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 .
Current Status
This action is responsive to the amended claims of 11/10/2025. Claims 19-38 are pending. Claims 26-31 have been withdrawn. Claims 19-25 and 32-38 have been examined on the merits.
Election/Restrictions
Applicant’s election of melanoma and NRASQ61L in the reply filed on 11/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
A search for Applicant’s elected species retrieved prior art (see SEARCH 3-4 and 6 of the attached search notes). Thus, the Markush search will not be unnecessarily extended in this action.
The elected species read on claims 19-25 and 32-38.
Claims 26-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025.
Priority
The effective filing date is 05/26/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/23/2023 and 12/02/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 19-25 and 32-38 are objected to because of the following informalities. Appropriate correction is required.
Claim 19 lacks a comma after “NRASQ61R mutation”, please add a comma after the recited phrase to improve the punctuation of the claim. Dependent claims 20-25 are similarly objected to since they do not rectify the underlying issue.
Claim 32 recites “aNRASG12C mutation, aNRASG12D mutation” under (3) line 3, (4) line 4, and (6) line 4; “aNRASG12D mutation” and “aNRASQ61K mutation” under (5) line 4. Please add a space between the article “a” and “NRAS” in each of these instances. Dependent claims 33-38 are similarly objected to since they do not rectify the underlying issue.
In line 2-3 of claim 33, under section (1), the recitation of “melanoma carrying” before “NRASQ61R” and “NRASQ61K” mutations is redundant. Since section (1) begins with the recitation of “melanoma carrying” and for consistency in claim wording, Examiner suggests the second and third recitation of “melanoma carrying” under section (1) be struck. It is clear all embodiments under (1) are drawn to melanoma. Dependent claim 34 is similarly objected to since it does not rectify the underlying issue.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-25 and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 19 recites the broad recitation “the cancer has at least one mutation selected from a BRAF mutation, a KRAS mutation, and a NRAS mutation”, and the claim also recites “the
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” which is the narrower statement of the range/limitation since these mutations are considered species of the broad recitation. The claim is considered indefinite because there is a question or doubt as to whether the species of mutation introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claims 20-25 are similarly rejected since they do not rectify the underlying issue.
To overcome: if Applicant requires the cancer to have one of the species of mutation recited in the narrower limitation, please strike the broad recitation from the claim.
Claim 34 recites wherein the cancer is “GIST”. There is insufficient antecedent basis for this limitation in the claims. Parent claim 33 recites wherein the cancer is melanoma, CRC, or combination thereof; the claim does not recite the cancer is GIST. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 34 recites a cancer “GIST” which is outside of the scope of cancers recited by parent claim 33. Thus, claim 34 does not properly further limit the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 19-24 and 32-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by KIM (Kim T.W. et al., ASCO Annual Meeting, “Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase 1 study,” 2019, pg. 1-18, provided IDS of 02/23/2023). Note, the exact day and month of public disclosure of KIM is unclear; it appears the ASCO meeting took place on May 31-June 4, 2019. Further, the following rejection is based upon art which was found incidental to the search for the elected species. This is not indicative that the entire scope of the claims has been examined; however, it is applied in an effort to promote compact prosecution.
Regarding claims 19-21 and 32-34, KIM teaches belvarafenib administration to human patients with KRASG12V mutant sarcoma, NRASG12D mutant melanoma, BRAFV600E mutant GIST, NRASQ61K mutant melanoma, NRASQ61K & BRAFV600E mutant melanoma, BRAFV600E mutant melanoma, and NRASQ61R mutant melanoma (Pg. 8) and with BRAFV600E CRC (Pg. 9). Note, in view of the 112b rejection in ¶15 above, the NRASG12D, KRASG12V, BRAFV600E mutant cancers read on instant claim 19.
Regarding claims 22-23 and 35-36, KIM teaches the recommended dose of belvarafenib is 450 mg BID (Pg. 16). Since KIM teaches a dosage within the range of instant claims 22 and 35 and the exact dosage of instant claims 23 and 36, these claims are anticipated.
Regarding claims 24 and 37, KIM does not teach a side effect of the treatment includes development of squamous cell carcinoma (SCC) (Pg. 13-14). Thus, the treatment is characterized by absence of SCC development.
Claims 19-21, 24, 32-34, and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023), evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023). Note, the following rejection is based upon art which was found incidental to the search for the elected species. This is not indicative that the entire scope of the claims has been examined; however, it is applied in an effort to promote compact prosecution.
Regarding claims 19-21 and 32-34, AARC teaches administration of HM95573 showed excellent antitumor activity in mouse models of melanoma mutant cell lines SK-MEL-2 and SK-MEL-30 compared to two RAF inhibitors approved for treatment of melanoma (Abstract; Sect. In vitro cellular activity Table; Sect. In-vivo efficacy Figs.). AARC teaches SK-MEL-2 and SK-MEL-30 comprise NRASQ61R and NRASQ61K mutations, respectively (Sect. In vitro cellular activity Table). AARC further teaches HM95573 is in phase I development in patients with solid tumors including melanoma (Abstract). The artisan would understand phase I development as phase I clinical trials in human patients wherein the patients are treated with HM95573. Further, since AARC teaches melanoma with NRASQ61R and NRASQ61K mutations are treated by the HM95573, the artisan would immediately envisage the patients with melanoma in the phase I trial to include those with NRASQ61R and NRASQ61K mutations. Thus, AARC teaches the treatment of melanoma comprising NRASQ61R and NRASQ61K mutations in human subjects by administration of HM95573. Finally, Examiner understands HM95573 is belvarafenib, evidenced by BAE. BAE discloses belvarafenib is also known as HM95573 or GDC5573 (Pg. 1 Abstract).
Regarding claims 24 and 37, AARC teaches HM95573 does not show paradoxical activation of RAS-RAF-MEK-ERK which induces tumor growth of squamous cell carcinoma (SCC) (Abstract). Thus, the treatment is characterized by absence of SCC development.
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 19-21, 24-25, 32-34, and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), and DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13).
Determining the Scope and Contents of the Prior Art:
The teachings of AARC, as evidence by BAE, are above in ¶22. AARC further teaches belvarafenib does not induce ERK activation, unlike vemurafenib (Sect. Acquired resistance & cuSCC side effect). AARC teaches belvarafenib inhibits the RAS-RAF-MEK-ERK signaling in NRAS mutated melanoma (Conclusion).
KLIJN teaches a method of treating an individual having a cancer with an NRAS mutation comprising administering a therapeutically effective amount of HM95573, i.e., belvarafenib (Pg. 68-69 claim 14 & 29) wherein the cancer is melanoma and the individual is human (Pg. 70 claim 36 & 42).
DORARD teaches selective BRAFV600E inhibitors, vemurafenib and dabrafenib, trigger a response rate of 80% in clinical trials for melanoma treatment; however, resistance rapidly occurs and most patients relapse (Pg. 2 Left ¶1). Further, such BRAFV600E inhibitors should not be used to treat melanoma patients with NRAS mutations since BRAF inhibitors induce paradoxical activation of the MAPK/ERK pathway (Pg. 2 Left ¶1). DORARD teaches NRAS mutations are present in 20% of all melanoma and NRASQ61K/R/L are the most frequent NRAS mutations (Pg. 2 Left ¶2). DORARD also teaches NRAS mutations represent an early event in the oncogenic process and more than 80% of congenital atypical moles are found mutated (Pg. 9 Right ¶3).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
AARC and KLIJN do not teach the melanoma has a NRASQ61L mutation nor the subject experiencing disease progression on prior treatment.
DORARD does not teach treatment of the NRAS mutant melanomas with belvarafenib.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of NRASQ61K/R/L mutant melanomas and possesses the technical knowledge necessary to make adjustments to the administered drugs to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments suitable for NRAS mutant melanomas and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references AARC (evidenced by BAE), KLIJN, and DORARD.
Regarding claims 19-21, 24, 32-34, and 37, the artisan would find it obvious to treat NRASQ61K/R/L mutant melanomas in human subjects by administering an effective amount of belvarafenib. The artisan would be motivated to do so, with a reasonable expectation of success since:
1) AARC teaches belvarafenib treatment of NRASQ61R and NRASQ61K mutated melanomas in both mice and humans (Abstract; Sect. In vitro cellular activity Table; Sect. In-vivo efficacy Figs.);
2) KLIJN teaches belvarafenib treatment of NRAS mutated melanomas in humans; and
3) DORARD teaches NRAS mutations are common in melanoma and NRASQ61K/R/L are the most frequent NRAS mutations (Pg. 2 Left ¶2; Pg. 9 Right ¶3).
Thus, the artisan would recognize belvarafenib as suitable for treatment of NRAS-mutated melanomas and would recognize NRASQ61K/R/L mutants as ripe for treatment due to their prevalence.
Recall, DORARD teaches BRAFV600E inhibitors results in rapid resistance/relapse and are not suitable to treat NRAS-mutated melanomas due to paradoxical activation of the MEK/ERK pathway (Pg. 2 Left ¶1). However, since AARC teaches belvarafenib does not show paradoxical activation of RAS-RAF-MEK-ERK pathway and does not induce ERK activation (unlike vemurafenib), but instead inhibits the RAS-RAF-MEK-ERK signaling in NRAS mutated melanoma (Abstract, Sect. Acquired resistance & cuSCC side effect, & Conclusion), the artisan would recognize belvarafenib as a suitable treatment alternative to typical BRAF inhibitors like vemurafenib. Due to this improvement upon existing treatments (i.e., belvarafenib does not induce SCC tumor growth by paradoxical activation – see AARC Abstract), the artisan would be motivated to treat humans with the most common NRAS-mutated melanomas (i.e., NRASQ61L, NRASQ61K, and NRASQ61R) by administration of belvarafenib.
Regarding claims 25 and 38, the artisan would recognize NRASQ61K/R/L -mutated melanoma patients who experienced resistance and/or relapse (i.e., disease progression) on BRAFV600E inhibitors (e.g., vemurafenib/dabrafenib) as prime candidates for belvarafenib treatment for the same reasons as discussed directly above. The combination of DORARD and AARC teach belvarafenib as a clear improvement over existing BRAFV600E inhibitors in treatment of melanoma.
Claims 19, 22-23, 32 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), and DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13) as applied to claims 19 and 32 above, and further in view of ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
AARC, as evidence by BAE, KLIJN, and DORARD teach the claims 19 and 32 as laid out in ¶ 27, above. Further, AARC teaches doses of HM95573 (i.e., belvarafenib) at 10 and 30 mg/kg once a day in a mouse model (Sect. In-vivo Efficacy). Converting to a human dose (ref. weight of 60 kg): ~0.8 and ~2.4 mg/kg or ~49 and ~146 mg/once a day. KLIJN further teaches typical daily dosages of 20 to 500 mg/m2 depending on factors including type and severity of disease (Pg. 50 Lines 23-31). Converting to mg (ref. surface area of 1.62 m2): ~32 to ~810 mg/day.
ANSEL teaches the safe and effective dose of a drug depends on a number of
factors including characteristics of the drug, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different
patients (Pg. 48 Left Col. para 4). ANSEL further teaches the schedule of dosage or the
dosage regimen is determined based on a drug’s duration of action, pharmacokinetics,
and characteristics of the dosage form (Pg. 40 Right Col. para 2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
AARC, KLIJN, and DORARD do not teach the exact instant dosages.
ANSEL does not teach the instant method.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of NRASQ61K/R/L mutant melanomas and possesses the technical knowledge necessary to make adjustments to the drug dosages to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments for NRAS mutant melanomas and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references AARC (evidenced by BAE), KLIJN, DORARD, and ANSEL.
As explained in ¶27, above, the methods of claims 19 and 32 are obvious. The artisan would be further motivated to optimize the dosage of belvarafenib in view of the combined references.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
In the instant case, AARC teaches a dose equivalent to a human dose of ~49 and ~146 mg/once a day (Sect. In-vivo Efficacy) and KLIJN teaches a dose of ~32 to ~810 mg/day (Pg. 50 Lines 23-31). These dosages are considered to overlap with/approach the instantly claimed 200-1300 mg/day and 450 mg BID per day (see claims 22-23 & 35-36). Since ANSEL teaches the dosage regimen is based on duration of action, pharmacokinetics, and the dosage form (Pg. 40 Right Col. para 2) and the effective dosing may be different for different patients (Pg. 48 Left Col. para 4), the artisan would recognize the dosage amount and timings (i.e., QD or BID) of belvarafenib as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. Therefore, the determination of the optimum or workable dosage regimen of belvarafenib would have been well within the practice of the artisan. Furthermore, absent any evidence demonstrating a patentable difference between the instant and prior art compositions and the criticality of the claimed dosage regimen, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the artisan.
To expedite time to allowance: Applicant is encouraged to provide surprising/unexpected results (MPEP 716.02(a)) commensurate with the full scope of the claims (i.e., covering the breadth of claimed mutations/cancers). Such results will preclude the Examiner from making similar 103 rejections over species found in future Markush search extensions. NOTE: withdrawn claims 26-31 could be similarly rejected (if not withdrawn) since KLIJN also teaches administration of HM95573 for treatment of thyroid and lung cancer (Pg. 70 claim 36) including non-small cell lung cancer (Pg. 63 Lines 18-22).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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 19-22 and 32-35 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9-10, 12-13, 15, 22-23, 27, 29-30, 33, 35-36, 58, and 60 of copending Application No. 18/549,622 (reference application – claims of 05/10/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims are drawn to a method of treating metastatic melanoma by administering belvarafenib to a subject (ref claim 1, 10), wherein the melanoma has a RAF, NRAS, or KRAS mutation (ref claim 2). Reference claim 3 recites mutations which fall under the broad interpretation (see 112(b) above; e.g., BRAFV600E) of instant claim 19 and species which are explicitly recited in the instant claims, e.g., NRASQ61K. Reference claims 7 and 9 recite dosages within the instantly claimed range. The reference claims are further drawn to a method of treating multiple metastatic cancers (e.g., melanoma, GIST, etc.) which are species of the instant claims (ref claim 12-13, 30, 33, 35-36, 58, and 60) wherein the cancer has a RAF, NRAS, or KRAS mutation (ref claim 15). Reference claims 22-23 recite mutations which fall under the broad interpretation (see 112(b) above; e.g., BRAFV600E) of instant claim 19 and species which are explicitly recited in the instant claims, e.g., melanoma with NRASQ61K. Reference claims 27 and 29 recite dosages within the instantly claimed range. Since the mutations and cancers of the reference claims are species of the instant claims, the reference claims anticipate the instant claims.
The disclosure of Application No. 18/549,622 is referred to in order to understand the target subject of the claimed method, in accordance with MPEP 804(II)(B)(1): “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).” Example 3 of the specification (Pg. 25) is drawn to treatment in a human. In view of the claimed “subject” and the supporting disclosure, the artisan would immediately envisage the method as administering to a human subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 19-25 and 32-38 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9-10, 12-13, 15, 22-23, 27, 29-30, 33, 35-36, 58, and 60 of copending Application No. 18/549,622 (reference application – claims of 05/10/2024) in view of AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13), and ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
The reference claims are discussed ¶30 above.
The teachings of AARC, BAE, KLIJN, DORARD, and ANSEL are above ¶27-28.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The reference claims do not teach the instant dosages, the absence of SCC, nor previous disease progression on immunotherapy/BRAF inhibitors. The claims are not explicitly drawn to a human subject.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of RAF, NRAS, or KRAS mutated cancers and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments for such cancers and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references Application No. 18/549,622, AARC, BAE, KLIJN, DORARD, and ANSEL
The prior art references make the instant claims obvious as detailed in ¶27-28 above. App. No. ‘622 teaches a method that is analogous to the methods of AARC and KLIJN. Due to this similarity, the artisan would view the co-pending app in view of the other prior art references in the same way AARC and KLIJN are viewed. By the same logic applied in ¶27-28, above, the reference claims, in view of the prior art, make obvious the instant claims.
Claims 19-22, 25, 32-35, and 38 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 46-65 of copending Application No. 18/554,041 (reference application – claims of 04/15/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims are drawn to administering belvarafenib to a subject with melanoma with NRAS mutations including Q61K, Q61R, G12C, Q61L, G13D, G12D, and G12C (ref claim 46-49, 51-53, 55-58, 60-64), which are species either under the BRI of instant claim 19 or are species explicitly taught in the instant claims. Ref. claims 50 and 59 recite the instant range of 200-1300 mg/day. Ref. claims 54 and 65 are drawn to the same limitation as instant claims 25 and 38. The disclosure of Application No. 18/554,041 is referred to in order to understand the target subject of the claimed method, in accordance with MPEP 804(II)(B)(1) (above). The specification defines subject as a human (Pg. 7). In view of the claimed “subject” and the supporting disclosure, the artisan would immediately envisage the method as administering to a human subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 19-25 and 32-38 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 46-65 of copending Application No. 18/554,041 (reference application – claims of 04/15/2025) in view of AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13), and ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
The reference claims are discussed ¶32 above.
The teachings of AARC, BAE, KLIJN, DORARD, and ANSEL are above ¶27-28.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The reference claims do not teach the instant dosages nor the absence of SCC. The claims are not explicitly drawn to a human subject.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of NRAS melanoma and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments for NRAS melanoma and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references Application No. 18/554,041, AARC, BAE, KLIJN, DORARD, and ANSEL
The prior art references make the instant claims obvious as detailed in ¶27-28 above. App. No. ‘041 teaches a method that is analogous to the methods of AARC and KLIJN. Due to this similarity, the artisan would view the co-pending app in view of the other prior art references in the same way AARC and KLIJN are viewed. By the same logic applied in ¶27-28, above, the reference claims, in view of the prior art, make obvious the instant claims.
Claims 19-22, 25, 32-35, and 38 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 10-12, 15, 19-23, 25-29, 34, 36 of copending Application No. 18/554,236 (reference application – claims of 07/05/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims are drawn to a method of treating a subject with cancer comprising administering belvarafenib (ref. claim 1, 19-22, 26-29, 34) wherein the cancer is selected from the instantly claimed species (e.g., melanoma, CRC, GIST, etc. in ref. claim 2) and the cancer has a mutation chosen from BRAF V600E, KRAS species of the instant claims, or NRAS species of the instant claims (ref. claims 4, 6, 10-12, 15). The ref. claims are drawn to 250-500 mg/BID (ref. claims 23, 25) which falls within the instantly claimed range. Ref. claim 36 is drawn to the same limitation as instant claims 25 and 38. The disclosure of Application No. 18/554,236 is referred to in order to understand the target subject of the claimed method, in accordance with MPEP 804(II)(B)(1) (above). The specification defines subject as human (Pg. 6). In view of the claimed “subject” and the supporting disclosure, the artisan would immediately envisage the method as administering to a human subject.
Claims 19-25 and 32-38 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 10-12, 15, 19-23, 25-29, 34, 36 of copending Application No. 18/554,236 (reference application – claims of 07/05/2024) in view of AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13), and ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
The reference claims are discussed ¶34 above.
The teachings of AARC, BAE, KLIJN, DORARD, and ANSEL are above ¶27-28.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The reference claims do not teach the instant dosages nor the absence of SCC. The claims are not explicitly drawn to a human subject.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of BRAF, KRAS, or NRAS mutated cancers and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments for such cancers and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references Application No. 18/554,236, AARC, BAE, KLIJN, DORARD, and ANSEL
The prior art references make the instant claims obvious as detailed in ¶27-28 above. App. No. ‘236 teaches a method that is analogous to the methods of AARC and KLIJN. Due to this similarity, the artisan would view the co-pending app in view of the other prior art references in the same way AARC and KLIJN are viewed. By the same logic applied in ¶27-28, above, the reference claims, in view of the prior art, make obvious the instant claims.
Claims 19-25 and 32-38 are provisionally rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 46-65 of copending Application No. 18/516,552 (reference application – claims of 11/21/2023) in view of AARC (Bae I.H. et al., AARC Poster, “Antitumor activity of the selective RAF inhibitor HM95573 in melanoma,” 2015, pg. 1, provided IDS of 02/23/2023) evidenced by BAE (Bae D.J. et al., “Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique,” In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Cancer Res 2019; Abstract 1305; pg. 1-2; provided IDS of 02/23/2023), KLIJN (WO 2019/051296, provided IDS of 12/02/2025), DORARD (Dorard, C. et al., Nat. Commun., 2017, 8:15262, 1-13), and ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
The reference claims are drawn to a method of treating an individual cancer with an NRAS mutation (ref. claims 1-5, 7, 9-10, 12) comprising administering HM95573 (i.e., belvarafenib) (ref. claim 6, 11) wherein the cancer is melanoma (ref. claim 8, 13).
The teachings of AARC, BAE, KLIJN, DORARD, and ANSEL are above ¶27-28.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The reference claims do not teach the individual is a human, the exact NRAS mutation, the instant dosages, the absence of SCC, nor previous disease progression on immunotherapy/BRAF inhibitors.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of NRAS mutated cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatments for NRAS cancers and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references Application No. 18/516,552, AARC, BAE, KLIJN, DORARD, and ANSEL
The prior art references make the instant claims obvious as detailed in ¶27-28 above. App. No. ‘552 is analogous to the method of KLIJN. Due to this similarity, the artisan would view the co-pending app in view of the other prior art references in the same way KLIJN is viewed. By the same logic applied in ¶27-28, above, the reference claims, in view of the prior art, make obvious the instant claims.
Claims 19-20 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,859,252. Although the claims at issue are not identical, they are not patentably distinct from each other.
The Patent claims 1-5 are drawn to a method of treating an individual having melanoma comprising a KRAS-G13D mutation comprising administering HM95573 (i.e., belvarafenib). KRAS-G13D mutant-melanoma falls under the broadest interpretation of instant claims 19-20 (see above 112(b)) and is explicitly recited in instant claim 32. Thus, the Patent claims anticipate the instant claims.
Conclusion
Claims 19-25 and 32-38 are rejected.
To expedite time to allowance: Applicant is encouraged to provide surprising/unexpected results (MPEP 716.02(a)) commensurate with the full scope of the claims (i.e., covering the breadth of claimed mutations/cancers). Such results would preclude the Examiner from making similar 103 rejections over species found in future Markush search extensions. NOTE: withdrawn claims 26-31 could be similarly rejected (if not withdrawn) since KLIJN also teaches administration of HM95573 for treatment of thyroid and lung cancer (Pg. 70 claim 36) including non-small cell lung cancer (Pg. 63 Lines 18-22).
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625