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 .
Priority
Acknowledgement is made that application 18/704,267, filed on 2024, Apr. 24, is a National Stage entry of PCT/US 2022/079109, filed on 2022, Nov. 02, which claims priority from provisional application 63,274,745, filed on 2021, Nov. 02.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2024, May 09 and 2024, Jul. 26 and 2024, Oct. 25 and 2025, Jun. 04 and 2025, Aug. 28 and 2025, Dec. 08 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure state is being considered by the examiner.
Claim Rejections - 35 USC § 112
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.
Claims 2-4, 9-14, 24-26, 28-29, 31, 35, 38, 42-43, 48, 50, 53, and 57 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. This rejection is based on improper written description of the invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do 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 (Fed. Cir. 1997); In re Gostelli, 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 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
In the instant case, the claims are drawn to a method of reducing the severity of or preventing toxicity or an adverse event associated with administration of a dual RAF/MEK inhibitor in a subject, comprising administering to the subject an effective amount of the dual RAF/MEK inhibitor, an effective amount of an antibiotic agent, and an effective amount of a corticosteroid. While the instant specification discloses that in some embodiments, the RAF/MEK inhibitor is a compound of formula I, IMM-1-104 (or pharmaceutically acceptable salt thereof), a compound of formula II, or a compound selected from Table 1 (page 2, paragraphs 10-13), this is not an exhaustive list that covers all embodiments. As such, the broadest reasonable interpretation of “a dual RAF/MEK inhibitor” is any pharmaceutically relevant agent that inhibits both RAF and MEK kinases either directly or indirectly. Based on the arguments herein, it is not clear that Applicant was in possession of the full scope of the claims given BRI.
Prior to the effective filing date of the claimed invention, the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations in cancer that can possess distinct functional characteristics was known (see Yaeger, et al., Targeting alterations in the RAF-MEK pathway. Cancer Discov., 2019, 9(3), 329-341. https://doi.org/10.1158/2159-8290). For example, Yaeger teaches that activated RAS proteins (KRAS, NRAS, and HRAS) will destabilize the autoinhibition of RAF proteins (ARAF, BRAF, CRAF) to cause activation/dimerization of RAF proteins (page 329, right column, paragraph 1). The activated RAF proteins will then then phosphorylate MEK kinases, which in turn activates ERK kinases (page 329, right column, paragraph 1). Yaeger further teaches the use of various BRAF mutant inhibitory agents, each with a different mechanism of action. For example, vemurafenib is a monomer-selective BRAF inhibitor, LXH254 is a BRAF dimer inhibitor, and PLX8394 is a BRAF dimer breaker (page 334, Figure 4). These drugs are a non-exhaustive list whose use would result in concomitant inhibition of both RAF and MEK, and therefore meet the BRI of the instant claim. However, negative feedback loops exist, including ERK inhibitory phosphorylation of BRAF and CRAF (page 329, right column, paragraph 1). Therefore, some ERK inhibitors such as SCH772984 that result in reduced MEK expression also fall within the BRI of the instant claim (page 335, right column, paragraph 4). Accordingly, the unpredictability of what constitutes a dual RAF/MEK inhibitor is high as there is no clear correlation between structure and function.
The instant specification provides two examples of administering to a subject in need a dual RAF/MEK inhibitor, wherein the dual RAF/MEK inhibitor in both examples is VS-6766 (pages 77-81). Yaeger teaches that VS-6766 acts as a dual RAF/MEK inhibitor by binding to an allosteric pocket of MEK, thereby forcing a conformation in which MEK cannot be phosphorylated by RAF and released from the RAF-MEK complex (page 335, right column, paragraph 2). As discussed above, Yaeger teaches many different compounds that act as dual RAF/MEK inhibitors with alternative mechanisms that do not include allosteric MEK binding. The instant application fails to offer representative examples of dual RAF/MEK inhibitors that are not allosteric modulators of MEK. Therefore, it is not clear that Applicant had possession of the knowledge of treating or preventing adverse events or toxicities associated with a dual RAF/MEK inhibitor. Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
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.
Claims 2-5, 9-14, 24-26, 28-29, 31, 35, 38, 42-43, 48, 50, 53, and 57 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 treatment of toxicity or an adverse event associated with administration of a dual RAF/MEK inhibitor in a subject, does not reasonably provide enablement for prevention of said toxicities or adverse events. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2nd 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include: (a) The nature of the invention; (b) The breadth of the claims; (c) The relative skill of those in the art; (d) Status of the prior art/predictability or unpredictability of the art (e) the amount of direction or guidance presented; (f) the presence or absence of working examples and (g) the quantity of experimentation necessary. Each factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention: The invention is directed to a method of reducing the severity of or preventing toxicity or an adverse event associated with administration of a dual RAF/MEK inhibitor in a subject.
The breadth of the claim: The scope of the claims includes the prevention of toxicity or an adverse event associated with administration of any pharmaceutically active agent that acts as an inhibitor of both RAF and MEK.
The relative skill of those in the art: The level of skill is high comparable to that of an M.D. or Ph.D.
Status of the prior art/predictability or unpredictability of the art: It is known in the art that RAF/MEK inhibitor treatment results in a diverse range of adverse events spanning multiple organ systems (see Heinzerling, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open, 2019, 4, e000491. doi:10.1136/ esmoopen-2019-000491). Heinzerling teaches the incidence and severity of adverse event(s) is/are dependent on the patient population and specific therapeutic agent used. For example, maculopapular rash was reported in 15% of patients taking a vemurafenib + cobimetinib combination regimen, with 7% experiencing high severity (grade 3-4). The same indication was reported in 4% of patients taking a dabrafenib + trametinib combination (0.6% high severity) and 3% of patients taking encorafenib + binimetinib combination (1.6% high severity) (page 5, Table 2). Heinzerling also teaches that the combination therapies are associated with adverse events across multiple organ systems, e.g., dermatological, gastrointestinal, musculoskeletal, cardiovascular, ocular, pulmonary, and renal events, and general disorders of the central nervous system (pages 5-6, Table 2). Adverse events affecting multiple organ systems are driven by distinct pathophysiological mechanisms and are unlikely to share a common etiology. This is further evidenced by Heinzerling, who teaches that 20% of the patient population experienced treatment-related fever when taking dabrafenib monotherapy, which was more strongly associated with the hydroxy-dabrafenib metabolite than dabrafenib itself (page 2, paragraph 4). Drug metabolism can lead to many downstream and off-target events involving different organ systems. As such, toxicities or adverse events induced by dual RAF/MEK inhibitor therapy is highly variable and one could not accurately predict the correct toxicity or adverse event for preventative treatment.
The amount of direction or guidance presented: In the instant case, Applicant has not provided guidance as to how one skilled in the art would accomplish the objective of preventing toxicities or adverse events associated with dual RAF/MEK inhibitor treatment, nor are any references provided that teach the same. Therefore, the instant application is viewed as lacking an adequate enablement of where toxicity or adverse events associated with dual RAF/MEK inhibitor treatment may actually be prevented.
The present or absence of working examples: No working examples are provided for preventing toxicity or adverse events associated with dual RAF/MEK inhibitors, for example, in a patient in the specification. The applicant has not provided any competent evidence or disclosed any tests that are highly predictive for the preventative effects of the instant composition. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The quantity of experimentation necessary: The quantity of experimentation would be an undue burden to one of ordinary skill in the art. Thus, factors such as “sufficient working examples,” “the level of skill in the art" and "predictability," etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claim”. In view of the breadth of the claims, the chemical nature for the instant claims and unpredictability of preventing toxicity or adverse events associated with dual RAF/MEK inhibitors, and the lack of working examples regarding the activity as claimed, one skilled in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
In consideration of the Wands factors, it is apparent that there is undue experimentation because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
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 2-5, 9-14, 24-26, 28-29, 31, 35, 38, 42-43, 48, 50, 53, and 57 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. Specifically, the phrase “adverse event associated with” renders the scope of the claim ambiguous.
The phrase “adverse event associated with” does not make clear what adverse events are or are not covered by the scope of the claim (e.g., common side effects, drug-drug interactions, allergic reactions, etc.). Furthermore, a skilled artisan cannot discern to what degree of association is needed to reduce the severity of or prevent toxicity of said adverse event. Accordingly, the above claims are ambiguous.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 2-5, 9-14, 24, 31, 35, 38, 42, 43, 48, and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Banerji et al. (hereafter, Banerji. WO 2021/047798 A1; published 2021, Mar. 18) in view of Dagher et al. (hereafter, Dagher. Cutaneeous toxicities from targeted therapies used in oncology: literature review of clinical presentation and management. Int J Women’s Dermatol, 2021, 7, 615-624. doi: 10.1016/j.ijwd.2021.09.009).
Regarding claims 2-5, 31, 35, 38, 42, 43, 48, and 53, Banerji teaches methods comprising the treatment of abnormal cell growth, such as cancer (e.g., a cancer with a RAS mutation), in a subject (e.g., human), by administering to a subject a therapeutically effective amount of VS-6063, or a pharmaceutically acceptable salt thereof (a FAK inhibitor) in combination with CH5126766, or a pharmaceutically acceptable salt thereof (a dual RAF/MEK inhibitor) (page 2, paragraphs 2-3). Banerji also teaches the RAF/MEK/FAK combination therapy can be administered with an effective amount of a steroidal anti-inflammatory agent (page 27, paragraph 1).
The difference between the teachings of Banerji and the instant application is that Banerji fails to teach the use of an effective amount of an antibiotic agent. However, this is rendered obvious in view of Dagher.
Dagher teaches the prevention recognition, and management of common dermatologic toxicities due to targeted oncological therapies (abstract). Dagher further teaches that MEK inhibitors commonly induce papulopustular eruption (acneiform rash), and exanthema (nonspecific rash), inter alia (page 617, Table 3). Preventative management of acneiform rash is taught to be oral antibiotics for 6 to 8 weeks (page 618, Table 4), wherein the oral antibiotic is either doxycycline 100 mg twice a day or minocycline 100 mg once a day (page 620, left column, paragraph 2).
A person who is skilled in the art would have been motivated to apply the therapeutic regimen as disclosed by Dagher into the combination RAF/MEK/FAK inhibitor therapy as taught by Banerji because Banerji discloses that rash was the most common side effect reported in their dose escalation study (page 41, paragraph 1). Therefore, a reasonable expectation of success exists for this patient population to have their rash ameliorated with an effective amount of an oral antibiotic agent, specifically doxycycline twice a day for 6 to 8 weeks or minocycline 100 mg once a day for 6 to 8 weeks. Accordingly, a skilled artisan would have found claims 2-5, 31, 35, 38, 42, and 43, and 53 to be prima facie obvious.
Regarding claims 9-14, Banerji teaches a method of administering the RAF/MEK/FAK inhibitor combination therapy wherein CH5126766 is administered at about 0.5 mg to about 10 mg, a method wherein CH5126766 is administered at a dose of about 3.2 mg, and a method wherein CH5126766 is administered at a dose of 4 mg (page 4, paragraph 3). Banerji also teaches a method wherein CH5126766 is administered orally and at a predetermined interval (e.g., twice a week), for three weeks followed by one week off in combination with a FAK inhibitor (VS-6063) (page 15, paragraph 2).
Regarding claim 24, Banerji teaches the combination of VS-6063 or a pharmaceutically acceptable salt thereof, with CH5126766, or a pharmaceutically acceptable salt thereof, can be administered with an anti-inflammatory agent, including hydrocortisone (cortisol), prednisone, prednisolone, methylprednisolone, triamcinolone, aldosterone, dexamethasone, (page 27, paragraph 1).
Claim(s) 25, 26, 28, 29, and 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Banerji in view of Dagher as evidenced by Lacouture et al. (hereafter Lacouture. Prevention and management of dermatological toxicities related to anticancer agents: ESMO clinical practice guidelines. Annals of Oncology, 2021, 32(2), 157-170. DOI: 10.1016/j.annonc.2020.11.005).
The teachings of Banerji and Dagher are discussed above and incorporated herein by reference.
The difference between the teachings of Banerji and those of the instant application is that the combined teachings fails to teach a method wherein the corticosteroid is administered topically, a method wherein the corticosteroid is administered twice daily, a method wherein the corticosteroid is hydrocortisone, a method wherein the corticosteroid is hydrocortisone, a method wherein the hydrocortisone is comprised in a composition comprising about 0.1 to about 10% hydrocortisone, and a method wherein the corticosteroid is administered for eight consecutive weeks. However, the above becomes obvious in view of Dagher as evidenced by Lacouture.
Dagher teaches the prevention recognition, and management of common dermatologic toxicities due to targeted oncological therapies (abstract). Dagher further teaches that MEK inhibitors commonly induce papulopustular eruption (acneiform rash), and exanthema (nonspecific rash), inter alia (page 617, Table 3). Treatment options for acneiform rash is taught to include concomitant use of antibiotics with a topical or oral corticosteroid (page 618, Table 4). The treatment option for nonspecific rash is taught to include topical or oral corticosteroid (page 618 Table 4). While a specific corticosteroid is not taught, Dagher makes an evidentiary reference to Lacouture for the use of the oral tetracycline antibiotic and topical corticosteroid as rash treatment (page 620, left column, paragraph 3). Based on Lacouture as referenced, the preferred corticosteroid to treat rash caused by RAF/MEK inhibitors is hydrocortisone 2.5% (page 158, right column, paragraphs 1-2).
A person who is skilled in the art would have been motivated to apply the management regimen as disclosed by Dagher as evidenced by Lacouture into the combination RAF/MEK/FAK inhibitor therapy as taught by Banerji because Banerji discloses that rash was the most common side effect reported in their dose escalation study (page 41, paragraph 1). Therefore, a reasonable expectation of success exists for this patient population to have their rash ameliorated with an effective amount of a topical corticosteroid, specifically hydrocortisone 2.5%. Accordingly, a skilled artisan would have found claims 25, 26, 28, 29, and 50 to be prima facie obvious.
Claim(s) 57 is/are rejected under 35 U.S.C. 103 as being unpatentable over Banerji in view of Dagher, and in further view of clinical trial ID: NCT04720417 (Study post date 2021, Jan. 22).
The teachings of Banerji and Dagher are discussed above and incorporated herein by reference.
Banerji further teaches that the RAF/MEK/FAK inhibitor combination therapy is used for the treatment of lung cancer (non-small cell lung cancer, Table 2), colorectal cancer (Table 3), pancreatic cancer (Table 4), and gynecologic cancer (ovarian cancer, Table 1).
The difference between the combined teachings above and the instant application is that the combined teachings fail to teach the combination therapy for the treatment of melanoma.
However, prior to the effective filing date of the claimed invention, a phase II clinical trial was published under the ID NCT04720417 wherein the combination of defactinib and VS-6766 was being used for treating patients with metastatic uveal melanoma. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to treat the same patient population with the RAF/MEK/FAK inhibitor combination therapy to arrive at the current invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Paul Arcoria whose telephone number is (571)272-8719. The examiner can normally be reached Mon-Fri 8:00-5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.A./ Examiner, Art Unit 1621 /CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights