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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 01/28/2026 has been entered.
The claims were amended on 01/28/2026 to encompass distinct subject matter, and new claims 38-64 were added.
A restriction requirement was mailed on 03/17/2026 and an election was made by applicant on 05/15/2026. Applicant elected to prosecute Group II, claims 50-64, without traverse. Claims 31, 33-34 and 38-49 have been canceled.
Claims 50-64 are currently pending and are the subject of this Office Action.
Priority
The instant application claims priority as follows:
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Claim Rejections - 35 USC § 103
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 50-64 are rejected under 35 U.S.C. 103 as being unpatentable over Contentti (Expert Opinion on Emerging Drugs (2020), Vol. 25, No. 4, 377-381) in view of Hunt (Regulatory Toxicology and Pharmacology 49 (2007) 90-100)) and FDA (Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation (FDA-2008-D-0128) July 2009; https://www.fda.gov/media/116737/download), and further in view of Treem ( Drug Saf 44, 133–165 (2021)), Clinical trials NCT01319006 (last updated 2017-06-26), and Bigica (FDA Pauses Tolebrutinib Trials in MS, Myasthenia Gravis over Liver Injuries, NeurologyLive Articles June 30, 2022).
Contentti
Contentti teaches that the compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1 H-imidazo [4,5-c]pyridin-2(3H)-one (tolebrutinib, SAR442168) was evaluated in various clinical trials by administering to subjects with relapsing multiple sclerosis. See at least Table 1. It is a second-generation BTK inhibitor with encouraging results of two-phase II trials in active MS. However, longer and larger trials are required to determine the efficacy and risks of this molecule. See the Expert opinion section.
Hunt
Hunt is drawn to monitoring liver safety during drug development. “Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure resulting in liver transplantation in the US. Despite considerable research efforts into mechanisms of drug-induced liver injury (DILI), it remains challenging to predict which compounds will result in clinically important idiosyncratic liver injury in drug development.” (p. 90)
Hunt discusses that regulatory authorities have provided information on clinically worrisome hepatotoxicity, coining the term, “Hy’s Law” to describe serious events of probable drug-induced hepatocellular injury. Diverse liver chemistry thresholds have been recommended as stopping criteria for subjects receiving novel therapeutic agents. The authors developed an evidence-based liver safety system for use in Phase I-III studies to improve clinical trial subject safety and other matters (see at least abstract and page 91). Although “Hy’s Law” was originally defined by Temple as: ALT equal to or exceeding 3 times ULN and bilirubin exceeding 2 times ULN, a more sensitive threshold can be selected as a liver chemistry subject stopping criteria (p. 94).
Hunt’s criteria is as follows: For Phase I, in subjects exhibiting an ALT equal to or exceeding 3 times ULN (Fig. 1), study drug must be stopped and subjects must undergo repeat liver chemistries (weekly) and further evaluation to determine event etiology and assessment of drug-relatedness. For subjects exhibiting ALT equal to or exceeding 3 times ULN and bilirubin equal to or exceeding 1.5 times ULN, a “Hy’s Law” event, rapid evaluation is required with close clinical follow-up. Liver chemistries are obtained twice weekly, or weekly for subjects that do not exceed the bilirubin threshold.
Additionally, in developing liver safety criteria for Phase II-III, Hunt proposes periodic liver chemistry evaluations at baseline, throughout treatment, and during follow-up, which are assessed more frequently when ALT equals or exceeds 3 times ULN (p. 95). The following liver chemistry threshold events were proposed:
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Acute liver injury was defined as hepatocellular liver injury when ALT equals or exceeds 2 x ULN and ALT (ULN)/alkaline phosphatase (ULN) equals or exceeds 5; cholestatic liver injury when alkaline phosphatase equals or exceeds 2 x ULN and AKT (ULN)/alkaline phosphatase (ULN) is less than or equal to 2; mixed liver injury when ALT equals or exceeds 2 x ULN and alkaline phosphatase equals or exceeds ULN and ALT (ULN)/alkaline phosphatase (ULN) is greater than 2 and less than 5. See 1st paragraph of page 97.
FDA
FDA provided guidance to the pharmaceutical industry and investigators who are conducting new drug development to detect, evaluate and manage drug-induced liver injury (DILI). See whole document. Appropriate testing and analysis in premarketing trials can detect drugs that can cause severe hepatocellular injury (p.3).
FDA shows that patients are evaluated at baseline, before drug exposure, for liver test abnormalities. “Patients are sometimes excluded from clinical trials because of baseline liver test abnormalities or a history of liver disease, but there is no well-established reason to do this, except perhaps to avoid confusion between the previous disease and an effect of the test drug. Patients with acute viral, autoimmune, alcoholic, or other types of hepatitis are unstable and generally not appropriate subjects for clinical trials other than trials of treatments for their acute illness. Patients with stable underlying liver disease can be included cautiously in late-stage clinical trials, but probably not if bilirubin excretory or protein synthetic functions are impaired, unless there is a strong need that they be treated. This implies that diagnostic screening for liver test abnormalities should be conducted before enrolling subjects into trials.” (see p. 7,9)
At page 8, Detection and confirmation of DILI: Early trials of a drug in trial subjects with presumably normal liver function should involve obtaining liver enzyme (ALT, AST, ALP) and bilirubin tests every 2 to 4 weeks, at least for a few months. For drugs being studied with short treatment courses, both baseline and post-treatment liver enzyme testing should be performed. Attention to symptoms does not supplant routine periodic assessment of AT, TBL and ALP in trial of investigational drugs. See page 8. “In general, an increase in serum AT to >3xULN should be followed by repeat testing withing 48 to 72 hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) to confirm the abnormalities and to determine if they are increasing or decreasing.” “The need for prompt repeat testing is especially great if AT is much greater than 3xULN and/or TBL is greater than 2xULN.” See p. 8-9.
FDA at page 9, Decision to Stop Drug Administration: “Promptly stopping the offending drug usually is the only potentially effective therapy.”
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FDA at page 12:
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FDA at page 15:
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Treem
Treem is directed to consensus guidelines for the detection, assessment and managements of DILI during clinical trials in particular patient populations. Treem disclosed: Published proceedings of previous workshops convening academic, industry, and regulatory experts have suggested that samples should be obtained at two or more time points during the pretreatment screening phase to determine whether liver tests are stable or subject to fluctuation.
Results of a recent survey conducted by the IQ DILI initiative revealed that 3 of 12 (25%) companies were using more than one determination of aminotransferase, TBL, and ALP during screening before baseline serum testing to generate mean baseline values available to the clinical investigators prior to administration of the first dose of study drug (unpublished data). In the proceedings of previous meetings, recommendations were made to obtain at least two determinations during the screening period separated by not less than 2 weeks and not more than 2 months prior to time of the initial dose of the study drug, with the mean value chosen as the screening value to meet the predefined inclusion/exclusion criteria [25]. Some experts have also advocated that if the second screening value exceeds the exclusion criteria for that liver test, or if the second value is more than 50% (1.5×) higher than the first value, then enrollment should be delayed and a third value obtained to aid with judgments about whether the subject’s underlying CLD is progressing and may limit eligibility [25]. See page 136.
An alternative strategy is to start with each subject’s liver tests prior to first dose of study drug (mean of screening and baseline values), and then use multiples of those values during the trial to trigger the above actions in that subject [43–45]. In particular, when subjects enter clinical trials with elevated baseline ALT values, it may not be appropriate to trigger the standard responses to evaluate a case of concern when the ALT rises to 3 × ULN, as this may reflect only a minor increase above the subject’s baseline and may be due to normal variability of the ALT fluctuations in the disease being studied. See section 2.3.
A subject’s baseline aminotransferases (ALT) which would trigger increased monitoring for potential DILI or cessation of study drug in clinical trials where subjects enter with abnormal (elevated) baseline values, is generally defined as > 1.5 × ULN. See at least p. 147 and p. 157 @ 24.(a).
Clinical trials
Liver chemistry parameters of AST, ALT, alkaline phosphatase and bilirubin <= 1.5xULN have been recognized as healthy subject parameters for drug-development studies. See for example, Clinical trials NCT01319006 or NCT01072214.
Bigica
Bigica discloses that the FDA placed a partial clinical hold on the phase 3 clinical trials for tolebrutinib, and that the hold was placed based on reported cases of drug-induced liver injury (DILI) in patients who received the study drug in the ongoing trials.
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
The difference between the disclosure of Contentti and the instant claims is that while Contentti discusses that tolebrutinib was being evaluated in clinical trials, it does not disclose determining ALT, total bilirubin or alkaline phosphatase in the patient and either continuing or stopping the treatment if the patient’s level were as claimed, and continuing monitoring the levels and when to resume the administration.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR prongs (A) or (G), it would have been prima facie obvious to the ordinary skilled artisan to determine the levels of ALT, total bilirubin and alkaline phosphatase in the patient taking tolebrutinib, then, to decide to stop administration of tolebrutinib if the patient has a level of
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, and to continue monitoring the level of ALT in the patient, because the prior art above taught to do this for monitoring liver safety during drug clinical evaluation, and for improving subject safety. The references teach determining the level of ALT at least weekly. The ordinary skilled artisan would have been motivated to re-administer the drug (rechallenge the patient), if the drug has shown an important benefit to the patient, per teachings of FDA, and if the artisan would have determined that the liver chemistry would return to the healthy/normal baseline values. The healthy/normal baseline values includes ALT <= 1.5xULN, per the teachings of Clinical Trials and Treem. Thus, claims 50-52, 54-57 and 59-62 and 64 would have been prima facie obvious.
Regarding claims 53, 58 and 63, the criterion of AST, ALT, ALP and bilirubin <= 1.5xULN as healthy/normal liver chemistry was well known and used in clinical-trials screening (as evidenced above). It would have been prima facie obvious to determine the levels of ALT, ALP and bilirubin prior to administering the drug to a patient, and to administer the drug to the patient with a healthy/normal liver chemistry, which was considered to be AST, ALT, ALP and bilirubin <= 1.5xULN. The motivation to do so would have been the expectation of a lower risk of liver injury.
Moreover, since Bigica discloses that tolebrutinib caused drug-induced liver injury (DILI) in some patients in clinical trials, the artisan would have been motivated to follow known sensitive guidelines.
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 50-64 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.
The claims recite “A method of preventing drug-induced liver injury comprising”, “ a therapeutically effective amount of”, “to a patient in need thereof”. The claims are ambiguous because one cannot discern the scope of “ a patient in need thereof” in the claims. The patient in need thereof in the specification is a patient that suffers from relapsing multiple sclerosis and the claims are not directed to treating relapsing multiple sclerosis. In addition, the therapeutically effective amount is unclear because, assuming that the therapy is for “preventing drug-induced liver injury”, no amount effective for preventing drug-induced liver injury has been disclosed in this application.
Conclusion
Claims 50-64 are rejected. No claim is in condition or allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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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.
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/VALERIE RODRIGUEZ-GARCIA/ Primary Examiner, Art Unit 1621
06/25/2026
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