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 .
Claim Status
The preliminary amendment filed February 20, 2024 has been received and entered.
Claims 1-6 and 10-20 have been amended.
Claims 7-9 and 21 have been canceled.
Claims 1-6 and 10-20 are pending and under consideration.
Priority
This application is a continuation of PCT/EP2022/065373 filed June 7, 2022, which claims the benefit of EP Application No. 22157499.9 filed February 18, 2022 and EP Application No. 21178462.4 filed June 9, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
EP Application No. 21178462.4, filed June 9, 2021, provides support for instant claims 1-6 and 10-20.
Claim Objections
Claims 2, 12, and 16-19 are objected to because of the following informalities:
Claim 2 (line 3) – recites the compound of formula (I), which should read “(3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide”.
Claim 12 (line 3) - contains a typographical error and should read “antagonist”.
Claims 16-17 are drawn to mutations in the BRAF gene. As such, BRAF should be italicized in the claims.
Claim 18 (lines 3-4) - step (a) is grammatically incorrect. The claim should read “(a) performing PCR with or sequencing of nucleic acid extracted from a sample…”.
Claim 19 (line 8) - contains a typographical error and should read “pathway”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 12 and 17 are rejected under 35 U.S.C. 112(b) 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.
Claim 12 recites the term “such as”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Applicant may amend the claim to read “…the PD-1 axis binding antagonist is administered by intravenous injection or subcutaneous injection”, or similar language.
Claim 17 recites “the method according to claim 16, wherein the cancer is BRAFV600X mutation-positive unresectable or metastatic cancer.” However, claim 17 depends from claim 16, which recites “the cancer is associated with BRAFV600X mutations”, and there is no antecedent basis for this limitation in the claim.
Applicant may amend the claim to read, “…wherein the cancer associated with BRAFV600X mutations is a BRAFV600X mutation-positive…”.
Claim Rejections - 35 USC § 112(a)
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.
ENABLEMENT
Claims 10-20 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a method for the treatment of BRAFV600E mutation-positive melanoma comprising administering a pharmaceutically effective amount of a combination of the BRAF inhibitor and a PD-1 axis binding antagonist according to claim 1; does not reasonably provide enablement for treating cancer as broadly claimed with the said combination of BRAF inhibitor and PD-1 axis binding antagonist.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. 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.
(1) The nature of the invention and (5) The breadth of the claims:
Claim 10 is drawn to a method for the treatment of cancer, the method comprising administering a pharmaceutically effective amount of a combination of a BRAF inhibitor and a PD-1 axis binding antagonist according to claim 1. Claim 10 is broad and inclusive of all types of all types of cancer in humans generally.
Claim 15 limits the type of cancer to thyroid cancer, colorectal cancer, melanoma, brain cancer, leptomeningeal cancer or non-small cell lung cancer. Claim 15 is also broad, and encompasses six classes of cancer types.
Claim 16 limits the cancer to a cancer associated with BRAFV600X mutations.
Claim 17 limits the cancer associated with BRAFV600X mutations to BRAFV600X mutation-positive unresectable or metastatic cancer. Claims 16 and 17 broadly encompass any cancer with a BRAFV600X mutation.
The breadth of the claims exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible cancer types represented by the terms “treatment of cancer”. Cancer is not one disease, but rather many different diseases with different causal mechanisms that share a similar characteristic: uncontrollable cell growth and division [Overview] (CDC. “Cancer Characteristics, Definitions, and Recent Investigations”. www.cdc.gov/cancer-environment/php/guidelines/characteristics; May 6, 2026). Cancers are highly heterogeneous at both the molecular and clinical level, and can occur in most parts of the body. The following are examples of some of the major classes of cancer, each having numerous types:
CNS cancers
Leukemias
Carcinomas of the liver
Lung and pleural cancers
Thyroid cancers
Melanomas
Colorectal cancers
Renal carcinomas
Prostate cancers
Breast cancers
Ovarian and uterine cancers
Testicular cancers
Esophageal cancers
Cervical cancers
Cardiothoracic cancers
Bladder cancers
Claim 15 limits the cancer to thyroid cancer, colorectal cancer, melanoma, brain cancer, leptomeningeal cancer or non-small cell lung cancer. There are several subclasses for the broadly recited cancer types, often classified by primary origin.
Thyroid cancers
Differentiated thyroid cancers: papillary carcinoma, follicular carcinoma, Hürthle cell carcinoma
Medullary thyroid carcinoma
Anaplastic thyroid carcinoma
Primary thyroid lymphoma
Colorectal cancers
Adenocarcinoma: mucinous, signet ring cell
Gastrointestinal stromal tumors (GISTs)
Carcinoid
Primary colorectal lymphomas
Sarcomas
Squamous cell carcinomas
Melanomas
Cutaneous: nodular, lentigo maligna, acral
Mucosal melanoma
Ocular melanoma
Amelanotic melanoma
Brain cancers
Gliomas: glioblastoma (GBM), astrocytoma, oligodendroglioma, ependymoma
Meningiomas
Medulloblastoma
Primary CNS lymphoma
Pituitary tumors
Acoustic neuroma (Schwannoma)
Meningiomas
Non-small cell lung cancer (NSCLC)
Adenocarcinoma
Squamous cell carcinoma
Large cell (undifferentiated) carcinoma
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
The state of the art regarding BRAF inhibitors for the use in treating cancer is highly complex. For example, as taught by Vranic et al. (Acta Med Acad, 2022; 51(3):217–231) the BRAF gene is frequently mutated in human cancer, with an estimated frequency of 3-7%. BRAF status has been explored in various solid tumors and hematological malignancies, including melanoma, carcinomas, brain tumors, hairy cell leukemia, multiple myeloma, and systemic histiocytosis. BRAF mutations have also been described in various soft tissue tumors including malignant peripheral nerve sheath tumors, Ewing sarcomas, and gastrointestinal stromal tumors [pg. 219, col. 2, par. 2]. Vranic et al. teaches tumors with the highest BRAF mutation rate (50-80%) include malignant melanoma, papillary thyroid carcinoma, pilocytic astrocytoma and low-grade serous carcinoma of the ovary. However, in other tumors, the frequency of BRAF gene mutations is usually seen in the minority of cases (<5%) [pg. 220, col. 1].
Vranic et al. further teaches three classes of BRAF gene mutations have been described. The majority (80-90%) of BRAF mutations are class 1 missense V600E mutations. The remaining (15-20%) of BRAF mutations include V600K, V600R, V600M, V600D and non-V600 mutations (e.g., K601, D594N, G469) [pg. 221, col. 1]. BRAF mutations have been associated with a more aggressive clinical course and poor outcomes in cancer patients are also strong predictors of response to anti-BRAF treatment modalities, such as BRAF inhibitors (vemurafenib, dabrafenib and encorafenib) and MEK inhibitors (trametinib, cobimetinib, binimetinib) alone or in combination [pg. 221, col. 2, par. 2].
However, not all cancers with BRAF mutations are responsive to BRAF inhibitors [pg. 221, col. 2, par. 2]. For example, BRAF inhibitors alone are ineffective in treating colorectal carcinoma. In fact, to date, all available treatments are effective only in patients with tumors harboring BRAF V600 mutations, and the benefit duration is often short lived [pg. 221, col. 2, par. 2-3]. Vranic et al. further teaches that combined therapy is likely necessary to overcome resistance mechanisms, but multi-drug treatment options are often too toxic [pg. 222, col. 1, par. 1].
Given the lack of predictability of BRAF inhibitors in the treatment of cancer, one of skill in the art would have to engage in undue experimentation to identify what specific cancer would be effectively treated by the instantly claimed combination of a BRAF inhibitor and a PD-1 axis binding antagonist.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification sets forth in vivo examples demonstrating the effect of the instantly claimed BRAF inhibitor and an anti-mouse PD-1 antibody (anti-mPD-1) [pg. 82, lines 14-17] in a xenograft mouse model of melanoma. In Example 1, mice were implanted with the cell line YUMM1.7 harboring the BRAF V600E mutation. Mice were treated with the BRAF inhibitor alone (Compound Ia), anti-mPD-1 alone, and a combination of the BRAF inhibitor and the antibody. The mice were treated from day 11 to day 45. Upon treatment conclusion mice were monitored until day 58 for signs of tumor relapse. Results reported in Figures 3 and 4 evidenced that the combination of Compound Ia and anti-mPD-1 manifests a strong impact on the number of mice showing disease relapse, wherein only one mouse (out of 10) had a detectable tumor at day 58 [pg. 84-85].
However, no experiments were carried out demonstrating that the combination is effective against any other cancer apart from BRAF V600E mutation-positive melanoma. Specifically, there is no evidence to support the instantly claimed combination is or would be effective in treating thyroid cancer, colorectal cancer, brain cancer, leptomeningeal cancer or non-small cell lung cancer; or that the combination is effective on a BRAF V600X mutation-positive cancer besides BRAF V600E mutation-positive melanoma. The effect of the combination on metastatic BRAF V600X mutation-positive cancer is also unclear. One of skill in the art would be required to engage in extensive, difficult experimentation to identify the specific types of cancer that can be treated with the instantly claimed combination apart from BRAF V600E mutation-positive melanoma. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for treatment of any cancer except BRAF V600E mutation-positive melanoma. Thus 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 § 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 1-6, 10-14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Dolente (WO 2021/116055) (“Dolente”) in view of Saenger (WO 2018/075447) (“Saenger”).
The instant claims are drawn to a combination of a BRAF inhibitor and a PD-1 axis binding antagonist, wherein the BRAF inhibitor is a compound of formula (I), wherein the compound of formula (I) is (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. The PD-1 axis binding antagonist is selected from the group consisting of cemiplimab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab. Further claimed is a method for the treatment of cancer comprising administering a pharmaceutically effective amount of a combination of a BRAF inhibitor and a PD-1 axis binding antagonist and one or more pharmaceutically acceptable excipients. The BRAF inhibitor is administered orally and the PD-1 axis binding antagonist is administered by injection, such as intravenous or subcutaneous injection, wherein the BRAF inhibitor is administered concurrently or sequentially with the PD-1 axis binding antagonist. The cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, leptomeningeal cancer or non-small cell lung cancer associated with BRAFV600X mutations, wherein the cancer is BRAFV600X mutation-positive unresectable or metastatic cancer.
Dolente teaches a BRAF inhibitor comprising Formula (I) [Abstract](instant claim 1 partial).
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Dolente teaches the compound of Formula (I) is (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide [pg. 25, lines 1-2](instant claim 2). The BRAF inhibitor, or a pharmaceutically acceptable salt thereof, taught by Dolente can be used for the treatment of thyroid cancer, colorectal cancer, brain cancer, melanoma, or non-small cell lung cancer [pg. 8, lines 16-18] (instant claim 15).
Dolente does not teach that the BRAF inhibitor of Formula (I) is in combination with a PD-1 axis binding antagonist.
Saenger teaches a method of treating solid malignant tumors or cancers, the method comprising administering to a patient, a therapeutically effective amount of a BRAF inhibitor and a PD-1 inhibitor [00036](instant claims 1 partial, 10). Saenger teaches the PD-1 inhibitor is an anti-PD-1 antibody [00083](instant claims 3-4). Saenger provides multiple examples of anti-PD-1 antibodies, including pembrolizumab and atezolizumab [00088](instant claims 5-6).
The combination therapy can be used for the treatment of various types of solid malignant tumors, including metastatic malignant melanoma, non-small cell lung cancer, thyroid cancer, and other neoplastic malignancies, and more generally solid tumors(instant claim 17). The combination therapy is particularly useful in treating tumors comprising BRAF gene mutations, including melanoma [00069]. Saenger teaches 80% of BRAF mutations results in a V600E mutation in B-Raf protein [00070](instant claim 16).
Saenger further teaches a pharmaceutical composition comprising a therapeutically effective amount of a BRAF inhibitor or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor [00058]. The composition comprises one or more additional components such as a physiologically acceptable carrier, excipient, or diluent (instant claims 1 partial, 11). Saenger teaches the BRAF inhibitor is administered orally and the anti-PD-1 compound (e.g., antibody) is administered intravenously [00092](instant claim 12). And the components of the combination therapy can be administered simultaneously, separately or sequentially [00060](instant claims 13-14).
Saenger treated mice harboring BRAF V600E mutated melanoma with a combination of the BRAF inhibitor and an anti-PD-1 antibody resulting in inhibition of tumor formation and a significant increase in survival compared to control treated mice [000117, 000120].
Lastly, Saenger teaches the combination therapy comprising a BRAF inhibitor and a PD-1 inhibitor is particularly advantageous because the anti-tumor effect of the combination is enhanced compared to the effect of each compound alone. Moreover, it is anticipated that the dosage of each agent in a combination therapy can be reduced as compared to monotherapy with each agent, while still achieving an overall anti-tumor effect. In addition, due to the synergistic effect, the total amount of compounds administered to a patient can advantageously be reduced, which may result in decreased side effects [00051].
One of ordinary skill in the art would be motivated to combine the BRAF inhibitor disclosed by Dolente with a PD-1 inhibitor as a treatment for BRAF V600 mutated cancers, given that Saenger teaches the synergistic effects of combining a BRAF inhibitor and a PD-1 inhibitor for the treatment of BRAF V600E mutated melanoma. The skilled artisan would have a reasonable expectation of success in using the BRAF inhibitor taught by Dolente in the combination therapy, because the BRAF inhibitor comprising Formula (I) taught by Dolente is also effective in the treatment of BRAF V600 mutated cancers, including BRAF V600E mutated melanoma, and when combined with a PD-1 inhibitor, is expected to have enhanced anti-tumor effect compared to the effect of each compound alone as evidenced by Saenger.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
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. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
The applied reference “Dolente” has a common assignee and joint inventors 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. 103 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); 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 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. See generally MPEP § 717.02.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Dolente (WO 2021/116055) (“Dolente”) in view of Saenger (WO 2018/075447) (“Saenger”) as applied to claims 1-6, 10-14, and 16-17 above, and in further view of Ribas et al. (Nature Medicine, 2019; 25:936-940) (“Ribas”) .
The instant claims are drawn to a combination of a BRAF inhibitor and a PD-1 axis binding antagonist, wherein the BRAF inhibitor is a compound of formula (I) for the treatment of BRAFV600X positive cancers, wherein the BRAFV600X mutation is determined by performing sequencing on nucleic acid (e.g., DNA) extracted from a sample of the patient's tumor tissue, and determining expression of BRAFV600 in the sample. Further comprising administering an additional anticancer agent such as a MEK inhibitor.
The teachings of Dolente and Saenger are set forth above.
Dolente and Saenger do not teach methods of detecting BRAF V600 mutations or further administering an additional anticancer agent, such as a MEK inhibitor, with the combination therapy.
Ribas teaches combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone (instant claims 19-20). Ribas enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab. Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months, suggesting the triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses [Abstract].
Ribas calculated tumor mutational load from whole-exome sequencing (WES) analysis from seven baseline DNA samples from patient tumors who had a response to therapy [pg. 939, col. 1, par. 2](instant claim 18].
One of ordinary skill in the art would be motivated to combine the BRAF inhibitor + PD-1 inhibitor therapy disclosed by Dolente and Saenger with a MEK inhibitor because Ribas teaches combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone for the treatment of BRAF V600E mutated melanoma. The skilled artisan would have a reasonable expectation of success in adding a MEK inhibitor to the BRAF inhibitor + PD-1 inhibitor combination, because combining a BRAF inhibitor and PD-1 inhibitor has been shown to effective in the treatment of BRAF V600 mutated cancers, including BRAF V600E mutated melanoma, and when combined with a MEK inhibitor, is expected to enhance the anti-tumor effect in a synergistic manner compared to the combination BRAF inhibitor PD blockade therapy alone as evidenced by Ribas.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
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. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 and 10-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-12, and 14-20 of U.S. Application No. 18/533,622 in view of Rosa (SMR Virtual Congress, 2020) (“Rosa”).
Copending claim 1 is drawn to a combination comprising a BRAF inhibitor and a MEK inhibitor, wherein the inhibitor is compound of Formula (I). Copending claim 2 recites the chemical formula of the BRAF inhibitor. Copending claims 9 and 15-17 are drawn to types of cancer to be treated with the recited combination. Copending claims 10-12 and 14 are drawn to administration regimen of the BRAF inhibitor. Copending claim 18 is drawn to methods for detecting a BRAF V600 mutation. Copending claim 19 recites additional anticancer agents to be administered with the combination. Copending claim 20 recites the chemical structure of Formula (I).
The BRAF inhibitor disclosed by the copending application is 100% identical to the BRAF inhibitor recited in the instant claims. Therefore, the claims of the copending application read on the administration of a BRAF inhibitor for the treatment of cancer, such as thyroid cancer, colorectal cancer, melanoma, brain cancer or non-small cell lung cancer, and cancers harboring a BRAF V600 mutation. The instant claims are drawn to a combination of a BRAF inhibitor of Formula (I), a PD-1 axis binding antagonist, and an additional anticancer agent, such as a MEK inhibitor. However, the copending claims do not disclose the BRAF inhibitor is further administered with a PD-1 axis binding antagonist, or any checkpoint inhibitor.
However, Rosa teaches targeted therapies, such as BRAF and MEK inhibitors, offer an advantage of rapid and high response rates in patients with advanced melanoma harboring a BRAF mutation. However, the limitation of this approach is the development of resistance, as most of the patients who receive BRAF/MEK inhibition experience disease progression [pg. 2].
Rosa teaches the addition of anti-PD-1/PD-L1 to combination BRAF and MEK inhibition has been shown to improve progression-free survival (PFS) and duration of response (DOR) in patients with BRAF-mutated melanoma across three separate trials, suggesting potential to overcome resistance to targeted approaches. The combination of BRAF and MEK inhibition induces an influx of CD8+ and CD4+ T cells in the tumor and generate a favorable tumor microenvironment with a reduction in Treg and myeloid-derived suppressor cells. Resistance to BRAF and MEK inhibitors can be overcome by enhancing this immune response with the addition of immune checkpoint inhibitors [pg. 2].
Therefore, it would have been obvious to one of ordinary skill in the art that the BRAF inhibitor/MEK inhibitor combination disclosed by the copending application could be further administered an immune checkpoint inhibitor such as anti-PD-1/PD-L1 to overcome resistance associated with said therapies for the treatment of BRAF mutated melanoma as evidenced by Rosa. Therefore, the combination of prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6 and 10-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-11 of U.S. Application No. 18/653,975 in view of Rosa (SMR Virtual Congress, 2020) (“Rosa”).
Copending claim 1 is drawn to a method of treating cancer comprising administering a BRAF inhibitor comprising the compound of formula (I). Copending claims 6-8 recite types of cancer treated, including melanoma. Copending claim 9 recites the cancer is associated with BRAF V600 mutations. Copending claims 10-11 recites the BRAF inhibitor can be administered with one or more anticancer agents, including MEK inhibitors and checkpoint inhibitors.
The copending claims do not specifically disclose that the checkpoint inhibitor is a PD-1 axis binding antagonist. These deficiencies are remedied by Rosa.
Rosa teaches targeted therapies, such as BRAF inhibitors, offer an advantage of rapid and high response rates in patients with advanced melanoma harboring a BRAF mutation. However, the limitation of this approach is the development of resistance, as most of the patients who receive BRAF inhibition experience disease progression [pg. 2].
Rosa teaches the addition of anti-PD-1/PD-L1 to combination BRAF inhibition has been shown to improve progression-free survival (PFS) and duration of response (DOR) in patients with BRAF-mutated melanoma across three separate trials, suggesting potential to overcome resistance to targeted approaches. The combination of BRAF and MEK inhibition induces an influx of CD8+ and CD4+ T cells in the tumor and generate a favorable tumor microenvironment with a reduction in Treg and myeloid-derived suppressor cells. Resistance to BRAF and MEK inhibitors can be overcome by enhancing this immune response with the addition of immune checkpoint inhibitors [pg. 2].
Therefore, it would have been obvious to one of ordinary skill in the art that the BRAF inhibitor recited in the copending applications could be further administered an immune checkpoint inhibitor such as anti-PD-1/PD-L1 to overcome resistance associated with said therapies for the treatment of BRAF mutated melanoma as evidenced by Rosa. Therefore, the combination of prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6 and 10-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23, 26-34, 36, and 38 of U.S. Application No. 19/138,422 in view of Rosa (SMR Virtual Congress, 2020) (“Rosa”).
Copending claims 21 and 38 are drawn to a method of treating cancer comprising administering a BRAF inhibitor comprising the compound of formula (I). Copending claim 22 recites the chemical name of formula (I). Copending claim 23 recites the BRAF inhibitor is a free base. Copending claim 26 recites the cancer is colorectal cancer. Copending claims 27-32 are drawn to BRAF V600E mutated cancers and methods of detecting BRAF V600X mutations. Copending claims 33-35 recite timing and route of administration. Copending claim 36 recites the BRAF inhibitor is administered with an additional anticancer agents, including MEK inhibitors and checkpoint inhibitors.
The copending claims do not specifically disclose that the checkpoint inhibitor is a PD-1 axis binding antagonist. These deficiencies are remedied by Rosa.
Rosa teaches targeted therapies, such as BRAF inhibitors, offer an advantage of rapid and high response rates in patients with advanced melanoma harboring a BRAF mutation. However, the limitation of this approach is the development of resistance, as most of the patients who receive BRAF inhibition experience disease progression [pg. 2].
Rosa teaches the addition of anti-PD-1/PD-L1 to combination BRAF inhibition has been shown to improve progression-free survival (PFS) and duration of response (DOR) in patients with BRAF-mutated melanoma across three separate trials, suggesting potential to overcome resistance to targeted approaches. The combination of BRAF and MEK inhibition induces an influx of CD8+ and CD4+ T cells in the tumor and generate a favorable tumor microenvironment with a reduction in Treg and myeloid-derived suppressor cells. Resistance to BRAF and MEK inhibitors can be overcome by enhancing this immune response with the addition of immune checkpoint inhibitors [pg. 2].
Therefore, it would have been obvious to one of ordinary skill in the art that the BRAF inhibitor recited in the copending applications could be further administered an immune checkpoint inhibitor such as anti-PD-1/PD-L1 to overcome resistance associated with said therapies for the treatment of BRAF mutated melanoma as evidenced by Rosa. Therefore, the combination of prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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