, based on the teachings of Tai, Yau, and Wolchok.
App’585 claims a combination of 1500 mg of PD-L1 antibody and 300 mg of anti-CTLA-4 antibody which, based on the teachings of Prisma, is equivalent to 20 mg/kg of PD-L1 antibody and 4 mg/kg of anti-CTLA-4 antibody. It would have been obvious to one of ordinary skill in the art to administer the antibodies in mg/kg according to the equivalence taught by Prisma as Prisma demonstrates that these were known administration methods for durvalumab in combination with tremelimumab, which are the same antibodies claimed in App’585. The use of the mg/kg equivalent dosages is further supported by KSR(E). See MPEP 2143. In this case, the prior art demonstrates that administration of the antibodies in both mg and mg/kg dosages were known in the prior art. Therefore, it would have been obvious to an ordinarily skilled artisan to try either of these dosing methods in the methods of treatment claimed by App’585 with the reasonable expectation that the dosing would be equivalent based on the teachings of Prisma.
It would have been obvious to use the combination therapy as a first line treatment with a reasonable expectation of success as Okusaka teaches that trials were underway using the combination of durvalumab and tremelimumab as a first line therapy in the treatment of HCC which is both the drug combination and cancer claimed in App’585. Additionally, an ordinarily skilled artisan would have been motivated to further administer TACE with the combination following administration of durvalumab and tremelimumab, for example, administration up to 36 days following checkpoint inhibitor administration, as Okusaka teaches that synergistic effects were expected when immune checkpoint inhibitors are combined with local therapeutic approaches including TACE. Okusaka also teaches that a pilot studying administration of TACE at day 36 had been conducted indicating that it was viewed as a valid treatment regimen. One of ordinary skill in the art would have had a reasonable expectation of success as Okusaka teaches administration of anti-PD-L1/anti-PD-1 and CTLA-4 antibodies alone and in combination for the treatment of HCC. Additionally, the combination therapy with TACE discussed includes CTLA-4 inhibitor tremelimumab, which is the CTLA-4 inhibitor claimed in App’585.
An ordinarily skilled artisan would have reasonably expected that the treatment would result in increased OS at 15, 18, and/or 21 months and/or PFS and/or SR of the subject at 12 months and/or 18 months compared to a subject not treated with the treatment method, based on the teachings of Tai, Yau, and Wolchok.
As discussed above, Tai provides an overview of anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy clinical trials in HCC and discloses overall median survival in the studies ranging from 8.2-16.4 months. Additionally, Tai teaches that for sorafenib and placebo, the median overall survival was 14.4 and 10.6 months, respectively (page 4, Table 1). Tai further teaches that in studies using a combination of anti-PD-1 and anti-CTL-4 antibodies, overall survival rates at 24 months were 40% (page 13, paragraph 1), referencing results from the CheckMate 040 study. The results from the study are further elaborated on by Yau, which teaches that the median overall survival with combination therapy was as high as 23 months with a 12-month overall survival rate as high as 61% (table). Based on these results, an ordinarily skilled artisan would have reasonably expected that subjects treated with the method taught by the combination of App’585 and the applied references would result in an increase in OS at 15, 18, and/or 21 months as Tai and Yau demonstrate significantly higher median overall survival rates compared to other therapies. For example, Tai teaches monotherapy median overall survivals of 8.2-16.4 months while Yau discloses median overall survival rates as high as 23 months with combination therapies demonstrating higher overall survival of patients treated with the combination therapy. As Tai and Yau demonstrate higher median overall survival using combination therapies vs monotherapies and alternative treatments, an ordinarily skilled artisan would also reasonably expect that survival rate would also be increased. This is particularly the case as Yau teaches overall survival rates at 12-months and 24-months to be as high as 61% and 40% while the median overall survival in monotherapies and alternative therapies suggest 50% survival by as low as 8.2 months.
An ordinarily skilled artisan would have also had a reasonable expectation that progression free survival would be increased through the use of combination therapy based on the teachings of Wolchok. Wolchok demonstrates that in clinical trials in melanoma, nivolumab and ipilimumab resulted in higher PFS at 12 and 18 months compared to studies using either as a monotherapy. Additionally, overall survival is higher for the combination at 18 months compared to either monotherapy and higher than ipilimumab monotherapy at 12 months. Wolchok also teaches that median overall survival was not met at 2 years for the combination therapy but was met for the nivolumab and ipilimumab groups. While Wolchok studied melanoma and not HCC, Tai teaches that results from melanoma provided impetus for other solid tumors, including HCC. As the results disclosed by Tai and Yau demonstrate that clinical responses in HCC, such as overall survival and overall response rates, are higher in subjects treated with a combination of PD-1/PD-L1 and CTLA-4 blockade, an ordinarily skilled artisan would also reasonably expect that progression free survival would also be increased such as is seen in the results of Wolchok in the treatment of melanoma.
It is noted that, while Tai, Yau, and Wolchok teach clinical trial results from the combination of nivolumab and ipilimumab, not durvalumab and tremelimumab, an ordinarily skilled artisan would nevertheless have expected similar results as nivolumab and ipilimumab are blocking the same pathways, specifically the PD-1/PD-L1 and CTLA4 pathways as demonstrated by the teachings of Tai.
It is also noted that, while the dosage regimens of the instant claims would have been obvious in view of App’585 and the applied art, the determination of an optimal treatment regimen is considered to be routine optimization where considerations were known in the prior art. MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, dosage and administration frequency were known to be result-effective variables and an ordinarily skilled artisan would have been able to use the teachings of the prior art and optimization that is routine in the field to determine optimal dosage regimens for the combination therapy.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments concerning the provisional nonstatutory double patenting rejection in the response filed 11/18/2025 are acknowledged. In the response, applicant states that the nonstatutory double patenting rejection will be addressed upon notification that rejection is no longer provisional and the claims are otherwise in condition for allowance. As both the instant and copending application are still pending, the rejection remains provisional. Additionally, the rejections under 35 USC 103 are maintained for the reasons discussed in detail above. Therefore, the double patenting rejection is also maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 extension fee 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.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693