DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 26Jan2026 has been entered.
Claims Status
The Amendment filed on 26Jan2026 is acknowledged in which claims 1-46, 48-50, and 58-70 are canceled and claims 71-75 are new.
Claim(s) 47, 51-57, and 71-75 is/are currently pending and presented for examination on the merits.
Response to Amendment
The recent claim Amendment filed on 26Jan2026, added new limitations to the claims that were not considered in the previous rejections and necessitated new rejections.
All other previously presented rejection(s) are maintained for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Rejections Maintained/New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 47, and 51-57 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT02821754 (XP055832854, published 04Jun2016, IDS 28Jun222 reference; hereinafter “NCT754”), as evidenced by Floudas et al. (J. Clin. Oncol. 37, 336(2019), 29Jan2019; hereinafter “Floudas”), view of Sharma et al. (WO 2019/241742 A 1, published 19 Dec 2019; hereinafter “Sharma”).
Regarding claim(s) 47, 51-57, NCT754 teaches a clinical trial protocol for the treatment of hepatocellular carcinoma (HCC) combination therapy comprising an anti-PD-L1 (durvalumab) at a dose of 1500 mg and an anti-CTLA-4 (tremelimumab) at a dose of 75 mg in a subject [e.g., pgs. 2-3, Design]. NCT754 teaches administration of durvalumab and tremelimumab every 28 days (4 weeks) [e.g., pgs. 2-3, Design]. Although NCT754 does not provide treatment data, 1500 mg durvalumab and 75 mg tremelimumab was known in the art to treat HCC at the time of filing, as evidenced by Floudas [e.g., title, abstract]. NCT754 teaches durvalumab and tremelimumab administration every four weeks for four doses followed by administration of durvalumab every for weeks until end of study [e.g., pgs. 2-3, Design]. One of ordinary skill in the art would understand that combination therapies may be given simultaneously, separately, or sequentially. NCT754 further teaches administering transarterial chemoembolization (TACE) to the subject [e.g., pg. pgs. 2-3, Design].
NCT754 does not expressly teach that (1) the anti-CTLA-4 antibody (tremelimumab) dose is 300 mg, or (2) that the anti-CTLA-4 antibody is administered once.
Sharma teaches combination therapy for the treatment of cancer, with one of the combination therapies being a checkpoint inhibitor [e.g., title and abstract], that the checkpoint protein target is CTLA-4, and that the CTLA-4 inhibitor is tremelimumab [e.g., para 0009]. Sharma teaches that the cancer is hepatocellular carcinoma [e.g., para 0052]. Sharma teaches various tremelimumab effective doses (e.g., 75 mg, 300 mg) and administration schedules (e.g., once, every 28 days) [e.g., para 0014].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the 75mg tremelimumab dose in the method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (75 mg) as taught by NCT754, with the 300mg tremelimumab dose administration taught by Sharma, in the context of designing and developing an anti-PD-1 antibody and anti-CTLA-4 antibody combination therapy to treat HCC. A PHOSITA would have been motivated to substitute the 75 mg tremelimumab dose in the method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (75mg) as taught by NCT754 with the 300 mg tremelimumab dose taught by Sharma, because both NCT and Sharma teach a 75 mg tremelimumab dose in a combination therapy to treat HCC, and Sharma further teaches a 300 mg effective dose of tremelimumab. There would have been a reasonable expectation of success for a PHOSITA to substitute the 75 mg tremelimumab dose in the method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (75mg) as taught by NCT754 with the 300 mg tremelimumab dose taught by Sharma, because both NCT and Sharma teach a 75 mg tremelimumab dose in a combination therapy to treat HCC, and Sharma further teaches a 300 mg effective dose of tremelimumab. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (300 mg) as taught by NCT754 and Sharma (see above) to include the that the anti-CTLA-4 antibody (tremelimumab) is administered once as taught by Sharma, because NCT754 and Sharama both teach HCC treatment comprising tremelimumab administration at 4 week intervals (e.g., every 28 days), and Sharma further teaches an effective dose of tremelimumab administered once. There is an expectation of success for a PHOPSITA to substitute the 28 day tremelimumab dose interval in the modified method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (300 mg) as taught by NCT754 and Sharma for a single administration of tremelimumab because NCT754 and Sharama both teach HCC treatment comprising tremelimumab administration at 4 week intervals (e.g., every 28 days), and Sharma further teaches an effective dose of tremelimumab administered once. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 71-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT02821754 (XP055832854, published 04Jun2016, IDS 28Jun222 reference; hereinafter “NCT754”) as evidenced by Floudas et al. (J. Clin. Oncol. 37, 336(2019), 29Jan2019, Abs; hereinafter “Floudas”), in view of Sharma et al. (WO 2019/241742 A 1, published 19 Dec 2019; hereinafter “Sharma”) as applied to claim(s) 47 and 51-57 above, and further in view of Floudas.
The teachings of NCT754 and Sharma as recited above for claims 47 and 51-57 are applied for claims 71-75.
NCT754 and Sharma do not expressly teach that a combination of 300 mg of Tremelimumab and 1500 mg of durvalumab increases PFS, OS, and/or SR in HCC subjects.
Regarding claims 71-75, the modified method of treating HCC comprising administration of 1500 mg durvalumab and 300 mg of tremelimumab as taught by NCT754 and Sharma (see rejection above for details) would naturally result in an increased OS at 15, 18, and/or 21 months; an increased PFS at 12 and/or 18 months; and/or an increased SR at 12 and/or 18 months (where increases are relative to patients not receiving the combination therapy). This is because the modified method of NCT754 and Sharma are the same as the instant claims, and without any additional steps and/or differences of the recited combination therapy and/or disease treated, one of ordinary skill in the art would expect the results to flow naturally from the method of treatment within a given population. Additionally, Floudas teaches combined immune checkpoint inhibition with tremelimumab (75 mg) and durvalumab (1500 mg) in patient with advanced HCC had early including median OS of 15.9 (95% CI 7.1 to 16.3 mo.) and a median PFS of 7.8 mo. (95% CI 4.6 to 10.6 mo.), and summarized that “combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC” [e.g., title, abstract].
Further, it would have been obvious to a PHOSITA to modify the modified method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (300 mg) as taught by NCT754 and Sharma (see above) to include that the modified method results in increased PFS, OS, and/or SR in HCC subjects because, as discussed above, the increase in PFS, OS, and/or SR in HCC subjects’ results is considered to flow from the method as instant claims 71-75 do not further modify the modified methods previously claim and rather just recite results that flow therefrom. There is an expectation of success for a PHOPSITA to include increased PFS, OS, and/or SR in the modified method of treating HCC comprising administering durvalumab (1500 mg) and tremelimumab (300 mg) as taught by NCT754 and Sharma, because not only do the limitations claim flow from the method, but Floudas additionally teaches that lowed doses of tremelimumab and durvalumab in advanced HCC result in increased PFS and OS, and therefore the higher doses would reasonably be expected by one of ordinary skill in the art to also result in increases in measure response metrics such as PFS, OS, and/or SR. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
NCT754 does not disclose all the claim limitations of new claims 71-75, which are directed to a combination comprising an anti-PDL1 Ab and an anti-CTLA4 Ab that increases OS, PFS, and SR in a subject having HCC. Briefly, NCT754 and Sharma don’t teach increased OS, PFS, and/or SR, nor does it teach those measurements at the specified months.
In response, the OS, PFS, and SR limitations are considered to be results of, and therefore flow naturally from, the recited method of treating HCC comprising administration of 1500 mg of durvalumab and 300 mg of tremelimumab. Additionally, the teachings of Floudas indicate that lower doses of 1500 mg of durvalumab and 75 mg of tremelimumab resulted in increased PFS, OS, and were considered “well tolerated” with “promising activity in patients with advanced HCC”. The teachings of Floudas suggest that the instant claimed combination for treating HCC would also be expected to result in increased response rates (e.g., PFS, OS, SR). In summary, one of ordinary skill in the art would expect the results to flow naturally from the method of treating, and prior art taught that a lower therapeutic dose resulted in increased PFS and OS in advanced HCC subjects; therefore, the instant limitations are considered obvious (see above for details). Applicant arguments have been fully considered and are not found persuasive.
The combination of NCT754 and Sharma does not provide a motivation to substitute dosages to arrive at the subject matter of claims 47, 51-57, and 71-75. Applicant contends that the Application provides no support for the combination.
In response to, it should be stressed that Sharma is a secondary reference and not the foundational reference for the rejection. Briefly, NCT754 is the primary foundation for the rejection and teaches the base method of instant claim 47, except that the tremelimumab dose is 75mg in NCT754 rather than the 300 mg dose of the instant claim. Sharma was relied upon to teach the 300 mg dose of tremelimumab dose, and the substitution was made on the basis that (1) the arts are overlapping in that they both recite (a) combination therapies wherein one therapeutic is tremelimumab and the second targets an entirely different pathway than tremelimumab, and (b) both teach treatment of HCC, and (2) one of ordinary skill in the art would understand that dose optimization (a) is standard practice in the art and (b) the benefit of beginning with doses reported in the art to be tolerable and/or safe (as in the case of Sharma), especially within the target indication(s), even if the second therapeutics are not in the same class as one-another. For additional details, please see the rejection above.
Additionally, In regard to the specific dosage and interval amounts recited in the instant claims "[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 see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious. Applicant arguments have been fully considered and are not considered persuasive.
Applicant notes that at the time NCT754 and Sharma were published that “no one – including the Applicant itself – expected that a combination containing 300 mg of tremelimumab and 1500 mg of durvalumab would be effective at treating HCC, especially without an increase in adverse side effects”. The disclosures did not motivate anyone – including the Applicant- to test a combination containing 300 mg tremelimumab and 1500 mg durvalumab for the treatment of HCC”. While Sharma discloses various concentrations of tremelimumab or durvalumab in combination with an EZH2 inhibitor for the treatment of cancer, Sharma does not consider combining both durvalumab and 300 mg tremelimumab in the absence of an EZH2 inhibitor, thereby providing evidence that the Applicant did not consider testing such a combination. This is further evidenced by the Applicant’s initiation of the time and resource-consuming clinical study outline in NCT434 and Sharma 2020, with the goal of demonstrating to the FDA that 750 mg of tremelimumab alone or a combination therapy comprising durvalumab and 75 mg of tremelimumab can be used to effectively treat advanced solid tumors. Applicant nor the inventors understood the Sharma reference as teaching or suggesting the claimed combination of 1500 mg durvalumab and 300 mg of tremelimumab for HCC treatment. “Surely, if neither the Applicant nor the inventors, who were actively investigating combinations…one of ordinary skill in the art would not have been motivated by the Sharma reference to make or use the instant claimed combination.
In response, the 300 mg tremelimumab and 1500 mg durvalumab (e.g., “T300 +D”) dose would have been reasonably expected to be “effective at treating HCC” because, as per Applicant’s own arguments (1) clinical trials are a large time and financial commitment and therefore one of ordinary skill in the art would expect that NCT754 would only have been undertaken if there was an expected positive response in HCC (despite not providing data as indicated by Applicant), and although this is likely supported by IND filing data the office doesn’t have access to, the lower 75 mg tremelimumab and 1500 mg durvalumab dose (e.g., T75 +D) regimen was already known in the art at the time of filing to be an effective and promising therapy, as evidenced by Floudas. Regarding the claims of unexpectedness of not increasing AEs, this is not a requirement of the instant claim set and therefore is not directly addressed in the rejection above. However, it is noted that evidentiary reference Floudas teaches AEs were managed and while Grade 3-4 AEs were reported, there is no report of dose-limiting toxicity, intolerability of treatment, or deaths attributable to the T75 + D treatment. Further, tremelimumab doses of up to 10 or 15 mg/kg (e.g., 10 mg/kg * 70 kg ave. adult = 700mg; far exceeding a 300 mg flat dose) in combination with up to “about” 20 mg/kg durvalumab (e.g., 20mg/kg * 70kg = 1400mg dose) were well-known in the art at the time of filing and observed AEs were not considered to comprise dose-limiting toxicity (DLT), and noted HCC as an intended indication, as evidenced by WO 2016156501 A1 (e.g., sponsor is Medimmune, an AstraZeneca company since 2007) [e.g., pgs. 4-5, 14, 32]. Additionally, Abou-Alfa et al. (J. Clin. Oncol. 36, TPS4144(2018), ASCO 2018 Abstract TPS4144; hereinafter “Abou-Alfa”) teaches (1) that while anti-PD-1 and anti-CLTA4 Abs have shown clinical benefit in HCC that early clinical data (NCT02519348) for the combination therapy of durvalumab and tremelimumab in HCC demonstrated safety and a durable objective response rate in HCC [e.g., abstract]. Abou-Alfa further teaches the focus of the abstract is a new clinical trial, HIMALYA (NCT03298451), is the first randomized, open label, multi-center study to assess the efficacy and safety of D+T combination therapy versus front-line therapeutic sorafenib monotherapy [e.g., title, abstract]. Although it is unclear if it was provided in the poster and/or talk associated with the abstract for the Abou-Alfa abstract as the office does not have access thereto, HIMALYA (NCT03298451; an AstraZeneca sponsored trial) had a study start date of 11Oct2017, and the researcher view provides that the primary outcome includes analysis of a T300 + D dose versus standard of care (SOC)Sora 400 mg dose, which suggests that Applicant had indeed thought of the combination prior to the WIPO publication of Sharma (19Dec2019), despite the attestation otherwise. Further, it is noted that (1) the failure of an applicant or inventor to recognize additional uses, combinations, and/or substitutions between their previous work in the state of the art is not sufficient to determine that another skilled artisan would not have reasonably arrived at the combination. The initiation of additional clinical trials in HCC that do not test the instant claimed dose range is not considered evidence that applicant did not believe T300 + D to have any potential efficacy with tolerable safety in view of the evidence provided above that higher doses were already known in the art to be safe, were suggested for the treatment of HCC, and the HIMALAYA study was started more than a year prior to the publication of Sharma.
Lastly, as stated above, the rejection is not based on Sharma considering the combination of tremelimumab and durvalumab, rather the combination of these 2 drugs as a treatment for HCC is taught by NCT754 (with efficacy well-known in the art; see Floudas, WO 2016156501 A1, and Abou-Alfa). Rather, Sharma was relied upon to teach an additional effective dose in HCC (see response to arguments and rejection above for details). Applicant arguments have been fully considered and are not found persuasive.
A skilled artisan would not have had a reasonable expectation of success at combining NCT754 with Sharma to arrive at claims 47, 51-57 and 71-75; unexpected improvements of claims 47, 51-57, and 71-75. Applicant recited MPEP2141 “[T]his is particularly true where the missing limitation goes to the heart of an invention” and “V. consideration of applicant’s rebuttal evidence… secondary considerations…commercial success, long felt but unsolved needs and failure of others”. Applicant recited MPEP 2145 and notes that “lack of reasonable expectation of success or unexpected results is sufficient to overcome a prima facie case of obviousness”. Applicant contends the office action lacks both elements thereof. Applicant asserts that NCT754 provides no data or disclosure that demonstrates efficacy in treating any cancer at any dosage, let alone the claimed combination. Sharma demonstrates that improved treatment of bladder cancer and melanoma requires EZH2 inhibitor with an anti-CLTA4 Ab. Finally, NCT434 discloses a study regarding the Tx of UBC, TNBC, and PDAC with 75 mg or a much higher dose of 750 mg of tremelimumab, also does not provide any data or disclosure that the instant combination is effective at treating HCC.
In response, as recited above, the base claim primary reference teaching T75 + D in HCC is the basis of the rejection, there was evidence in the art of the success of T + D in HCC at the time of filing, and Sharma was relied upon for additional known therapeutic doses of T in HCC (see response to arguments and rejection above for details). As stated above, based on the teachings of the prior art, the results provided to the Office are not considered to be unexpected improvements (see above for details). Regarding the repeated argument of the Sharma reference not providing data in HCC, and arguments regarding the T300 + D regimen, please see the response to arguments and rejections above for details.
Applicant has provided explicit evidence that it was well known to those of ordinary skill in the art that administration of anti-PDL1 and anti-CLTA Abs can result in serious immune related AEs and that such AEs are dose-dependent, with increased risk of such AEs increasing concomitantly with administration of increasing dosages. In support of this well-known risk, Applicant previously cited “Bertrand et al” which provides a meta-analysis demonstrating that the risk of immune related AEs for anti-CTLA4 Abs is dose-dependent. Based on the office’s response, Applicant assumes that the Office concludes that effective doses of tremelimumab when used in combination with an EZH2 inhibitor would be exactly the same when only one of the drugs in that combination is used in combination with a totally different drug, “thereby improperly shifting the burden to the Applicant to refute this unsupported assertion. Applicant contends that such assertion is impermissible” and recites MPEP 2144.03 that it is improper for an Examiner to take official notice of facts without citing prior art. Applicant argues that in addition to Bertrand previously they additionally provide “factual evidence from Sharma 2020… “ including that the tolerability of combination therapies appears dose and schedule dependent highlighting the need for optimal dose selection to minimize toxicity of combination regimens while maintaining clinical efficacy… Thus, Applicant has now provided two examples of evidence demonstrating that one of ordinary skill in the art would not have understood that a 75 mg dose could be substituted for a 300 mg dose of tremelimumab. Applicant again asserts Sharma is a totally different combination therapy, and that a skilled artisan would not have considered this change merely simple substitution that would yield predictable results. Further, pathophysiology is different across cancer types and a skilled artisan would understand that treatment required can vary greatly even when using the same antibodies.
In response, although applicant provided data that suggest anti-PL1 and anti-CTLA Abs can result in serious immune related AEs, especially with related doses, these teaching must be taken in context of additional knowledge in the art at the time of filing. Specifically, as recited above, the teachings of NCT754 in view of the well-known tolerable T + D doses in the state of the art at the time of filing would suggest to an artisan that while some anti-PD1 and anti-CTLA4 antibodies may have reported AE related issues, the instant claimed doses fall well within the well-known in the art tolerable ranges of T + D regimens at the time of filing and would reasonably be expected to (a) treat HCC and (b) be tolerable. Further, Sharma teaching that tolerability is dose-dependent and requires testing further supports that an artisan understand that specific T + D tolerability data in the art would be applicable in this instance and that as higher doses (see above) were found to be tolerable, the T300 + D dose would be eligible for substitution as it would also be expected to be tolerable.
Regarding the argument for varying doses across indications, (1) the prior art references teaching treatment in HCC (including Applicant’s own prior work) suggests an expectation of success at the time of filing, and (2) provides further support that, as discussed above, dose optimization is routine in the art (see above for details).
In direct contrast with the knowledge in the art at the time of the instant application, applicant notes that the instant application is the FIRST disclosure demonstrating an actual improvement in the treatment of HCC using the combination of 300 mg tremelimumab and 1500 mg durvalumab. The 300 mg dose is significantly lower than the 750 mg described in Sharama 2000 and NCT434 (monotherapy arm). The office, however, asserts that a skilled artisan would have known to ignore the other 23 tremelimumab doses mentioned in Sharma selecting only the specific dose claimed and would have reasonably predicted that such combination would yield predictable results. Applicant, in view of the evidence above disagrees. Applicant contends that absent the instant application, a skilled artisan would not have reasonable expectations of success and focuses on the same arguments as above, and that Sharma only provides data for bladder cancer and melanoma. Applicant also contends that skilled artisan would have avoided using higher doses of tremelimumab in combination with durvalumab, as recited in the instant claims, in order to avoid documented immune related AEs.
In response, the instant application is not the first to demonstrate T75 + D treatment success in HCC, and the T300 + D treatment would be expected to demonstrate success in HCC as well. Regarding the repeated arguments of Sharma, please see response to arguments and rejections above.
NCT754 and Sharma changes the principle operation of Sharma, rending the combination unsatisfactory for its intended purpose. Applicant recites MPEP 2145(X)(D), 2142.02(VI), and 2143.01(VI), and argues essentially that doses of tremelimumab in Sharma cannot be applied with NCT754 because they teach different combinations (e.g., EZH2 inhibitor vs durvalumab), and thus Applicant believes it is improper per MPEP sections cited above. Applicant contends that the Office’s previous response was non-responsive because the Office asserted that there is no evidence in the art that the mechanism of action of tremelimumab changes based on co-administration with another drug, nor is there evidence of unexpected results that would suggest a different mechanism, and therefore the previously known in the art safe and/or efficacious doses of tremelimumab are considered applicable even if the second therapeutic selected changes. Applicant argues that this is non-responsive because it is “not scientifically sound” given that the second therapeutic doesn’t target EZH2. Applicant argues that as clearly stated in MPEP that the claimed combination cannot change the principle of operation of a reference or render a reference inoperable for its intended purpose. Applicant repeats arguments regarding NCT754 vs. Sharma combinations. Applicant also repeats arguments regarding Sharma teaching bladder cancer and melanoma data only, and that Sharma doesn’t teach tremelimumab alone or in combination with another therapy that isn’t EZH2 inhibitor.
In response, as stated above, NCT754 is the primary reference that is relied upon for the T75 + D in HCC method, and Sharma was relied upon for additional T doses in the prior art for HCC (see response to arguments and rejections above for more detail). Additionally, the argument that the previous response was not “scientifically sound” given that the second therapeutic doesn’t target EZH2 is not elaborated upon, nor is prior art provided to support the claim. Therefore, the argument as to why it is “scientifically unsound” is unclear and not able to be addressed herein. Rather, applicant again argues MPEP (not scientific foundation), stating that Applicant believes the combination changes the operation of the references. Briefly, as Sharma was not the primary reference, and was only relied upon to provide a tremelimumab dose in HCC for substitution in the primary NCT754 reference method, and the dose in Sharma was within a dose range previously known to be safe in the art for T + D dose regimens in HCC, the combination is considered to be appropriate (see response to arguments and rejections above for additional details). In summary, for reasons provided in depth in the rejection and responses to arguments above, the combination of references are considered overlapping art, are not considered to change the operation of the reference, and are considered appropriate under MPEP guidance. Applicant arguments have been fully considered and are not found persuasive.
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 47, 51-57, and 71-75 are maintained.
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643