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 .
Election/Restrictions
Applicant’s election without traverse filed April 15, 2026 is acknowledged. Applicant elected the following species: efavirenz as the moderate CYP3A4 inducer, infantile fibrosarcoma as the cancer, ETV6-NTRK3 as the neurotrophic receptor kinase gene fusion, fungal infection as the secondary diagnosis, and dexamethasone as the steroid. The election is accepted.
Claims 1-25 are examined only to the extent that they read on the elected species. Species not elected are withdrawn from further consideration pursuant to 37 CFR 1.142(b), pending the allowance of a generic claim.
Applicant’s remarks identify group i as “moderate CYP3A4 inhibitor.” Because the claims and the restriction requirement are directed to a moderate CYP3A4 inducer, and Applicant elected efavirenz, the Office treats “inhibitor” as an apparent typographical error. If this interpretation is incorrect, Applicant is required to clarify the election.
Status of the Claims
Claims 1-25 are pending. Claims 1-25 are examined only to the extent that they read on the elected species. Species not elected are withdrawn from further consideration pursuant to 37 CFR 1.142(b), pending the allowance of a generic claim.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e), which claims priority to, and the benefits of U.S. Provisional Application No. US63/426,390, filed on November 18 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/08/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 4, 8, 12, 16 and 24 are objected to because of the following informalities:
Claim 4 recites “claim1” and should be corrected to “claim 1.”
Claim 8 recites “12 hours before or after of the patient receiving the moderate CYP3A4 inducer.” The phrase “after of” is not grammatically correct and should be corrected, for example, to 12 hours before or after the patient receives the moderate CYP3A4 inducer.
Claim 12 recites “CTCAE.” This abbreviation should be spelled out on first use, for example, as Common Terminology Criteria for Adverse Events (CTCAE).
Claim 16 recites “according to claims 1.” This should be corrected to according to claim 1.
Claim 24 appears to omit a comma between “cutaneous T-cell lymphoma” and “pulmonary arterial hypertension.” As written, “cutaneous T-cell lymphoma pulmonary arterial hypertension” is grammatically incorrect.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10-14 and 24 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.
Claims 10 and 11 recite producing a Larotrectinib plasma concentration “within 50%” or “within 75%” of a comparator plasma concentration. It is unclear whether “within 50%” means no less than 50% of the comparator, within ±50% of the comparator, no more than 50% different from the comparator, or another relationship. Because the metes and bounds of the plasma exposure limitation are not reasonably clear, claims 10 and 11 are indefinite.
Claim 12 recites that the increased dose “does not increase the occurrence of either CTCAE Grade 3 or Grade 4 events in the patient.” The phrase “the occurrence of either CTCAE Grade 3 or Grade 4 events” lacks antecedent basis because no occurrence of such events is previously recited in claim 1 or claim 12. It is also unclear whether “events” refers to adverse events, laboratory abnormalities, toxicities, or another event category. Therefore, the scope of claim 12 is unclear.
Claims 13 and 14 recite “the rate of adverse events.” The phrase lacks antecedent basis because claim 12 does not previously recite a rate of adverse events. Further, because claim 12 recites “CTCAE Grade 3 or Grade 4 events” but does not clearly recite “adverse events,” it is unclear whether the “rate of adverse events” in claims 13 and 14 refers to the same events recited in claim 12 or to a different set of adverse events. Therefore, the scope of claims 13 and 14 is unclear.
Claim 24 is rejected under 35 U.S.C. 112(b) as indefinite because the phrase “cutaneous T-cell lymphoma pulmonary arterial hypertension” lacks punctuation or conjunction sufficient to determine whether the claim recites one condition or two separate diagnoses.
Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the 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 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.
Claims 1-20, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over the VITRAKVI (VITRAKVI 2021 prescribing information), in view of SUSTIVA(SUSTIVA/efavirenz labeling 2016), and Darling et al. (AAPS PharmSci 360 in 2019).
VITRAKVI teaches Larotrectinib for the treatment of adult and pediatric patients with solid tumors having a neurotrophic receptor kinase (NTRK) gene fusion (see INDICATIONS AND USAGE), and teaches selection of patients based on the presence of an NTRK gene fusion in tumor specimens (see DOSAGE AND ADMINISTRATION). VITRAKVI teaches a standard adult dosage of 100 mg orally twice daily, i.e., 200 mg/day, and a pediatric dosage of 100 mg/m² orally twice daily, i.e., 200 mg/m²/day (see DOSAGE AND ADMINISTRATION; see also 6.1 Clinical Trial Experience).
VITRAKVI further teaches that Larotrectinib is metabolized predominantly by CYP3A4, that coadministration with a strong CYP3A4 inducer may decrease Larotrectinib plasma concentrations and thereby decrease efficacy, and that, when coadministration with a strong CYP3A4 inducer cannot be avoided, the VITRAKVI dose should be doubled and then returned to the prior dose after the inducer is discontinued (see 7 DRUG INTERACTIONS, Strong CYP3A4 Inducers). VITRAKVI also teaches that Larotrectinib exposure is dose proportional over the 100 mg to 400 mg dose range, thereby providing a pharmacokinetic basis for using an increased/doubled dose to compensate for induction-mediated exposure reduction (see 12.3 Pharmacokinetics). These teachings provide the Larotrectinib treatment, NTRK fusion-positive cancer patient, standard dose, increased dose relative to the standard dose, 1.5-2.5 fold dose increase, 2-fold dose increase, 400 mg/day adult increased dose, and 400 mg/m²/day pediatric increased dose limitations recited in claims 1 and 3-7, except for the moderate CYP3A4 inducer limitation discussed below.
VITRAKVI further teaches Larotrectinib sulfate, capsule dosage forms, oral solution dosage forms, interchangeability of capsule and oral solution, and twice-daily administration (see 2 DOSAGE AND ADMINISTRATION; see 2.7 Administration). VITRAKVI also teaches CTCAE-based adverse-reaction reporting and dose-modification guidance for Grade 3 or Grade 4 adverse reactions (see 2 DOSAGE AND ADMINISTRATION; see 6.1 Clinical Trial Experience). These teachings provide the timing, plasma-exposure-maintenance, adverse-event, salt, formulation, and dosing-event limitations recited in claims 8-18.
VITRAKVI further teaches clinical studies including NTRK fusion-positive tumors, infantile fibrosarcoma, and ETV6-NTRK3 fusion. VITRAKVI reports infantile fibrosarcoma in the tumor-type efficacy table and ETV6-NTRK3 in the NTRK-fusion-partner efficacy table (see 14 CLINICAL STUDIES). These teachings provide the elected cancer species and elected gene-fusion species recited in claims 19 and 20. VITRAKVI also instructs avoiding strong CYP3A4 inducers, thereby supporting the limitation of claim 25 that the patient is not concurrently receiving a strong CYP3A4 inducer.
VITRAKVI does not expressly teach that the patient is concurrently treated with a moderate CYP3A4 inducer, does not expressly teach that the moderate CYP3A4 inducer is efavirenz, and does not expressly teach the moderate CYP3A4 inducer AUC-reduction definition recited in claim 2.
SUSTIVA teaches efavirenz as an antiretroviral agent for treatment of HIV-1 infection and teaches a 600 mg once-daily adult dose (see 2 DOSAGE AND ADMINISTRATION). SUSTIVA further teaches that efavirenz induces CYP3A and CYP2B6 in vivo, that substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with SUSTIVA, and that appropriate dose adjustments may be necessary for such coadministered drugs (see 7 DRUG INTERACTIONS). Thus, SUSTIVA provides efavirenz as the selected coadministered drug of claims 1 and 23 and provides the reason why coadministration of efavirenz would have been expected to decrease exposure of a CYP3A-metabolized drug such as Larotrectinib. SUSTIVA also teaches once-daily efavirenz administration, which, together with VITRAKVI twice-daily Larotrectinib administration, supports routine coordination of the Larotrectinib dose with the efavirenz dose as recited in claims 8 and 9.
VITRAKVI in view of SUSTIVA does not expressly teach that efavirenz 600 mg once daily is a moderate CYP3A4 inducer under the claimed AUC-reduction standard, and does not expressly teach the AUC decrease range recited in claim 2.
Darling et al. teaches the moderate-inducer AUC-reduction definition recited in claim 2, namely that moderate inducers decrease the AUC of sensitive index substrates of a given metabolic pathway by ≥50% to <80%. Darling et al. further identifies efavirenz 600 mg once daily as a moderate CYP3A4 inducer (see Background/Purpose). Thus, Darling et al. provides the claimed moderate CYP3A4 inducer classification for efavirenz and the AUC-reduction definition recited in claims 1, 2, and 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to administer an increased dose of Larotrectinib to a patient having an NTRK fusion-positive cancer while the patient is concurrently treated with efavirenz because VITRAKVI identifies Larotrectinib as a CYP3A4-metabolized drug, identifies CYP3A4 induction as reducing Larotrectinib plasma concentration and efficacy, and provides dose doubling as the known adjustment strategy for inducer coadministration. SUSTIVA and Darling et al. provide the reason to apply that strategy to efavirenz specifically, because efavirenz was known to induce CYP3A and was classified as a moderate CYP3A4 inducer. A person of ordinary skill would have had a reasonable expectation of success because Larotrectinib exposure is dose proportional from 100 mg to 400 mg, and the claimed 400 mg/day or 400 mg/m²/day increased dose is the direct arithmetic result of doubling the known 200 mg/day or 200 mg/m²/day standard dose. VITRAKVI further teaches Larotrectinib sulfate, capsule and oral solution dosage forms, interchangeability of capsule and oral solution, and twice-daily administration. VITRAKVI’s clinical studies include patients with infantile fibrosarcoma and ETV6-NTRK3 fusion, with Table 5 reporting infantile fibrosarcoma and Table 6 reporting ETV6-NTRK3. Therefore, the elected cancer and elected fusion species are taught.
Accordingly, Claims 1-20, 23 and 25 are rendered obvious.
Claims 1 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over VITRAKVI (VITRAKVI 2021 prescribing information), in view of HEMADY(the HEMADY/dexamethasone clinical pharmacology review 2018).
VITRAKVI teaches Larotrectinib treatment of NTRK fusion-positive cancer, standard adult and pediatric twice-daily dosing, CYP3A4 metabolism of Larotrectinib, decreased Larotrectinib plasma concentration and efficacy during CYP3A4 inducer coadministration, dose doubling as an exposure-maintenance strategy for CYP3A4 inducer coadministration, and dose-proportional exposure from 100 mg to 400 mg, as discussed above. These teachings provide the Larotrectinib treatment, NTRK fusion-positive cancer, standard dose, increased dose, and CYP3A4 metabolism framework of claim 1.
VITRAKVI does not expressly teach that the moderate CYP3A4 inducer is a steroid, or that the steroid is dexamethasone, as recited in claims 1 and 21-22.
HEMADY teaches dexamethasone as a synthetic glucocorticoid/steroid and teaches that dexamethasone is a moderate inducer of CYP3A4. HEMADY further teaches that coadministration with drugs metabolized by CYP3A4 may increase clearance and decrease plasma concentration of those drugs (see p. 13, line 2). Thus, HEMADY provides dexamethasone as the moderate CYP3A4 inducer of claim 1, the steroid limitation of claim 21, and the dexamethasone species of claim 22.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to increase the dose of Larotrectinib during concurrent dexamethasone treatment because dexamethasone was known to be a steroid and a moderate CYP3A4 inducer, and was known to decrease plasma concentrations of CYP3A4-metabolized drugs, while VITRAKVI teaches that Larotrectinib is metabolized predominantly by CYP3A4 and that dose adjustment is used to address CYP3A4 induction-mediated loss of Larotrectinib exposure. A person of ordinary skill would have had a reasonable expectation of success for the same dose-proportionality reasons discussed above.
Accordingly, claims 1 and 21-22 are rendered obvious.
Claims 1-20 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over VITRAKVI, in view of SUSTIVA/efavirenz labeling and Darling et al., as applied above, and further in view of Ruhnke et al. (Mycoses. 2020; 63:653–682) and Granwehr et al. (Fungal Infections in Cancer Patients. In: Nates, J., Price, K. (eds) Oncologic Critical Care. 2019, pp 1337-1360).
The teachings of VITRAKVI, SUSTIVA, and Darling et al. are set forth above and provide the Larotrectinib treatment of an NTRK fusion-positive cancer patient, concurrent efavirenz treatment as a moderate CYP3A4 inducer, the claimed increased-dose strategy, the dependent limitations of claims 2-20, 23, and 25, and the reason to increase Larotrectinib dose during efavirenz coadministration.
VITRAKVI, SUSTIVA, and Darling et al. do not expressly teach that the patient having the NTRK fusion-positive cancer is also diagnosed with a fungal infection, as recited in claim 24.
Ruhnke et al. teaches that invasive fungal diseases remain an important complication in cancer patients, causing morbidity and mortality, and that the guideline focuses on patients with hematologic malignancies and/or solid tumors (see p. 654, 2 OBJECTIVES). Granwehr et al. teaches that invasive fungal infections are a leading cause of morbidity and mortality in cancer patients admitted to intensive care units and identifies risk factors including chemotherapy, neutropenia, corticosteroid exposure, renal/hepatic dysfunction, surgery, drains, and catheters (see p. 1337, Abstract). Thus, Ruhnke et al. and Granwehr et al. provide the elected fungal-infection secondary diagnosis recited in claim 24.
It would have been obvious to a person of ordinary skill in the art before the effective filing date that an NTRK fusion-positive solid tumor patient treated with Larotrectinib could also be diagnosed with a fungal infection because fungal infections were known complications in cancer patients, including patients with solid tumors. The secondary diagnosis does not change the Larotrectinib target, mechanism, CYP3A4 metabolism, or dose-adjustment rationale; it merely identifies a known cancer-patient subpopulation in which the same Larotrectinib dose-adjustment strategy would have been applied.
Accordingly, claims 1-20 and 23-25 are rendered obvious.
Therefore, the claimed invention is obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/G.S./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
