Detailed Notice
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 .
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 [RCE submission date] has been entered.
Status of Claims
Claims 9-11 are cancelled. Claim 1 is amended. Claims 1-8 and 12-14 are currently pending and under examination.
Response to Remarks filed 01/06/2026
Applicant’s amendments and arguments with respect to the 35 USC 103 rejections of claims 1-8 and 12-14 have been fully considered and are not persuasive.
Specifically, Applicant amended claim 1 to recite a method for treating a BRAF-wild type, RAS mutant cancer in a subject, comprising administering to the subject a therapeutically effective amount of a selective BRAF inhibitor (BRAFi) in combination with immunotherapy.
It is noted that neither Colburn et al or Fernandez-Medarde et al limit their methods of treatment to BRAF-mutant cancer subtypes. For example: Colburn et al teach methods of treating cancer in an individual wherein cancer treatment comprises first administering to the individual an effective amount of a B-RAF inhibitor and second administering to the individual an effective amount of the B-RAF inhibitor and an effective amount of immune checkpoint inhibitor, wherein the cancer treatment has increased efficacy compared to administering to the individual an effective amount of the B-RAF inhibitor and an effective amount of the immune checkpoint inhibitor alone. (Colburn et al, paragraph 0012)
Applicant asserts that they discovered that there is an "optimal" regime of ERK pathway output in oncogenic signaling, and as a consequence, BRAF inhibitors (BRAFi) have divergent effects depending on the context. First, strong oncogenes such as classical cancer-associated mutant RAS alleles rarely co-occur in tumors. In particular, mutant BRAF and NRAS, as dominant oncogenic drivers of melanoma, rarely co-occur unless in the context of targeted therapy resistance. It was previously known that RAS-mutant cancers involve the hyperactivation of the RAS-RAF-MEK-ERK signaling pathway, driving uncontrolled cell growth by constantly pushing the MEK and ERK kinases downstream, leading to abnormal cell division, survival, and proliferation. Consequently, MEK/ERK inhibitors are promising strategies, even though they are often challenged by resistance. It was also previously known that BRAF-mutant cancers often rely on the RAS-RAF- MEK-ERK pathway for growth, making BRAF inhibitors (Vemurafenib) suitable treatments for BRAF-mutant cancers. However, nothing in the art suggests using a BRAFi for anything other than a BRAF-mutant cancer.
However, Fernandez-Medarde et al teach the use of a BRAFi in RAS mutant melanoma, not specifying the requirement for the presence of a BRAF mutation. (Fernandez-Medarde et al, pg. 348, last paragraph). Furthermore in view of the references cited, it would have been prima facie obvious to administer a BRAF inhibitor to an individual that does not have a BRAF mutation, and the claims do not specifically require any sort of screening step to differentiate between patients having wild-type BRAF and those that have a BRAF mutation.
Applicant’s arguments with respect to Sanchez et al have been fully considered and are not persuasive. It is known to those skilled in the art that treatment of cancer has variable results. However, the combined invention of Colburn et al and Fernandez-Medarde et al meet the limitations of the claimed invention. Furthermore, Fernandez-Medarde teach the treatment of RAS mutant cancer with a BRAFi. Therefore, one would be motivated to try with a reasonable expectation of success to treat RAS mutant cancer with a BRAFi.
Applicant’s arguments with respect to Colburn et al and Fernandez-Medarde et al have been fully considered but are not deemed persuasive. It is initially noted that “[o]ne cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).”
Therefore the previous 35 USC 103 rejections of claims 1-8 and 12-14 are maintained.
Claim Rejections - 35 USC § 103 (Previous Rejections are all Maintained)
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.
Claim(s) 1-8 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Colburn et al, (US-2018/0256552-A1, published 13 September 2018) in view of Fernandez-Medarde et al (“Ras in Cancer and Developmental Diseases”, Genes and Cancer, 2011).
The instant claims are drawn to a method and composition comprising administering a selective BRAF inhibitor with immunotherapy (claim 1). The claims are further drawn to wherein the BRAFi is optionally vemurafenib, dabrafenib, or encorafenib (claim 4), and the immunotherapy is optionally one or more checkpoint inhibitor (claim 2), optionally from among an anti-PD1, anti-PD-L1, and/or anti CTLA-4 antibody (claim 3).
It would have been obvious to a person of ordinary skill in the art at the time of the instant invention effective filing to have provided a method as instantly claimed, based on the teachings of Colburn (2018) in view of Fernandez-Medarde (2011).
Regarding claim 1, Colburn et al however discloses a method of treating melanoma in an individual, the method comprising first administering to the individual vemurafenib and cobimetinib on a 28 day schedule, wherein vemurafenib is administered at a dosage of 960 mg twice a day for 21 days and then 720 mg twice a day for 7 days of the 28 day schedule and cobimetinib is administered at a dosage of 60 mg daily for 21 days and 7 days off of the 28 day schedule and second administering to the individual vemurafenib, cobimetinib, and atezolizumab, wherein vemurafenib is administered at a dosage of 720 mg twice a day, cobimetinib is administered at a dosage of 60 mg daily for 21 days on and 7 days off, and atezolizumab is administered at a dosage of 800 mg q2w (Colburn et al, e.g. paragraph 0018 and Claim 28). Vemurafenib is a BRAF inhibitor and atezolizumab is a PD-1 axis inhibitor (immunotherapy) (Colburn et al, e.g. paragraphs [0006, 0017-0018] and [0008, 0014-0018], respectively; see also para [0041-0060]).
Regarding claims 2-4 and 9-11, Colburn et al teaches, atezolizumab a checkpoint inhibitor and a PD-L1 antibody, and vemurafenib a BRAFi (see Colburn et al, Claim 28 and as cited supra).
Regarding claims 5-6, Colburn et al teaches that the combination may be administered at the same time in an individual (Colburn et al, claim 28) or administered in the same pharmaceutical composition (Colburn et al, pg. 31, e.g. paragraph 0051).
Regarding claims 7 and 8, Colburn et al additionally teaches that the BRAFi is administered for 28 days prior to the administration of the immunotherapy (Colburn et al, Claim 28). With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. the claimed order of steps is an obvious variant of the steps of the cited prior art.
Colburn et al is distinguished from the instant claims in that it doesn’t specify that the melanoma is a RAS mutant.
Fernandez-Medarde et al, however, discloses that melanoma can have a RAS mutation (Fernandez-Medarde et al, pg. 348, malignant melanoma section, paragraph 1).
One skilled in the art would be motivated to combine the teachings to use a BRAF inhibitor with an immune checkpoint inhibitor such as atezolizumab in a RAS mutant cancer, as it is known that BRAF and RAS mutations may occur exclusive to one another (Fernandez-Medarde et al, pg. 348, malignant melanoma section, paragraph 1), and cancer cells with RAS mutations are targeted by cytotoxic T-cells (Fernandez-Medarde et al, pg. 348, malignant melanoma section, paragraph 3).
The cited references, Colburn and Fernandez-Medarde, are relied upon for the reasons discussed above. If not expressly taught, based upon the overall beneficial teaching provided by the references with respect to providing the disclosed therapeutic antibodies and inhibitors, in the manner disclosed therein and as discussed above, the adjustments of particular conventional working conditions (e.g., determining one or more suitable condition, including treating regimens (sequence of steps, combination or separate administrations, time, and amounts of each administered material, to elicit the therapeutic effects, in which to perform such a treating of a cancer in a subject), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the one of ordinary skill in the art.
From the teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Regarding claims 12-14, claim 1 is discussed above. Additionally, Fernandez-Medarde et al further discloses that the RAS mutations in melanoma can be H-RAS, N-RAS, or K-RAS (Fernandes-Medarde, pg. 346 Table 1). One skilled in the art at the time of effective filing would have been motivated with a reasonable expectation of success to use the invention of Colburn et al which comprises administrating a composition of a BRAFi and immunotherapy to patients with melanoma to further comprise treating patients with RAS mutant melanomas because it would have a reasonable expectation of success at treating RAS mutant melanoma.
Therefore, the above claims were prima facie obvious at the time of effective filing.
Conclusion
No claims are allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642