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 .
DETAILED ACTION
This office action is response to Applicant’s communication filed on 12/16/2025.
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 12/16/2025.
Status of Claims
Claims 67-82 are pending in the instant application and currently under examination.
Action Summary/Response to Arguments
Applicant's remarks filed 12/16/2025 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s persuasive arguments .The text of those sections of Title 35 U.S. Code can be found in a prior office action.
Applicant filed continuation application 19/422,064 on 03/16/2026. Claims 67, 80 and 81 are provisionally rejected on the ground of statutory double patenting as claiming the same invention as that of claims 1, 20 and 21 of copending Application No.19/422,064. Please note the filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant’ argument have been fully considered, but they are NOT persuasive to overcome the rejections under 35 USC §112 (a) and 35 USC §103 being unpatentable over Crawford in view of Montalban and OCREVUSTM.
Applicant argues the disclosure of the result of clinical study is not required for enablement... the dosage regiment in the example studies corresponds to that claimed. Applicant further argues the press release on November 09, 2025 discussed the result of phase III clinical trial.
RESPONSE: Please note the 35 USC §112 (a) requirement must be satisfied as of the effective filing date of instant application. Evidence submitted later cannot cure/ substitute the deficiency of original disclosure. Instant claims recite limitation directed to the treatment outcome, e.g. EDSS scores, etc. Instant specification does not disclose any efficacy data or preliminary result of the clinical study to support instantly claimed administration regimen of 200mg fenebrutinib twice daily can achieve instantly claimed treatment outcome, e.g. slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, based on the evaluation of the EDSS scores, CDP12, etc. Instant claim 82 recites limitation that’s vague and ambiguous, e.g. reducing the psychological impact of MS, improving work status, decreasing global impression of MS severity, or any combination thereof. Due to the high unpredictability of treating multiple sclerosis(PPMS, RMS, etc.) as Applicant argues later (See page 7) wherein tolebrutinib (a BTK inhibitor) failed in its registrational Phase 3 RMS trial, an ordinary skilled in the art would not know if 200mg fenebrutinib or salt thereof twice daily is potent enough to achieve the intended treatment outcome in absence of sufficient efficacy data support by instant specification. Subjects with primary progressive multiple sclerosis might respond differently to administering of 200mg fenebrutinib or salt thereof twice daily, and might progress differently at different aspects of MS disability or progression thereof.
As stated in M.P.E.P. § 716: “When any claim of an application or a patent under reexamination is rejected or objected to, any evidence submitted to traverse the rejection or objection on a basis not otherwise provided for must be by way of an oath or declaration under this section.” No declaration has been filed. Unexpected results have therefore not been shown. Thus, the rejections under 35 USC § 112(a) are maintained.
Priority
The instant application 17/905,121 filed on 08/26/2022, is a 371 of PCT/US2021/019502 filed on 02/25/2021, which claim benefit of US provisional application No. 63/051,756 filed 07/14/2020 and
No. 62/982,872 filed on 02/28/2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed 12/16/2025 and 03/16/2026 are in compliance have been considered by the Examiner.
Claim Interpretation
As disclosed by instant specification (See [0212]-[0217] of US 2023/0091561 A1), instantly claimed fenebrutinib is also known as GDS-0853, originally disclosed by US patent No. 8,716,274 and WO 2017/148837.
Instant claims are directed to a method of treating primary progressive multiple sclerosis (PPMS), comprising administering to the subject in need thereof about 200 mg fenebrutinib twice daily. Claims 68-69, 72-78 and 80-81 are further directed to intended treatment outcome/result of administering 200 mg fenebrutinib in the subjects in need thereof, for example, slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event “wherein time to a progression event in the subject is increased, wherein the progression event is :an increase from baseline in EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points or an increase from baseline in EDSS score of at least 0.5 point in a subject with a baseline EDSS score of greater than 5.5 points”. As disclosed by instant specification (See [0231]-[0245] of US 2023/0091561 A1), the limitation of treatment outcome (e.g. Expanded Disability Status Scale/ EDSS, 9-Hole Peg Test/ 9-HPT, etc. ) recited in instant claims are commonly measurement/evaluation for multiple sclerosis treatment and are considered as general knowledge of multiple sclerosis treatment.
As stated in MPEP 2111.04: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)… The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met” .
As such, the limitation of slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event “wherein time to a progression event in the subject is increased”, etc. are considered as simply expression of intended result/ treatment outcome of a process step of administering fenebrutinib to the subjects in need thereof and general knowledge of multiple sclerosis treatment that do not add patentable weight to the method of treating primary progressive multiple sclerosis (PPMS) with fenebrutinib in absence of efficacy evidence supported by instant specification.
Maintained Rejections
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.
Claims 67-82 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention. Instantly claimed treatment outcome of method for treating primary progressive multiple sclerosis (PPMS) is not considered as enabled by administering about 200 mg fenebrutinib twice daily to the subject in need thereof, in absence of efficacy data as of effective filing date of instant specification.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Instant claims are directed to a method of treating primary progressive multiple sclerosis (PPMS), comprising administering about 200 mg fenebrutinib twice daily to the subject in need thereof with limitation of intended treatment outcome/result, for example, slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, or reducing disability in the subject with PPMS, etc. The instantly claimed treatment outcome are directed to evaluation of efficacy in human subjects in clinical study as disclosed by instant specification.
The State of the Prior Art and Predictability or Lack Thereof in the Art
Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system with heterogeneous features and it’s well-known in the art that treating multiple sclerosis is highly unpredictable due to many factors. The complexity and ambiguity involved in a diagnosis/evaluation of MS lead to prognostic uncertainty of treatment for multiple sclerosis. Montalban 2018 ( European Journal of Neurology 2018, 25: 215–237, ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis) reviews the pharmacological treatment of multiple sclerosis: “There is no curative treatment available for MS, and the current therapeutic strategy is aimed at reducing the risk of relapses and potentially disability progression…However, the variety of mechanisms of action, monitoring requirements and risk profiles together with the existing knowledge gaps make individualized medicine a complex task. There is still controversy about the relative efficacy of the drugs available, who should receive therapy and the optimum time to start. The heterogeneity of MS together with the changes in the diagnostic criteria over the years and the recent redefinition of the clinical subtypes hamper direct comparisons across studies for different drugs. Moreover, despite the identification of several prognostic factors , there is no accepted consensus definition that allows physicians to classify patients into high risk and low risk groups in order to prioritize treatment strategies” (See page 216, Background).
Regarding method of treating multiple sclerosis with BTK inhibitors, Dolgin (Nature Biotechnology, VOL 39, January 2021, pp 3–12, “BTK blockers make headway in multiple sclerosis”) reviews BTK inhibitors (e.g. evobrutinib, tolebrutinib, fenebrutinib) in clinical development for autoimmune disorders (e.g. MS, lupus, etc.) (See Table 1). As evidenced by Dolgin, the clinical outcome/result of BTK inhibitors (e.g. tolebrutinib, fenebrutinib) in treating multiple sclerosis (PPMS) was not available as of January 2021. Dolgin and cited reference teach the rationale of BTK inhibitors for treating MS, a disease in which microglia is thought to drive inflammatory lesion formation associated with disability/progression, However, “microglia can support both inflammatory and reparative functions in the brains of people with MS… We really still don’t have a strong grasp on what role microglia play in the disease, and at what times they play varying roles… Which function will ultimately be affected by BTK blockade is therefore a very difficult thing to predict.”(See page 3, right column; page 4, left column).
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The level of one of ordinary skill in the art
The level of skill required to use the instant invention would likely require many years of professional experience conducting research in the art (e.g. medicine, pharmaceutical science, biology, biochemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the use of instant invention.
The Presence or Absence of Working Examples and The quantity of experimentation needed
Instant specification disclosed the rationale and potential of BTK inhibitor fenebrutinib for treating multiple sclerosis: “B cells and myeloid/microglia may be central to the immunopathology of MS. BTK inhibition has direct effects on myeloid lineage cells. As a result, there is a potential for BTK inhibition to affect microglia that are associated with the pathological hallmark of MS disease progression” (See [0009]). Instant specification disclosed a study design of phase III clinical study to evaluate the efficacy and safety of fenebrutinib compared with ocrelizumab in adult patients with primary progressive multiple sclerosis (PPMS) (see Example 1 and 2, with objective and study design starting from [0354]). Instant specification only discloses study design of clinical trial, but no subject suffering primary progressive multiple sclerosis (PPMS) is actually administered 200mg fenebrutinib or salt thereof twice daily as of the effective filing date of instant application. Instant specification does not disclose any efficacy data or preliminary result of the clinical study to support instantly claimed administration regimen of 200mg fenebrutinib twice daily can achieve instantly claimed treatment outcome, e.g. slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, etc. Subjects with primary progressive multiple sclerosis might respond differently to administering of 200mg fenebrutinib or salt thereof twice daily, and might progress differently at different aspects of MS disability or progression thereof. Due to the highly unpredictability of treating multiple sclerosis(PPMS, RMS, etc.), an ordinary skilled in the art would not know if 200mg fenebrutinib or salt thereof twice daily is potent enough to achieve the intended treatment outcome in absence of sufficient efficacy data support by instant specification. An extensive amount of experimentation would be required for one of ordinary skilled in the art to evaluate the efficacy of administering of 200mg fenebrutinib or salt thereof twice daily, e.g. EDSS, PROMIS, 9-HPT, T25FWT, etc.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to instantly claimed method of treating primary progressive multiple sclerosis with instantly claimed fenebrutinib regimen for the intended treatment outcome in absence of efficacy data as of effective filing date of instant specification. In other words, one skilled in the art could not practice the claimed invention in full scope without undue experimentation.
WRITTEN DESCRIPTION REJECTION
Claims 67-82 are rejected under 35 U.S.C. 112 (a), first paragraph, as failing to comply with the written description requirement. Claims 67-82 contain 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, at the time the application was filed, had possession of the method of treating primary progressive multiple sclerosis PPMS comprising administering about 200mg fenebrutinib or salt thereof twice daily to the subject that could achieve the intended treatment outcome, e.g. slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, or reducing disability in the subject with PPMS, etc. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the MPEP 2163 and Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
MPEP 2163.02 states “ Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date, the inventor was in possession of the invention, and that the invention, in that context, is whatever is now claimed.”
Instant claims recite limitation of intended treatment outcome regarding progression in primary progressive multiple sclerosis PPMS, e.g. slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, etc. Claim 80 and 81 recite a method of reducing disability in the subject with PPMS , e.g. reducing the psychological impact of MS; increasing upper limb function; increasing walking ability; decreasing fatigue, improving work status; or decreasing global impression of MS severity . The Applicant is required to provide adequate written description and evidence of possession of instantly claimed method of treating primary progressive multiple sclerosis PPMS with instantly claimed treatment outcome by administering about 200mg fenebrutinib or salt thereof twice daily to the subject, as of the effective filing date of instant application.
Instant specification (US 2023/0091561 A1) disclosed a study design of phase III clinical study to evaluate the efficacy and safety of fenebrutinib compared with ocrelizumab in adult patients with primary progressive multiple sclerosis (PPMS) (see Example 1 and 2, with objective and study design starting from [0354]). Instant specification only discloses study design of clinical trial, but no subject suffering primary progressive multiple sclerosis (PPMS) is actually administered 200mg fenebrutinib or salt thereof twice daily. As evidenced by NCT04544449 (FENtrepid, Applicant’s IDS dated 04/11/2023) which is instantly claimed clinical study, recruiting of subjects starts on 09/30/2020 after priority filing of US provisional application No. 63/051,756 on 07/14/2020 and No. 62/982,872 on 02/28/2020.
Instant specification does not disclose any efficacy data or preliminary result of the clinical study to support instantly claimed administration regimen of 200mg fenebrutinib twice daily can achieve instantly claimed treatment outcome, e.g. slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event, etc. Subjects with primary progressive multiple sclerosis might respond differently to the administering of 200mg fenebrutinib or salt thereof twice daily, in different aspects of MS disability or progression thereof. Due to the highly unpredictability of treating primary progressive multiple sclerosis, an ordinary skilled in the art would not know if 200mg fenebrutinib or salt thereof twice daily is potent enough to achieve the intended treatment outcome or it might need higher dose of fenebrutinib or alternative administration regimen for the desirable intended treatment outcome. As such, instant specification in absence of sufficient efficacy data as of the effective filing date of instant application does not provide sufficient written description /support for the instantly claimed treatment outcome of method for treating primary progressive multiple sclerosis (PPMS) that can be achieved by administering 200mg fenebrutinib or salt thereof twice daily.
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 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 non-obviousness.
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 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 67-82 are rejected under 35 U.S.C. 103 as being unpatentable over Crawford et al. ( Journal Of Medicinal Chemistry, 2018, vol. 61, no. 6, 2227-2245, available on 2018-02-19, Applicant’s IDS dated 04/11/2023, "Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development"), in view of Montalban et al. (hereafter “Montalban 2019” ,New England Journal of Medicine, 2019, 80:2406-17, DOI: 10.1056/NEJMoa1901981, “ Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis”) and OCREVUSTM (ocrelizumab) Prescribing information (2017)(maintained).
Regarding instantly claimed fenebrutinib / GDC-0853 for treating autoimmune disease, Crawford and cited references teach GDC-0853/compound 29 (i.e. fenebrutinib ) is a potent, selective, and noncovalent Bruton’s Tyrosine Kinase inhibitor in early clinical development: “GDC-0853 suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria” (See abstract, conclusion).
Crawford teaches the potency of GDC-0853 (fenebrutinib) compared with other clinical stage of BTK inhibitors(e.g. ibrutinib, evobrutinib, etc.) in vitro and in human whole blood CD69 and CD 63 assays, wherein GDC-0853 exhibit the best whole blood potency in both assays (See page 2236, right column, Table 9, Figure 6). Crawford teaches in-vitro safety profile of CD-0853 for subjects associated with CYP3A4 inhibition(See Table 7, Supporting information).
Regarding the administration limitation recited in instant claims 67, 70, and 79, Crawford teaches preclinical study of GDC-0853 in rheumatoid arthritis and lupus wherein GDC-0853 was administered orally to rat at variety of dose, e.g. 16 mg/kg QD, 2 mg/kg /kg BID etc. (See page 2236, right column; Figures 8 and 9, Supplementary data page S45). Crawford also teaches single ascending dose(SAD) study (0.5 mg to 600 mg) and multiple ascending dose(MAD) study (250 mg of BID to 500 mg of QD) in healthy volunteers wherein GDC-0853 was very well tolerated with no severe adverse events, no safety signals, and no dose limiting toxicities(See page 2239, right column). It’s noted NCT03596632 (2018) is the phase 1 open-label study for pharmacokinetics and metabolism study of a fenebrutinib wherein 200 mg of fenebrutinib was administered orally to healthy volunteers.
Crawford concludes GDC-0853 might be the best and most selective in-class BTK inhibitor with favorable preclinical pharmacokinetic/safety characteristics that are potential useful in treating B-cell or myeloid cell mediated autoimmune diseases, and GDC-0853 are already in several phase 2 clinical studies for treating immune disorders, e.g. rheumatoid arthritis (NCT028333500), lupus (NCT02908100), and chronic urticaria (NCT03137069),etc. (See page 2239, Conclusion). It’s noted NCT02908100 teaches phase II, randomized, double-blind, placebo-controlled study of the safety and efficacy of GDC-0853 in patients with moderate to severe active systemic lupus erythematosus, wherein GDC-0853 tablet was administered orally once or twice daily. NCT03407482 (V15 on 10/08/2019) teaches a phase II, open-label extension study to evaluate the long-term safety and efficacy of GDC-0853 in patients with moderate to severe active systemic lupus erythematosus who have completed NCT02908100, wherein 4 tablets of GDC-0853 was orally administered BID. It’s noted multiple sclerosis (MS) and systemic lupus erythematosus (SLE) are both autoimmune diseases with overlapping symptoms(e.g. fatigue, muscle weakness, progressive neurological disability/symptoms, etc.) as evidenced in instant disclosure (See [0256], [0463] of instant US 2023/0091561 A1). Where 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. MPEP 2144.05.
Crawford is silent about GDC-0853/fenebrutinib for treating multiple sclerosis.
Regarding method of treating multiple sclerosis with Bruton’s tyrosine kinase (BTK)inhibitor, Montalban 2019 teaches the mechanism /rationale and potential of BTK inhibitor in treating multiple sclerosis: “The activity and interactions of B cells, T cells, and myeloid cells are involved in the immunopathological features of multiple sclerosis. Antigen-activated B cells exert effector functions through antigen presentation and the production of cytokines and antibodies. Macrophages and microglia that are abundant in multiple sclerosis lesions contribute to tissue damage and repair. Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, transmits signals through a variety of receptors in B cells and myeloid cells, so it presents a rational target in multiple sclerosis. BTK inhibitors are currently under investigation in several types of autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis” (See abstract; page 2407, left column). Montalban 2019 teaches the goals in the treatment of patients’ disabling symptoms in MS include reducing the frequency of relapses and slowing disability progression (See page 2407, left column, first paragraph).
Montalban 2019 teaches BTK inhibitor, evobrutinib, was administered at dose of 75mg once or twice daily, to patients in phase 2 clinical trial (NCT 02975349) for treating relapsing multiple sclerosis (See Methods, Results). Montalban 2019 teaches the clinical trial design ( (See page 2407, Methods and Supplementary Appendix) and outcome analysis for subjects with different clinical disability progression CDP from weeks 12 through week 24 based on relapse rate/ disability progression wherein recurrent neurologic symptoms/signs or an increase in the EDSS is considered as worsening/ progression event (See page 2408 , End point, Statistical Analysis; Results, Table 1 and 2).
Crawford and Montalban 2019 are silent about limitation of progression in primary progressive multiple sclerosis PPMS subject and intended treatment outcome regarding progression of PPMS recited in instant claims 68-69, 72-78 and 80-81. Although relapsing multiple sclerosis RMS and primary progressive multiple sclerosis PPMS are categorized as different multiple sclerosis on the record, RMS and PPMS shared similar clinical disability progression and drug/medicine is used for treating both RMS and PPMS. For example, ocrelizumab is currently the only disease-modifying therapy (DMT) approved by FDA in March 2017 for treating PPMS which can help slow the progression of disability for adults with primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS).
Ocrelizumab (Ocrevus) label 2017 disclosed the phase III clinical study of ocrelizumab for treating PPMS (See page 13, Section 14.2) with treatment outcome measurement. “In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume”. Ocrelizumab 2017 label explicitly lists key clinical and MRI endpoints in PPMS patients for study 3, e.g. proportion of patients with 12-week confirmed disability progression CDP12 (defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or an increase of 0.5 or more when the baseline score is more than 5.5), risk reduction, etc. (See Table 5, Figure 2). Please note NCT01194570 is the clinical study 3 of ocrelizumab referred in ocrelizumab label 2017 and considered as general knowledge of treating multiple sclerosis (PPMS and RMS). A skilled artisan would know to refer to clinical study/design of ocrelizumab for exploring alternative drug for treating primary progressive multiple sclerosis (PPMS).
It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug as shown in Crawford teaching of GDC-0853 for treating multiple autoimmune diseases/disorders. It would have been prima facie obvious to one of the ordinary skilled in the art before the effective filing date of instant invention to explore the potent selective BTK inhibitor GDC-0853/ fenebrutinib taught by Crawford for treating multiple sclerosis with BTK inhibitor as taught by Montalban 2019, in combination with Ocrelizumab label 2017 as reference for treating primary progressive multiple sclerosis, and arrive at instant claimed invention with reasonable expectation of success. At the time the instant application was filed, it was already known that GDC-0853/ fenebrutinib might be the best and most selective in-class BTK inhibitor with favorable preclinical pharmacokinetic/safety characteristics that are potential useful in treating B-cell or myeloid cell mediated autoimmune diseases as taught by Crawford. It was also known that BTK inhibitor (e.g. evobrutinib) in clinical trial for treating multiple sclerosis as taught by Montalban 2019 which explicitly teaches the rationale and potential of BTK inhibitor in treating B-cell or myeloid cell mediated multiple sclerosis. A skilled artisan would also know to refer to ocrelizumab for clinical study/design of potential drug for treating primary progressive multiple sclerosis (PPMS). A skilled artisan would be motivated to explore BTK inhibitor GDC-0853/ fenebrutinib for treating multiple progressive multiple sclerosis (PPMS) because GDC-0853/ fenebrutinib is already in multiple clinical trial for treating B-cell or myeloid cell mediated autoimmune disease (e.g. lupus) and more potent and selective than other BTK inhibitors (e.g. evobrutinib) in clinical trial for treating multiple sclerosis. The combined teachings of prior art, together with general knowledge of treating multiple sclerosis (PPMS, RMS, etc.) would provide an alternative novel treatment with selective BTK inhibitor GDC-0853/ fenebrutinib for treating PPMS with potential desirable treatment outcome.
Please note the limitation of slowing the progression of PPMS, delaying the onset of at least one progression, or reducing the risk of a subject with PPMS having at least one progression event wherein time to a progression event in the subject is increased, etc. are considered as simply expression of intended result/ treatment outcome of a process step of administering fenebrutinib to the subjects in need thereof and general knowledge of multiple sclerosis treatment that do not add patentable weight to the method of treating primary progressive multiple sclerosis (PPMS) with fenebrutinib in absence of efficacy evidence supported by instant specification. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention of administering fenebrutinib for treating PPMS in a subject in need thereof, based on the combined teachings of prior art together with exploration/optimization based on general knowledge of multiple sclerosis (PPMS, RMS, etc.). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues safety and efficacy results are not transferrable between compounds,...,Crawford, Montalban and OCREVUSTM would not provide motivation for use of fenebrutinib in treatment of PPMS.
RESPOSNE: The examiner agrees that each molecule must be thoroughly evaluated during clinical development as explained in above 35 USC 112(a). It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug as shown in Crawford teaching of GDC-0853 for treating multiple autoimmune diseases/disorders. A skilled artisan would be motivated to explore GDC-0853 for treating PPMS in search for alternative treatment for PPMS.
Applicant argues Example 3 of the current application shows that fenebrutinib has higher selectivity for Bruton's tyrosine kinase (BTK) than evobrutinib and tolebrutinib.
RESPOSNE: Please note the increased selectivity of fenebrutinib is already taught by Crawford.
As MPEP 2143.02.I. stated : “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 67, 80 and 81 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1, 20 and 21 of copending Application No. 19/422,064 (reference application)(Newly applied)
This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Reference claim 1 recites a method of treating primary progressive multiple sclerosis (PPMS) in a subject in need thereof, comprising administering to the subject about 200 mg fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, which is the same scope as instant claim 67.
Reference claim 20 and 21 recite a method of reducing disability in a subject with PPMS, the method comprising administering to the subject about 200 mg fenebrutinib twice per day, or an equivalent amount of a pharmaceutically acceptable salt thereof, which is the same scope as instant claims 80 and 81.
It’s noted reference claims 10, 13 and 14 reciting narrow scope of different measures of treating PPMS anticipate instant claim 72.
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 67-82 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68-84 of copending Application No. 17/995,259(reference application), evidenced by OCREVUSTM (ocrelizumab) Prescribing information (2017). Please note NOA of 17/995,259 is mailed on 12/13/2025.
Reference claims are directed to a method of treating relapsing multiple sclerosis (RMS) in a subject in need thereof, comprising administering to the subject about 200 mg fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.
Reference claims 72 and 78 recite limitation of CYP3A4 inhibitor or inducer that read on instant claim 71.
Reference claim 75 and 80 recite limitation of EDSS that read on instant claim 68 and 74-78.
Reference claim 80-81 recite limitation of cCDP that read on instant claim 69.
Reference claim 77 recites fenebrutinib I administered orally as one or more tablets or capsules that read on instant claim 70 and 79.
The difference between reference claims and instant claims are treating relapsing multiple sclerosis (RMS) vs primary progressive multiple sclerosis (PPMS). The pharmacological activity is the property of fenebrutinib. Although relapsing multiple sclerosis RMS and primary progressive multiple sclerosis PPMS are categorized as different multiple sclerosis on the record, RMS and PPMS shared similar clinical disability progression and active drug is used for treating both RMS and PPMS. For example, ocrelizumab is effective at treating both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) as elaborated in preceding 103 rejection. It's common practice in the pharmaceutical industry to explore/expand therapeutic area or subjects/patient for an active drug. It would be prima facie obvious for a skilled artisan to explore fenebrutinib for treating more subjects suffering primary progressive multiple sclerosis based on the combined teaching of reference claims and general knowledge of multiple sclerosis, e.g. ocrelizumab treating both RMS an PPMS.
The instant application shares one common inventor/applicant with reference application. Based on the continuing data on the record, instant application is not related to the reference application, thus no 35 USC 121 shield exists. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues “Given the clear and fundamental differences in the pathophysiology of RMS and PPMS, a person of ordinary skill in the art would not have been able to predict ahead of rigorous clinical development that a single therapeutic agent could effectively treat both multiple sclerosis phenotypes, each having its own diagnostic criteria, symptoms, progression, and biomarker signature”.
RESPONSE: The examiner does not dispute the difference between RMS and PPMS and single therapeutic is not always effective for both PPMS and RMS. It’s noted reference claim recite limitation of EDSS , cCDP that are used in treatment evaluation of both RMS and PPMS and read on instant claims. As MPEP 2143.02.I. stated : “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’").
In response to Applicant’s argument based on later press release in 2025, As stated in M.P.E.P. § 716: “When any claim of an application or a patent under reexamination is rejected or objected to, any evidence submitted to traverse the rejection or objection on a basis not otherwise provided for must be by way of an oath or declaration under this section.” No declaration has been filed. Unexpected results have therefore not been shown.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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