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 .
Status of the Claims
Amendment filed on July 05, 2024 is acknowledged.
Claims 3, 5, 7-9, 13-14, 16-18, 24, 30-33 and 35 are cancelled.
Claims 1, 4, 6, 10, 15, 19, 22-23, 25-27, 29, 34 and 36 are amended.
Claims 1-2, 4, 6, 10-12, 15, 19-23, 25-29, 34, and 36 are pending and under consideration.
Information Disclosure Statement (IDS)
The information disclosure statement (IDS) submitted on October 6, 2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
This application’s claim of priority to U.S. Provisional Application Serial No. 63/173,207 filed on April 9, 2021, is acknowledged.
Specification Objections
The disclosure is objected to because of the following informalities: In Brief Description of the Drawings, the animal models used for Figures 7-9 is EMT6 mouse model for KRASG12D TNBC (paragraphs 0018- 0020), but the animal model listed in example 3, which also refers to Figures 7-9, is KRASWT TNBC (paragraphs 0199-0202). Appropriate correction is required.
The use of the term PICOLAB®, MITUTOYO®, FACSCantoTM, FLowJoTM, Invitrogen®, GRAPHPAD®, GRAPHPAD PRISM®, MICROSOFT®, OHAUS®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Appropriate correction is required.
Claim Interpretation
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor. The specification fails to define if “a mutated MAPK signaling pathway” includes only mutations in the classic Ras/RAF/MEK/ERK pathway, or includes mutations in JNK, P38 and ERK5 (Shi et al. J Cancer Res Clin Oncol 150 (6), 2024, section Major MAPK-signaling pathways). It is interpreted as any mutations in any genes in the classic, JNK, P38 and ERK5 MAPK pathways.
Claim Rejections - 35 USC § 112
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.
Claim 1 is 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 phrase “characterized by” in claim 1 renders the claim indefinite because its meaning is unclear. The specification fails to explain the term and the metes and bounds are not clear.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-2, 4, 6, 10-12, 15, 19-23, 25-29, 34 and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method of treating a subject having cancer characterized by mutated MAPK signaling pathway, the method comprising administering to the subject belvarafenib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of PD-1 axis inhibitor. The cancer could carry a RAF mutation such as BRAF V600E in various types of cancers, or could carry a NRAS or a KRAS mutation in various types of cancers. The PD-1 axis inhibitor could be a PD-L1 inhibitor or atezolizumab.
The specification fails to define if a cancer ‘characterized by a mutated MAPK signaling pathway” includes only mutations in the classic Ras/RAF/MEK/ERK pathway, or includes mutations in JNK, P38 and ERK5 (Shi et al. J Cancer Res Clin Oncol 150 (6), 2024, section Major MAPK-signaling pathways). It is interpreted as any mutations in any genes in the classic, JNK, P38 and ERK5 pathways. This is a functional statement and provides no structure of what confers the function. There are unlimited number of mutations or combination of mutations, which can cause mutated MAPK signaling pathway.
The specification states the term “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth and a tumor comprises one or more cancerous cells (instant specification paragraph 0022). Therefore, the cancers could be any type of cancer as long as it has mutated MAPK signaling pathway, which includes many different types of cancer. In fact, Sinkala et al (Commun Biol. 2021 Jan 4; 4:9) teach that mutations in MAPK pathway genes are found in 58% of all 40,848 tumor samples that represent 101 distinct human cancers (abstract, page 2 right column last paragraph). Among the 101 cancers tested in the study, the only type of cancer that does not have mutated MAPK tumor sample is small cell carcinomas of the ovary (page 3 left column paragraph 4, Supplementary File 1).
The specification states the term “PD-1 axis inhibitor” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with its binding partner, such as PD-1 inhibitor, a PD-L1 inhibitor, and a PD-L2 inhibitor (paragraph 0040). Therefore, the PD-1 axis inhibitor could be any molecule, such as small molecules, peptides, fusion proteins or antibodies, that inhibit PD-1, PD-L1 and/or PD-L2 function. This is a functional statement and provides no structure of what confers the function. There could be unlimited number of molecules that are PD-1 axis inhibitors.
Similarly, PD-L1 inhibitor refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signaling transduction resulting from the interaction of PD-L1 with either one or more of its binding partners (e.g. PD-1, B7-1), such as an anti-PD-L1 antibody (paragraph 0043). Therefore, the PD-L1 inhibitor could be any molecule, such as small molecules, peptides, fusion proteins or antibodies, that inhibit PD-L1 binding with its binding partners. This is a functional statement and provides no structure of what confers the function. There could be unlimited number of molecules that are PD-L1 inhibitors.
The specification states the subject is a mammal, including human and non-human mammals (paragraph 0082).
Therefore, the claims recite administering belvarafenib or a pharmaceutically acceptable salt, and a genus of PD-1 axis inhibitors (or a genus of PD-L1 inhibitors), to treat a genus of cancers characterized by a mutated MAPK signaling pathway.
Regarding a PD-1 axis inhibitor (or a PD-L1 inhibitor), although the claims are inclusive of two PD-1 axis inhibitors, atezolizumab and Mu igG1 anti-PDL1 antibody, the claims also broadly encompass all the PD-1 axis inhibitors (or PD-L1 inhibitors). As explained above, PD-1 axis inhibitor could be any molecule, such as small molecules, peptides, fusion proteins or nucleic acids, that inhibits PD-1, PD-L1 and/or PD-L2 function. Similarly, PD-L1 inhibitor could also be any molecule, such as small molecules, peptides, fusion proteins or nucleic acids, that inhibits the binding between PD-L1 with its binding partners. These are functions and provide no structure of what confers the function. There could be unlimited number of molecules that are PD-1 axis inhibitors or PD-L1 inhibitors.
The specification does not provide adequate written description to identify the broad and variable genus of the inhibitors because, inter alia, the specification does not disclose a correlation between the necessary structure of the protein and the function(s) recited in the claims. A definition by function does not suffice to define the genus because it is only an indication of what the molecule does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus is highly variable, the generic description is insufficient to describe the genus. Further, given the highly diverse nature of molecules, even one of skill in the art cannot envision the structure of inhibitors by its functional characteristics. Thus, the specification does not provide substantive evidence for possession of the large and variable genus, encompassing a potentially massive number of the molecules claimed only by a functional characteristic.
Furthermore, Applicant has not shown procession of a representative number of species that have the claimed function(s). The specification has written description for atezolizumab and Mu igG1 anti-PDL1 antibody, but the claims are not limited to these two antibodies, and encompass any molecules that inhibit the PD-1 axis (or PD-L1). Thus the genus has substantial variation because of the numerous alternatives and combinations permitted. The structure of the Mu igG1 anti-PDL1 antibody is not provided in the specification. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only two species have been described and this is not considered to be representative of the breadth of the genus. Given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
In the state of the art, the effect of different PD-1 axis inhibitors are not predictable. Banna et al (Oncol Rev. 2020. 14(2):490) teach anti-PD1 and anti-PDL1 antibodies have possible inter- and intra-class dissimilarities and differences in the treatment of non-small cell lung cancer (NSCLC) patients in efficacy and adverse events (abstract). Many small molecule inhibitors against PD-1 and/or PD-L1 are being developed and tested, but the first oral PD-1 inhibitor to enter clinical testing has been discontinued due to toxicity reasons (News in Brief, “Oral PD-L1 inhibitors Crows into the clinic, Cancer Discov. 2023. 13(1): OF2). Therefore, the state of the art supports the position that the effect of PD-1 axis inhibitor (or a PD-L1 inhibitor) in treating cancer, is not predictable.
Therefore, neither the art nor the specification provides a sufficient representative number of species to meet the written description requirement.
Regarding treating all cancer characterized by a mutated MAPK signaling pathway, the specification has written description of three examples: 1) treating a mutant K1735 subcutaneous mouse model, which is a NRAS G13D melanoma model (example 1); 2) treating a CT26 syngeneic mouse model (KRAS G12D, colorectal cancer, example 2); and 3) treating a EMT6 syngeneic model (triple negative breast cancer, TNBC (example 3). Note that in the EMT6 mouse model used for example 3, it is unclear whether the mouse model is KRAS WT or KRAS G12D due to the conflicting information given in the specification (see paragraphs 0018 and 0200). It is interpreted as EMT6 syngeneic model (KRAS G12D, TNBC) as stated in the Brief Description of the Drawings.
The specification fails to provide written description to use claimed method to treat all types of cancers that are characterized by a mutated MAPK signaling pathway.
In the state of the art, the effect of belvarafenib and PD-1 axis inhibitor (or PD-L1 inhibitor) in treating all cancers characterized with mutated MAPK signaling pathway is unpredictable.
As stated above, mutated MAPK signaling pathway could involve genes from RAS/RAF/MEK/ERK (MAPK) pathway, but also involve genes in JNK and P38 pathways. Many types of cancer can carry mutations in the MAPK signaling pathway as explained above: among the 101 cancers tested, only one type of cancer, carcinomas of the ovary, that does not have mutated MAPK tumor sample identified (Sinkala et al, page 3 left column paragraph 4, Supplementary File 1). Belvarafenib is a pan-RAF kinase inhibitor. One of skill in the art would expect that belvarafenib is unlikely to treat a cancer that is caused by a mutated MAPK gene that is not on the same signaling pathway as RAF.
In fact, even cancers caused by RAF mutations might not be treated by belvarafenib. For instance, Yen et al (Nature 594, 418-423, 2021) teach mutations in ARAF confer resistance to the RAF inhibitor belvarafenib in melanoma (see abstract). ARAF is a RAF protein, which is key signaling members of the MAPK pathway (page 418, left column 1st paragraph). In addition, in a phase I clinical trial where belvarafenib was administered to treat solid tumors including melanoma and colorectal cancers that contain BRAF and RAS mutations, only a subset of the patients harboring the mutations show responses to belvarafenib (see section Clinical data confirm resistance). Dziadziuszko et al (Ann Oncol 2024; 35: S498-S499) teach belvarafenib monotherapy in patients with BRAF class II or III alteration-positive advanced/metastatic solid tumors, only one out of 49 patients have confirmed responses (whole document). Lebert et al (Neuro Oncol. 2024 Jun 18;26(Suppl 4):0.) teach that belvarafenib is not able to significantly decrease the viability of tumor cells derived from pediatric low-grade gliomas (LGGs) with BRAF fusions (see methods, results and conclusions). Similarly, Levinson et al (Blood (2024) 144 (Supplement 1): 1390) teach that certain mutations, such as MEK K57T, confers pronounced resistance to belvarafenib (see results).
In addition, the effect of PD-1 axis inhibitors, when combined with inhibitors for the MAPK signaling pathway, is not predictable in treating cancers with mutated MAPK signaling pathway. Callahan et al (J Clin Oncol 40, 1393-1395, 2022) teach that the addition of anti-PD-1 or anti-PD-L1 antibodies to combination RAFi (RAF inhibitor) plus MEKi (MEK inhibitor) is not associated with a significant clinical benefit while associated with increased toxicity, and should not be studied further in melanoma (whole document). Long et al (Nat Med 30, 2540–2548, published 2024) suggest that immunotherapy (pembrolizumab, a PD-1 axis inhibitor) and targeted therapy (Dabrafenib, a BRAF inhibitor, and trametinib, a MEK1/2 inhibitor) should not be combined in the neoadjuvant setting for BRAF V600 melanoma due to the risk of higher toxicity and loss of curative potential (see abstract and discussion).
Therefore, the state of the art support the position that using the claimed method to treat all cancers characterized by a mutated MAPK signaling pathway, is not predictable.
Claim 12 is drawn to using the claimed method to treat 12 specific cancers and combination thereof. Again, the specification only has written description of three examples: 1) melanoma carrying a NRAS G13D mutation, 2) CRC carrying a KRAS G12D mutation, both of which are listed in the claim, and 3) a EMT6 breast cancer which is not listed in claim 12. The specification does not have written description of other cancers listed in the claim, such as a bladder cancer carrying a KRAS G12V mutation, or sarcoma carrying a KRAS G12V mutation.
In the state of the art, Lee et al (Cancer Res (2015) 75 (15_Supplement): 2607.) teach HM95573 have antitumor activity in mouse models xenografted with Calu-6 (KRAS Q61K for non-small cell lung cancer), HCT-116 (KRAS G13D for colorectal carcinoma), HepG2 (hepatoblastoma NRAS Q61L) cell lines, none of which is listed in claim 12. Bae et al (Cancer Res 1 August 2015; 75 (15_Supplement): 2606.) teach HM95573 shows antitumor activity in mouse models xenografted with SK-MEL-2 (NRAS Q61R melanoma) and SK-MEL-30 (melanoma NRAS Q61K) cell lines, both of which are included in claim 12 and the effect is due to HM95573 monotherapy. Hong et al (J Clin Oncol 34, 2570(2016) Volume 34, Number 15_suppl) teaches HM95573 is tested in patients with colorectal cancer, melanoma, lung cancer, GIST and bladder cancer, and the solid tumor carry KRAS (45%) or NRAS (10%) mutation, but does not teach the combination of the cancers and the point mutations. In addition, among the 31 patients enrolled, only one patient with NRAS melanoma experienced an unconfirmed partial response and 9 patients had stable disease. The effect of HM95573 is not clear in the majority of the patients. Kim et al (J Clin Oncol 37, 3000(2019) Volume 37, Number 15_suppl) teach in patients treated with HM95573 (belvarafenib), two PRs were observed in nine patients with NRAS-mutant melanoma (2/9), two PRs were observed in six BRAF-mutant melanoma (2/6) and two PRs were observed in seven BRAF-mutant CRC patients (2/7), but Kim et al do not teach the specific cancer and specific point mutation combination as cited in claim 12.
Therefore, neither the art nor the specification provides a sufficient written description to all the cancers cited in claim 12.
Taken together, the specification fails to provide written description to use the method comprising administering belvarafenib or a pharmaceutically acceptable salt thereof and a PD-1 axis inhibitor (or a PD-L1 inhibitor) to treat all types of cancers that are characterized by a mutated MAPK signaling pathway (or specific cancers cited in claim 12).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed molecules in all PD-1 axis inhibitor or all PD-L1 inhibitor. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant application has many similarities to Abbvie above. First, the claims clearly attempt to define the genus of PD-1 axis inhibitors (or PD-L1 inhibitors) by the functions. As noted by Abbvie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed examples would be representative of the entire genus. The specification discloses no structure to correlate with the function.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171). Because the specification does not describe the structures for unlimited options of PD-1 axis inhibitors (or PD-L1 inhibitors) that would have the recited functions, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed invention of administrating belvarafenib and a PD-1 axis inhibitor (or an PD-L1 inhibitor) to treat any cancers that are characterized by a mutated MAPK signaling pathway.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, there is not identification of any particular portion of the structure that must be conserved or present. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
Claims 1-2, 4, 6, 10-12, 15, 19-23, 25-29, 34 and 36 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for 1) administering belvarafenib and atezolizumab to treat a K1735 syngeneic mouse model for NRAS G13D melanoma, 2) administering belvarafenib and Mu igG1 anti-PDL1 to treat a CT26 KRAS G12D colorectal cancer (CRC) mouse model, and 3) administering belvarafenib and Mu igG1 anti-PDL1 to treat a EMT6 syngeneic mouse mode for triple negative breast cancer (TNBC), it does not reasonably provide enablement for treating all cancers characterized by mutated MAPK signaling pathway in all mammals by administrating belvarafenib and any PD-1 axis inhibitor (or any PD-L1 inhibitor) to treat all cancers characterized by a mutated MAPK signaling pathway. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The nature of the invention and the breadth of the claims
The claims are drawn to a method of treating any cancers in mammal characterized by mutated MAPK signaling pathway, the method comprising administering belvarafenib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a PD-1 axis inhibitor (or PD-L1 inhibitor).
Regarding cancer characterized by a mutated MAPK signaling pathway, MAPK signaling pathway is interpreted as any mutations in any genes in the classic, JNK, P38 and ERK5 MAPK signaling pathways. There are unlimited types of mutations that can lead to mutated MAPK signaling pathway. There are many different types of cancers that have mutated MAPK signaling pathway.
The specification is enabling for the following examples: 1) a K1735 syngeneic mouse model for NRAS G13D melanoma, 2) a CT26 KRAS G12D colorectal cancer (CRC) mouse model, and 3) a EMT6 syngeneic mouse mode for triple negative breast cancer (TNBC). Due to the conflicting explanation for the EMT6 model used in the specification (paragraphs 0018 and 0200), it is unclear if KRAS G12D or KRAS WT breast cancer is tested in example 3. It is interpreted as the method is tested in KRAS G12D breast cancer model.
Regarding the method comprising administering belvarafenib and PD-1 axis inhibitor (or PD-L1 inhibitor), there are also unlimited number of PD-1 axis inhibitors and unlimited number of PD-L1 inhibitors, and they have different properties.
The specification is enabling for atezolizumab and Mu igG1 anti-PDL1 antibody.
The state of the prior art and the level of predictability of the art
While the state of the art is relatively high with regard to the treatment of specific mutations in specific cancers with specific reagents, the state of the art with regard to using different regents to treat all cancers having mutations contributing to mutated MAPK signaling pathway is underdeveloped. The cancer treatment art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to treating any cancers characterized by any mutations leading to mutated MAPK signaling pathway by administering belvarafenib and a PD-1 axis inhibitor (or a PD-L1 inhibitor), makes practicing the claimed invention unpredictable.
First, the effect of belvarafenib in treating all cancers characterized with mutated MAPK signaling pathway is unpredictable. Yen et al (Nature 594, 418-423, 2021) teach mutations in ARAF confer resistance to the RAF inhibitor belvarafenib in melanoma (see abstract). ARAF is a RAF protein, which is key signaling members of the RAS-RAF-MEK-ERK (MAPK) pathway (page 418, left column 1st paragraph). In addition, in a phase I clinical trial where belvarafenib was administered to treat solid tumors including melanoma and colorectal cancers that contain BRAF and RAS mutations, only a subset of the patients harboring the mutations show responses to belvarafenib (see section Clinical data confirm resistance). Lebert et al (Neuro Oncol. 2024 Jun 18;26(Suppl 4):0.) teach that belvarafenib is not able to significantly decrease the viability of tumor cells derived from pediatric low-grade gliomas (LGGs) with BRAF fusions (see methods, results and conclusions). Similarly, Levinson et al (Blood (2024) 144 (Supplement 1): 1390) teach that certain mutations, such as MEK K57T, confers pronounced resistance to belvarafenib (see results).
Second, the effect of PD-1 axis inhibitor, when combined with an inhibitor for the MAPK signaling pathway, is not predictable in treating cancers with mutated MAPK signaling pathway. Callahan et al (J Clin Oncol 40, 1393-1395, 2022) teach that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi plus MEKi is not associated with a significant clinical benefit while associated with increased toxicity, and should not be studied further in melanoma (whole document). Long et al (Nat Med 30, 2540–2548, published 2024) suggest that immunotherapy (pembrolizumab, a PD-1 axis inhibitor) and targeted therapy (Dabrafenib, a BRAF inhibitor, and trametinib, a MEK1/2 inhibitor) should not be combined in the neoadjuvant setting for BRAF V600 melanoma due to the risk of higher toxicity and loss of curative potential (see abstract and discussion).
In addition, cancers arising from different tissues differ in etiology and response to treatment. Heppner et al (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue, and tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
With regard to cancer treatment, Bally et al (US 5,595,756) teach although a number of bioactive agents have been found to be effective against tumor cells, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities (Bally et al. col. 1, lines 17-24).
Sporn et al (“Chemoprevention of Cancer,” Carcinogenesis, Vol. 21 (2000), 525-530) teach the magnitude of mortality of cancers and that new approaches to a variety of different cancer are critically needed. Sporn et al also teach because the genotype and phenotype heterogeneity in advanced malignant lesions in individual patients, it is hard to know the specific molecular and cellular targets a potential therapy should target.
Furthermore, the art indicates the difficulties in going from animal model to clinical studies for drug development for treatment of cancers. Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that the model systems used in cancer drug discovery are not predictive at all (see p. 1, 2nd paragraph).
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “data suggest that the overall success rate for oncology products in clinical development is -10%” (page 253 left column 1st paragraph). Hait further teaches several reasons why the outcome for a particular cancer target may be disappointing, such as incomplete understanding of the target in the pathogenesis of specific human malignancies, the putative role of cancer stem cells in limiting the efficacy of cancer therapeutics, the roles of single nucleotide polymorphisms in genes responsible for drug metabolism by affecting drug pharmacokinetics (page 253, Section “Understanding the target in context).
Hait also teaches drug effects in preclinical cancer models often do not predict clinical results. Despite several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems and newer genetic mouse models, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost (page 253, Section “Predictive models).
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3(2):22, pages 1 -5). Gravanis et al. teach the constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results, systemic biology approaches of the -omic type still generate largely incomprehensible, and animal models of cancer are similarly unable to predict the clinical situation (page 3 right column 2nd paragraph).
Given Yen et al, Lebert et al, and Levinson et al teachings of the unpredictability of belvarafenib in treating cancers with mutated MAPK signaling pathway; Callahan et al, Long et al teachings about the unpredictability of PD-1 axis inhibitor, when combined with a BRAF inhibitor, in treating cancers characterized with mutated MAPK signaling pathway; Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Gura's teaching that the models are unpredictable; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; the cited references demonstrate that treatment of cancer characterized by the mutated MAPK signaling pathway by administering belvarafenib and a PD-1 axis inhibitor (or a PD-L1 inhibitor), is highly unpredictable.
Taken together, the cited references demonstrate that treatment of all cancers characterized by mutated MAPK signaling pathway with belvarafenib and any PD-1 axis inhibitor (or any PD-L1 inhibitor), is unpredictable.
The amount of direction or guidance provided by the inventor and the existence of working examples
The instant specification is only enabling for three examples: 1) administering belvarafenib with atezolizumab to treat NRAS G13D melanoma in mouse, 2) administering belvarafenib with mu igG1 PD-L1 antibody to treat KRAS G12D colorectal cancer in mouse, and 3) administering belvarafenib with Mu igG1 PD-L1 antibody to treat a breast cancer in mouse (unclear it has KRAS G12D mutation or not).
Given the evidence above and the unpredictable responsiveness of different cancers with different mutations in the MAPK signaling pathway to belvarafenib and different PD-1 axis inhibitor (or PD-L1 inhibitor), one of skill in the art could not reasonably extrapolate the findings from two specific methods of administering belvarafenib with a PD-1 axis inhibitor in treating three specific cancers in mouse, to administering belvarafenib and unlimited option of PD-1 axis inhibitor (or PD-L1 inhibitor) to treat all cancers with any mutated MAPK signaling pathway, such as the KRAS Q61 mutations, NRAS Q61 mutations, and the ARAF mutations, without undue experimentation.
In conclusion, the claimed invention does not provide enablement for the treatment of all cancers characterized with mutated MAPK signaling pathway with a method comprising administering belvarafenib and any PD-1 axis inhibitor (or any PD-L1 inhibitor). Therefore, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, 6, 10, 11, 12, 15, 19-23, 25-29, 34 and 36 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Anderson et al (US 2024/0366609 A1, published November 7, 2024 and filed April 6, 2021).
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 2 is drawn to the method of claim 1, wherein the cancer is selected from melanoma, lung, breast, colorectal (CRC), bladder, gallbladder, nephroblastoma, gastrointestinal stromal tumor (GIST), prostate, glioblastoma, myeloid leukemia, multiple myeloma, thyroid, biliary, adenocarcinoma, choriocarcinoma, sarcoma, and combinations thereof.
Claim 4 is drawn to the method of claim 1, wherein the cancer carries a RAF mutation.
Claim 6 is drawn to the method of claim 4, wherein the cancer is selected from nephroblastoma carrying a BRAF V600E mutation, melanoma carrying a BRAF V600E mutation, GIST carrying a BRAF V600E mutation, CRC carrying a BRAF V600E mutation, and combinations thereof.
Claim 10 is drawn to the method of claim 1, wherein the cancer carries a NRAS mutation or a KRAS mutation.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 12 is drawn to the method of claim 11, wherein the cancer is selected from sarcoma carrying a KRAS G12V mutation, melanoma carrying a NRAS G13D mutation, melanoma carrying a NRAS G12D mutation, melanoma carrying a NRAS Q61K mutation, melanoma carrying a NRAS Q61R mutation, melanoma carrying a NRAS G12C mutation, gallbladder cancer carrying a KRAS G12D mutation, CRC carrying a KRAS G12C mutation, CRC carrying a KRAS Q61H mutation, CRC carrying a KRAS G12D mutation, bladder cancer carrying a KRAS G12D mutation, bladder cancer carrying a KRAS G12V mutation, and combinations thereof.
Claim 15 is drawn to the method of claim 10, wherein the cancer is melanoma carrying a NRAS mutation.
Claim 19 is drawn to the method of claim 1, wherein the PD-1 axis inhibitor is a PD-L1 inhibitor.
Claim 20 is drawn to the method of claim 19, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:24), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:25), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:12); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:26), HVR-L2 sequence of SASFLYS (SEQ ID NO:27), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:28). Claim 21 is drawn to the method of claim 19 wherein the PD-L1 inhibitor is an antibody comprising: a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPY GGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDY WGQGTLVTVSS (SEQ ID NO:7) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYLYHPATFGQGTK VEIKR (SEQ ID NO:9). The HVR sequences set forth in claim 20, and the heavy and light chain variable region sequence set forth in claim 21 are part of the atezolizumab antibody.
Claim 22 is drawn to the method of claim 1, wherein the PD-L1 inhibitor is atezolizumab.
Claim 23 is drawn to the method of claim 1, wherein the subject is treated with from about 100 mg to about 1500 mg of the RAF inhibitor belvarafenib, or a pharmaceutically acceptable salt thereof, per day.
Claim 25 is drawn to the method of claim 23, wherein the subject is treated with about 250 mg to about 500 mg of belvarafenib, or a pharmaceutically acceptable salt thereof, twice per day.
Claim 26 is drawn to the method of claim 25, wherein the belvarafenib is administered daily for 28 consecutive days of a 28-day treatment cycle.
Claim 27 is drawn to the method of claim 1, wherein the subject is treated with from about 400 mg to about 1200 mg of PD-1 axis inhibitor for two days of a 28-day treatment cycle.
Claim 28 is drawn to the method of claim 27, wherein the PD-1 axis inhibitor is Atezolizumab, and further wherein the subject is treated with about 840 mg for two days of a 28-day treatment cycle.
Claim 29 is drawn to the method claim 1, wherein the subject is treated with the PD-1 axis inhibitor every 14 days of a 28-day treatment cycle.
Claim 34 is drawn to the method of claim 1, wherein the subject was previously administered a course of treatment with an anti-PD-1 drug or anti-PD-L1 drug.
Claim 36 is drawn to the method of claim 1, wherein the cancer is melanoma, and wherein, prior to said treatment, the subject experienced disease progression after treatment with immunotherapy, BRAF V600E therapy, or a combination of immunotherapy and BRAF V600E therapy.
Anderson et al teach a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway (NRAS-mutant melanoma), the method comprises administering to the subject a therapy consisting of a therapeutically effective amount of belvarafenib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a PD-1 axis inhibitor (atezolizumab) (paragraphs 0011 and 0014). Anderson et al also teaches melanoma carries a NRAS Q61K, NRAS Q61R, NRAS G12C, NRAS G13D, a NRAS G12D or NRAS G12C mutation (paragraph 0084). Atezolizumab is a PD-L1 inhibitor (paragraph 0080). This is relevant to claims 1, 2, 10, 11, 12, 15, 19-22.
Anderson et al also teach the melanoma continued to progress in a subject after treatment with BRAF V600E therapy (paragraph 0086). The subject would only have received the BRAF V600E therapy if subject is carrying the BRAF V600E mutation. BRAF V600E mutation is a RAF mutation. This is relevant to claims 4 and 6.
Anderson et al teach belvarafenib or a pharmaceutically acceptable salt thereof, is suitably dosed at from about 200 mg to about 1300 mg per day (paragraph 0069). Anderson et al also teach the subject is administered about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of belvarafenib, or a pharmaceutically acceptable salt thereof, twice per day (paragraph 0069). Anderson et al further teach belvarafenib may be dosed on days 1 to 28 of a 28-day cycle (paragraph 0070). This is relevant to claims 23, 25 and 26.
Anderson et al teach atezolizumab exhibits pharmacokinetics that are linear and consistent, and a fixed dose of atezolizumab 800 mg every two weeks have been tested and it is equivalent in exposure to a dose of 1200 mg administered every three weeks (paragraph 0081). Anderson et al also teach the subject is administered about 1680 mg of the atezolizumab on day one of the 28-day treatment cycle (paragraph 0082), which is about 840 mg for two days of a 28-day treatment cycle. In addition, atezolizumab is administered every 14 days of a 28-day treatment cycle (paragraph 0082). This is relevant to claims 27 - 29.
In addition, Anderson et al teach the subject was previously administered a course of treatment with an anti-PD-1 drug or anti-PD-L1 drug (paragraph 0087). This is relevant to claim 34.
Anderson et al further teaches the cancer is melanoma and the subject experienced disease progression after treatment with immunotherapy, BRAF V600E therapy, or a combination of immunotherapy and BRAF V600E therapy (paragraphs 0086 – 0089). This is relevant to claim 36.
Claims 1-2, 4, 10, 11, and 19-22 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Vogelstein et al (US 2019/0256924 A1, published on Aug 22 2019, referred to as Vogelstein thereafter).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 2 is drawn to the method of claim 1, wherein the cancer is selected from melanoma, lung, breast, colorectal (CRC), bladder, gallbladder, nephroblastoma, gastrointestinal stromal tumor (GIST), prostate, glioblastoma, myeloid leukemia, multiple myeloma, thyroid, biliary, adenocarcinoma, choriocarcinoma, sarcoma, and combinations thereof.
Claim 4 is drawn to the method of claim 1, wherein the cancer carries a RAF mutation.
Claim 10 is drawn to the method of claim 1, wherein the cancer carries a NRAS mutation or a KRAS mutation.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 19 is drawn to the method of claim 1, wherein the PD-1 axis inhibitor is a PD-L1 inhibitor.
Claim 20 is drawn to the method of claim 19, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:24), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:25), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:12); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:26), HVR-L2 sequence of SASFLYS (SEQ ID NO:27), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:28). Claim 21 is drawn to the method of claim 19 wherein the PD-L1 inhibitor is an antibody comprising: a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPY GGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDY WGQGTLVTVSS (SEQ ID NO:7) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYLYHPATFGQGTK VEIKR (SEQ ID NO:9). The HVR sequences set forth in claim 20, and the heavy and light chain variable region sequence set forth in claim 21 are part of the atezolizumab antibody.
Claim 22 is drawn to the method of claim 1, wherein the PD-L1 inhibitor is atezolizumab.
Vogelstein teaches methods of treating subjects having cancer that have one or more genetic biomarkers, such as KRAS, BRAF and NRAS (mutation in the genes in the MAPK signaling pathway), by administering one or more therapeutic interventions, including targeted therapy (such as administration of kinase inhibitors that target a particular genetic lesion) and/or an immune checkpoint inhibitor (paragraph 0030 and 0161). Examples of the immune checkpoint inhibitor includes a PD-1 and/or PD-L1 immune checkpoint inhibitor (paragraph 0779). The target therapy is a BRAF inhibitor such as HM95573 (belvarafenib, see instant application specification paragraphs 0011), when the subject is identified as having a genetic biomarker (mutation) in NRAS (Vogelstein paragraph 0783). The cancer could be colorectal cancer, lung cancer, breast cancer (paragraph 0030). This is relevant to claims 1 and 2.
Vogelstein also teaches the cancer could have RAF mutations, such as BRAF V600E, a KRAS mutations such as KRAS G12V and KRAS G12D, and/or NRAS mutations such as NRAS Q61K (paragraph 0574). BRAF is a member of the RAF family of protein kinases. This is relevant to claims 4,10 and 11.
Vogelstein further teaches examples of immune checkpoint inhibitors include atezolizumab, a PD-L1 inhibitor (paragraph 0780). This is relevant to claims 19-22.
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.
Claims 1-2, 4, 6, 11, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al (Cancer Immunol Res. 2014 Jul;2(7):643-54) in view of Smalley et al (Pigment Cell Melanoma Res. 25; E1-E11. 2011) and Bae et al (Cancer Res 1 August 2015; 75 (15_Supplement): 2606).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 2 is drawn to the method of claim 1, wherein the cancer is selected from melanoma, lung, breast, colorectal (CRC), bladder, gallbladder, nephroblastoma, gastrointestinal stromal tumor (GIST), prostate, glioblastoma, myeloid leukemia, multiple myeloma, thyroid, biliary, adenocarcinoma, choriocarcinoma, sarcoma, and combinations thereof.
Claim 4 is drawn to the method of claim 1, wherein the cancer carries a RAF mutation.
Claim 6 is drawn to the method of claim 4, wherein the cancer is selected from nephroblastoma carrying a BRAF V600E mutation, melanoma carrying a BRAF V600E mutation, GIST carrying a BRAF V600E mutation, CRC carrying a BRAF V600E mutation, and combinations thereof.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 19 is drawn to the method of claim 1, wherein the PD-1 axis inhibitor is a PD-L1 inhibitor.
Cooper et al teach that BRAF-targeted therapy results in objective responses in the majority of patients, but the responses are short-lived (~6-months) (abstract). Administration of anti-PD-1 or anti-PD-L1 (PD-1 axis inhibitor or PD-L1 inhibitor) together with a BRAF inhibitor PLX4720, a pre-clinical analog of vemurafenib that selectively targets BRAF V600E, have synergistic effect in slowing tumor growth and increasing survival in a BRAAF V600E melanoma mouse model (Abstract, Materials and Methods, and section PD-1 pathway blockade and BRAF inhibition synergize to enhance survival and slow melanoma growth). This is relevant to claims 1, 2, 4, 6, 11, and 19.
Cooper et al fail to teach administering belvarafenib in the method.
However, Vemurafenib is known to induce the growth or develop cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC/KA) in the patients and in mouse models. For instance, Smalley et al teach PLX4720 accelerated the growth of cuSCC/KAs (page E8 right column first paragraph).
Smalley et al fail to teach administering belvarafenib in the method.
However, Bae et al teach HM95573 (belvarafenib) has excellent antitumor activity in mouse models xenografted with BRAF V600E mutation cell lines (A375 and SK-MEL-28) and it does not show a potential to paradoxical activation inducing tumor growth in mouse xenografted with A431 cuSCC cancer cells.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cooper et al, Smalley et al and Bae et al, to administering belvarafenib and a PD-1 axis inhibitor (anti-PD-1 or anti-PD-L1) to treat a subject having BRAF V600E melanoma, because belvarafenib does not paradoxically induce cuSCC tumor growth as vemurafenib (PLX4720) and belvarafenib is shown to be effective in treating BRAF V600E melanoma. The rationale to do is that: 1) vemurafenib paradoxically induce cuSCC tumor growth and belvarafenib does not; and 2) belvarafenib has excellent anti-tumor effect in treating BRAF V600E melanoma. One would have a reasonable expectation of success in making the combination because the belvarafenib’s efficacy and better safety outcomes have been demonstrated in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1-2, 4, 10-11, 19-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al (US 2019/0256924 A1, published on Aug 22 2019, referred to as Vogelstein thereafter) in view of Kim et al (J Clin Oncol 37, 3000-3000, May 26, 2019).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 2 is drawn to the method of claim 1, wherein the cancer is selected from melanoma, lung, breast, colorectal (CRC), bladder, gallbladder, nephroblastoma, gastrointestinal stromal tumor (GIST), prostate, glioblastoma, myeloid leukemia, multiple myeloma, thyroid, biliary, adenocarcinoma, choriocarcinoma, sarcoma, and combinations thereof.
Claim 4 is drawn to the method of claim 1, wherein the cancer carries a RAF mutation.
Claim 10 is drawn to the method of claim 1, wherein the cancer carries a NRAS mutation or a KRAS mutation.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 19 is drawn to the method of claim 1, wherein the PD-1 axis inhibitor is a PD-L1 inhibitor.
Claim 20 is drawn to the method of claim 19, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:24), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:25), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:12); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:26), HVR-L2 sequence of SASFLYS (SEQ ID NO:27), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:28).
Claim 21 is drawn to the method of claim 19 wherein the PD-L1 inhibitor is an antibody comprising: a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPY GGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDY WGQGTLVTVSS (SEQ ID NO:7) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYLYHPATFGQGTK VEIKR (SEQ ID NO:9). The HVR sequences set forth in claim 20, and the heavy and light chain variable region sequence set forth in claim 21 are part of the atezolizumab antibody.
Claim 22 is drawn to the method of claim 1, wherein the PD-L1 inhibitor is atezolizumab.
Claim 23 is drawn to the method of claim 1, wherein the subject is treated with from about 100 mg to about 1500 mg of the RAF inhibitor belvarafenib, or a pharmaceutically acceptable salt thereof, per day.
Claim 25 is drawn to the method of claim 23, wherein the subject is treated with about 250 mg to about 500 mg of belvarafenib, or a pharmaceutically acceptable salt thereof, twice per day.
Vogelstein teaches methods of treating subjects having cancer that have one or more genetic biomarkers, such as KRAS, BRAF and NRAS (mutation in the genes in the MAPK signaling pathway), by administering one or more therapeutic interventions, including targeted therapy (such as administration of kinase inhibitors that target a particular genetic lesion) and/or an immune checkpoint inhibitor (paragraph 0005, 0030 and 0161). Examples of the immune checkpoint inhibitor includes a PD-1 and/or PD-L1 immune checkpoint inhibitor, such as atezolizumab (paragraph 0779 and 0780). The targeted therapy is a BRAF inhibitor such as HM95573 (belvarafenib, see instant application specification paragraphs 0011), when the subject is identified as having a genetic biomarker (mutation) in NRAS (Vogelstein paragraph 0783). This is relevant to claims 1 and 19-22.
Vogelstein also teaches the cancer could be melanoma, colorectal cancer, lung cancer, gastrointestinal stromal tumor (GIST), and breast cancer (paragraph 0030, 0574 and 0753). This is relevant to claim 2.
Vogelstein further teaches the cancer could have RAF mutations, such as BRAF V600E, a KRAS mutations such as KRAS G12V and KRAS G12D, and/or NRAS mutations such as NRAS Q61K (paragraph 0574). BRAF is a member of the RAF family of protein kinases. This is relevant to claims 4, 10 and 11.
Vogelstein fails to teach the doses and dosing schedule of belvarafenib as cited in claims 23 and 25. However, Volgestein teaches effective doses can vary depending on many factors, such as the severity of the cancer, the route of administration, the age and general health condition of the subject, possibility of co-usage (paragraph 0820). In addition, an effective amount of a composition can be any amount that reduces the number of cancer cells without producing significant toxicity to the subject, and it can be adjusted based on many factors, such as toxicity, effectiveness, route of administration, duration of treatment and severity of the condition (paragraph 0821).
Kim et al teach that belvarafenib was tested in the clinical trial at a starting dose of 50 mg once daily to 800 mg twice a day (BID) to assess safety and tolerability (see methods). Kim et al also teach 650 mg twice per day (BID) is considered the maximum tolerated dose (MTD) and 450 mg twice a day (BID) is identified as the recommended dose (RD) for belvarafenib (see results). Kim et al further teach that belvarafenib exhibits anti-tumor activity in patients with NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST (see results and conclusions).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Vogelstein and Kim et al to administering belvarafenib at or below 650 mg twice a day (which equals to 1300 mg total a day), or at 450 mg twice per day (which equals to 900 mg total per day), to treat melanoma that has NRAS mutation, because 1) exceeding MTD could lead to undesirable side effects and toxicity in patients, 2) 450 mg twice per day is the recommended dose for belvarafenib, and 3) belvarafenib exhibits anti-tumor activity at this dose in patients with NRAS-mutation melanoma. The rationale to do so is in the teachings of Vogelstein and Kim et al, that the effective doses of a composition can be adjusted based on many factors (Vogelstein paragraphs 0820 and 0821), and belvarafenib administered at 450 mg twice per day is the recommended dose, it is tolerated, and it exhibits anti-tumor activity against NRAS-mutant melanoma (Kim et al). One would have a reasonable expectation of success in making the combination because administering compounds below MTD, and at a recommended dose that is shown safe and efficacious based on previous results, are common practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 26 is rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al in view of Kim et al over claims 1-2, 4, 10, 11, 19-23 and 25, and further in view of Yamazaki et al (J Dermatol, 42: 661-666. 2015).
Claim 26 is drawn to the method of claim 25, wherein the belvarafenib is administered daily for 28 consecutive days of a 28-day treatment cycle.
The teachings of Vogelstein and Kim et al have been discussed previously.
In addition, Vogelstein teaches an effective duration for administering a composition can be any duration that reduces the number of cancer cells without producing significant toxicity to the subject, and it can vary from several days to several weeks, such as one week to about four weeks (paragraph 0823). Multiple factors can influence the actual effective duration used for a particular treatment, such as frequency of administration, effective amount, use of multiple treatment agents, route of administration and severity of the condition being treated (paragraph 0823).
Vogelstein and Kim et al fail to teach that belvarafenib is administered daily for 28 consecutive days of a 28-day treatment cycle.
However, Yamazaki et al teach vemurafenib, a BRAF inhibitor used commonly to treat BRAF V600E melanoma, is administered daily for 28-day treatment cycles, and resulted in an overall response rate of 75% in Japanese patients with metastatic BRAF V600 melanoma (abstract, study design, efficacy).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Vogelstein, Kim et al, and Yamazaki, to administering belvarafenib at 450 mg twice a day, every day for 28 consecutive days of a 28-day treatment cycle, because the dosing daily for 28 days of a 28-day treatment cycle has been shown to be safe and efficacious with vemurafenib, a BRAF inhibitor, to treat cancer. The rationale to do is this dosing regimen is shown to be safe and efficacious in patients with BRAF V600 melanoma using vemurafenib. One would have a reasonable expectation of success in making the combination because this specific dosing cycle length has been shown in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1-2, 4, 10-11, 19-22, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al (US 2019/0256924 A1, published on Aug 22 2019, referred to as Vogelstein thereafter) in view of TECENTRIQ® prescribing information (revised December 2019).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 2 is drawn to the method of claim 1, wherein the cancer is selected from melanoma, lung, breast, colorectal (CRC), bladder, gallbladder, nephroblastoma, gastrointestinal stromal tumor (GIST), prostate, glioblastoma, myeloid leukemia, multiple myeloma, thyroid, biliary, adenocarcinoma, choriocarcinoma, sarcoma, and combinations thereof.
Claim 4 is drawn to the method of claim 1, wherein the cancer carries a RAF mutation.
Claim 10 is drawn to the method of claim 1, wherein the cancer carries a NRAS mutation or a KRAS mutation.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 19 is drawn to the method of claim 1, wherein the PD-1 axis inhibitor is a PD-L1 inhibitor.
Claim 20 is drawn to the method of claim 19, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:24), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:25), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:12); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:26), HVR-L2 sequence of SASFLYS (SEQ ID NO:27), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:28).
Claim 21 is drawn to the method of claim 19 wherein the PD-L1 inhibitor is an antibody comprising: a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPY GGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDY WGQGTLVTVSS (SEQ ID NO:7) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYLYHPATFGQGTK VEIKR (SEQ ID NO:9). The HVR sequences set forth in claim 20, and the heavy and light chain variable region sequence set forth in claim 21 are part of the atezolizumab antibody.
Claim 22 is drawn to the method of claim 1, wherein the PD-L1 inhibitor is atezolizumab.
Claim 27 is drawn to the method of claim 1, wherein the subject is treated with from about 400 mg to about 1200 mg of PD-1 axis inhibitor for two days of a 28-day treatment cycle.
Claim 28 is drawn to the method of claim 27, wherein the PD-1 axis inhibitor is Atezolizumab, and further wherein the subject is treated with about 840 mg for two days of a 28-day treatment cycle.
Claim 29 is drawn to the method claim 1, wherein the subject is treated with the PD-1 axis inhibitor every 14 days of a 28-day treatment cycle.
Vogelstein teaches methods of treating subjects having cancer that have one or more genetic biomarkers, such as KRAS, BRAF and NRAS (mutation in the genes in the MAPK signaling pathway), by administering one or more therapeutic interventions, including targeted therapy (such as administration of kinase inhibitors that target a particular genetic lesion) and/or an immune checkpoint inhibitor (paragraph 0005, 0030 and 0161). Examples of the immune checkpoint inhibitor includes a PD-1 and/or PD-L1 immune checkpoint inhibitor, such as atezolizumab (paragraph 0779 and 0780). When the subject is identified as having a genetic biomarker (mutation) in NRAS, the subject is administered with a BRAF inhibitor such as HM95573 (belvarafenib, see instant application specification paragraphs 0011) (Vogelstein paragraph 0783). This is relevant to claims 1 and 19-22.
Vogelstein also teaches the cancer could be melanoma, colorectal cancer, lung cancer, gastrointestinal stromal tumor (GIST), and breast cancer (paragraph 0030, 0574 and 0753). This is relevant to claim 2.
Vogelstein further teaches the cancer could have RAF mutations, such as BRAF V600E, a KRAS mutations such as KRAS G12V and KRAS G12D, and/or NRAS mutations such as NRAS Q61K (paragraph 0574). BRAF is a member of the RAF family of protein kinases. This is relevant to claims 4, 10 and 11.
Vogelstein fails to teach the limitation of the dosing schedule and doses at which the PD-1 axis inhibitor or atezolizumab is administered, as cited in claims 27-29. However, Volgestein teaches effective doses can vary depending on many factors, such as the severity of the cancer, the route of administration, the age and general health condition of the subject, possibility of co-usage (paragraph 0820). In addition, an effective amount of a composition can be any amount that reduces the number of cancer cells without producing significant toxicity to the subject, and it can be adjusted based on many factors, such as toxicity, effectiveness, route of administration, duration of treatment and severity of the condition (paragraph 0821).
The doses and dosing schedule of atezolizumab, which is a PD-1 axis inhibitor, is well established in the art. For instance, TECENTRIQ® prescribing information teaches TECENTRIQ®, which is atezolizumab, a PD-L1 inhibitor, is administered at 840 mg every 2 weeks for urothelial carcinoma and small cell lung cancer, 840 mg at days 1 and 15 for each 28 day cycle for TNBC (triple negative breast cancer) (see page 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Vogelstein and TECENTRIQ® prescribing information to administer atezolizumab, a PD-1 axis inhibitor at 840 mg 2 days in a 28-day treatment cycle (or dosed every 14-day in a 28-day treatment cycle), because the dosing schedule and dose is approved by FDA, is safe and efficacious against a few different types of cancers, and it is how atezolizumab is prescribed to patients with a few different types of cancers. The rationale to do is atezolizumab is shown to be safe and efficacious at 840 mg every 2 weeks in a 28 day treatment cycle against a few types of cancer, and thus it is obvious to use the dose and the dosing regimen. One would have a reasonable expectation of success in making the combination because administering compounds at a dose and dosing regimen that have been shown to be safe and efficacious are common practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Burton et al (Annals of Oncology. 30(5): v534-v535. October 2019) in view of Anonymous (ClinicalTrials.gov ID NCT02910700, v. 21, date of record March 10 2021, referred to as NCT02910700 thereafter) and Bae et al (Cancer Res 1 August 2015; 75 (15_Supplement): 2606).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 34 is drawn to the method of claim 1, wherein the subject was previously administered a course of treatment with an anti-PD-1 drug or anti-PD-L1 drug.
Claim 36 is drawn to the method of claim 1, wherein the cancer is melanoma, and wherein, prior to said treatment, the subject experienced disease progression after treatment with immunotherapy, BRAF V600E therapy, or a combination of immunotherapy and BRAF V600E therapy.
Burton et al teach that in a phase II study (NCT02910700) in patients with BRAF-mutated metastatic melanoma (MM) who have received immunotherapy before, the triple combination therapy of nivolumab (a PD-1 inhibitor), dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor), is well-tolerated and shows promising clinical activity in patients with immunotherapy refractory.
Burton et al fail to teach the immunotherapy that the patients were refractory for, and using belvarafenib in the therapy.
However, NCT02910700, which is the study protocol for Burton et al, teaches in the study, only patients with BRAF V600 mutated melanoma are eligible, and the patients have progressed on prior PD-1 directed therapy (see section Eligibility, inclusion criteria).
NCT02910700 fails to teach using belvarafenib in the method.
However, Bae et al teach HM95573 (belvarafenib) inhibits mutant BRAF melanoma cell lines (A375 and SK-MEL-28) that carry V600E mutation, and also shows antitumor activity in mouse models xenografted with both BRAF mutant cell lines compared to two other RAF inhibitors approved in melanoma. Furthermore, HM95573 does not have a potential to paradoxically induce tumor growth in a mouse xenograft study using A431 cuSCC cancer cells.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Burton et al, NCT02910700 and Bae et al, to administer belvarafenib with nivolumab (a PD-1 inhibitor) and trametinib (a MEK inhibitor), to treat BRAF V600E melanoma patients who have been previously treated with PD-1 immune therapy and experienced disease progression, because belvarafenib does not have a potential to paradoxically induce tumor growth and doing so would achieve similar or better antitumor effect in the patients. The rationale to do so is: 1) Burton et al and NCT029010700 teach a method that is only different from the claimed method by using a different BRAF inhibitor; 2) belvarafenib has shown antitumor activity against BRAF V600E mutant melanoma as dabrafenib; 3) one of ordinary skill in the art could have substituted dabrafenib with belvarafenib for the similar effect against BRAF V600E mutant melanoma, and 4) belvarafenib does not show a potential to paradoxical activation inducing tumor growth in a mouse xenograft study. One would have a reasonable expectation of success in making the combination because the function of belvarafenib in inhibiting BRAF V600E mutation similar to dabrafenib is established in the art, and this is a simple substitution in the method.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 10-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al (Cancer Immunol Res, 2015, 3(3): 288-295) in view of Munoz-Couselo et al (2017. OncoTargets and Therapy, 10, 3941–3947.) and Kim et al (J Clin Oncol 37, 3000-3000, May 26, 2019).
Claim 1 is drawn to a method of treating a subject having cancer characterized by a mutated MAPK signaling pathway, the method comprising: administering to said subject (i) a therapeutically effective amount of belvarafenib, or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a PD-1 axis inhibitor.
Claim 10 is drawn to the method of claim 1, wherein the cancer carries a NRAS mutation or a KRAS mutation.
Claim 11 is drawn to the method of claim 10, wherein the cancer has at least one mutation selected from a BRAF V600E mutation, a KRAS G12V mutation, a KRAS G12D mutation, a KRAS G12C mutation, a KRAS Q61H mutation, a NRAS G13D mutation, a NRAS G12D mutation, a NRAS Q61K mutation, a NRAS Q61R mutation, and a NRAS G12C mutation.
Claim 12 is drawn to the method of claim 11, wherein the cancer is selected from sarcoma carrying a KRAS G12V mutation, melanoma carrying a NRAS G13D mutation, melanoma carrying a NRAS G12D mutation, melanoma carrying a NRAS Q61K mutation, melanoma carrying a NRAS Q61R mutation, melanoma carrying a NRAS G12C mutation, gallbladder cancer carrying a KRAS G12D mutation, CRC carrying a KRAS G12C mutation, CRC carrying a KRAS Q61H mutation, CRC carrying a KRAS G12D mutation, bladder cancer carrying a KRAS G12D mutation, bladder cancer carrying a KRAS G12V mutation, and combinations thereof.
Claim 15 is drawn to the method of claim 10, wherein the cancer is melanoma carrying a NRAS mutation.
Johnson et al teach immune therapies, particularly anti-PD-1/PD-L1 therapy (nivolumab, pembrolizumab, MPDL3280A, etc.) have anti-cancer effect in metastatic melanoma patients, especially in patients with NRAS mutations (Abstract, page 288 last paragraph to page 289 first paragraph). Johnson et al also teach the most common NRAS mutation identified in the study is NRAS Q61R, but other mutations, such as Q61K, G12D, G13D and G12C, are also identified (see section Demographics, also see table 1). In addition, the superior outcome or trend to superior outcome in NRAS-mutant melanoma patients compared with other genotypes might be correlated with have higher PD-L1 expression (abstract). Johnson et al further teach understanding the link between genetic alterations in melanoma with the antitumor immune response may also provide a better rationale for approaching combination strategies of molecularly targeted and immune-based therapy (page 293 left column).
Johnson et al fail to teach the method comprising administering a therapeutically effective amount of belvarafenib or a pharmaceutically acceptable salt thereof.
Munoz-Couselo et al teach current therapies, including target and immunotherapeutic agents, for NRAS-mutant melanoma remain limited, showing a modest increase in progression-free survival but without any benefit in overall survival (abstract, future perspectives). Combination for pathway interference as well as combination of targeted therapy with immunotherapy are the most promising strategy to interfere with NRAS-mutant melanoma (future perspectives).
Munoz-Couselo et al fail to teach administering belvarafenib in combination therapy to treat NRAS-mutant melanoma.
However, Kim et al teach that belvarafenib exhibits anti-tumor activity in patients with NRAS-mutant melanoma in a clinical trial (see results).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Johnson et al, Munoz-Couselo et al and Kim et al to administering belvarafenib and anti-PD-1/PD-L1 to treat melanoma patients with NRAS mutation, such as Q61R, Q61K and G12D, because both belvarafenib and anti-PD-1/PD-L1 have anti-tumor activity against melanoma carrying NRAS mutation and combining the two with different mechanisms of action is a standard approach to improve efficacy or reduce resistance in cancer treatment. The rationale to do so is: 1) both belvarafenib and anti-PD-1/PD-L1 have anti-tumor activity against melanoma carrying NRAS mutation; 2) combination therapy is the most promising strategy for NRAS-mutant melanoma; and 3) combining two treatment with different mechanisms of action is a standard approach to improve efficacy or reduce resistance in cancer treatment. One would have a reasonable expectation of success in making the combination because administering a combination of targeted therapy and a PD-1 or PD-L1 inhibitor to treat melanoma are common practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Relevant Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Klijin et al (US 11,859,252 B2, patent date Jan 2 2024, priority date Sep 8, 2017) teaches using the pan-RAF inhibitor HM95573 (belvarafenib) and the MEK inhibitor cobimetinib (GDC-0973) to treat melanoma with KRAS-G13D mutation. In addition, the pan-RAF inhibitor and the MEK inhibitor may be administered in conjugation with a PD-1 axis binding antagonist, such as a PD-L1 antibody.
A clinical trial (ClinicalTrials.gov ID NCT04835805, record history of Apr 06, 2021, version 1) teaches a phase 1b study to evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus atezolizumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.
Conclusion
No claims are allowed.
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/TIAN YANG/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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