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 .
Claims 13-32 are currently pending and under consideration.
Priority
Receipt is acknowledged of certified copies of papers (JP2021-040206) required by 37 CFR 1.55.
Information Disclosure Statement
The listing of references in the specification (e.g., pages 2-3) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 31 is objected to because of the following informalities: The phrase “anticholinesterase inhibitor” does not appear to be the proper terminology, as the art of record predominately uses the term “cholinesterase inhibitor” (see Evoli et al.) or just “anticholinesterase”. Clarification is requested.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 13-17, and 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20210017286 (Kakehi et al., published January 21, 2021).
As to claims 13-16, Kakehi et al. teach a method for treating myasthenia gravis [14, 0126, Claim 34] in a human patient comprising administering an anti-IL-6 receptor antibody wherein the antibody comprises heavy chain CDRs of SEQ IDs 5-7 and light chain CDRs of SEQ IDs 8-10. See boxed amino acids below. Further Kakehi et al. teach that the heavy chain variable region comprises SEQ ID NO:1 and the light chain variable region comprises SEQ ID NO:2 (see underline regions) and that the antibody comprises a heavy chain comprising SEQ ID NO:3 and light chain comprising SEQ ID NO:4. Specifically, Kakehi et al. teach [0028] that SA237 (also known as “satralizumab”) is an antibody having the heavy chain sequence of SEQ ID:3 and the light chain sequence of SEQ ID NO:4. A comparison of applicant’s SEQ ID NO:3 compared to Kakehi’s SEQ ID NO:3 shows 100% similarity as set forth below.
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A comparison of applicant’s SEQ ID NO:4 compared to Kakehi’s SEQ ID NO:4 shows 100% similarity as set forth below:
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As to claim 17, Kakehi et al. teach [15, 0139] that the pharmaceutical composition comprising the antibody is administered subcutaneously.
As to claims 19-20, Kakehi et al. et al teach [0128] that the antibody dosage can range from 2-20mg of Il-6 inhibitor per kg body weight (2-20 mg/kg). Thus, for a myasthenia gravis patient with a body weight of 60kg adhering to a 2 mg/kg dosage, the dosage would be 120mg administration. At 3 mg/kg the same patient would have a dosage of 180mg. Similarly, for a patient with a body weight of 120kg the dosage would be 240 mg.
As to claims 21, Kakehi et al. et al teach [0127] that multiple doses are administered to the patient wherein each dose and the next are separated by an interval of two to eight weeks.
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.
Claim(s) 18 and 22-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20210017286 (Kakehi et al., published January 21, 2021).
Claim 18 is drawn to specific dosages. Kakehi teaches the first part (body weight 100 kg or less is 120 mg/administration but not 180 mg. Claim 22 (and dependents) are drawn to separating dosage intervals.
Kakehi et al. teach [0128] that the antibody dosage can range from 2-20mg of Il-6 inhibitor per kg body weight (2-20 mg/kg). Thus, for a myasthenia gravis patient with a body weight of 60kg adhering to a 2 mg/kg dosage, the dosage would be 120mg administration. At 3 mg/kg the same patient would have a dosage of 180mg. Similarly, for a patient with a body weight of 120kg the dosage would be 240 mg.
Kakehi et al. further delineate routine and shorter dosing intervals [17] wherein the IL-6 inhibitor is administered routinely after a short-interval dosing period where the same dose as the routine dose is administered multiple times at a shorter interval than the routine dosing interval. Also, Kakehi et al. teach [0129] that the “short-interval dosing period” refers to an administration period for inducing immunological tolerance against drugs (pharmaceutical compositions of the present invention) to suppress the generation of anti-drug antibodies due to immunogenicity. The short-interval dosing period in the present invention refers to a period where the same dose as the routine dose is administered multiple times at a shorter interval than the routine dosing interval. “(Being) administered multiple times” refers to two or more administrations including the initial administration, and is preferably two to five administrations including the initial administration, more preferably three administrations including the initial administration. Kakehi et al. further teach (claim 24) that the interval of time between sequential doses administered during the short-interval dosing period is one half the length of the routine dosing interval. This anticipates the weekly dosage intervals as set out in claims 23-24.
As to claim 18, Kakehi et al. does not specifically teach that the amount of antibody administered to a myasthenia gravis patient with a body weight of more than 100kg is 180 mg per administration. As to claim 22, Kakehi et al. does not specifically teach that “at least 4 doses of the pharmaceutical composition are administered to the patient”.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to modify the dosages of Kakehi so as to optimize the efficacy of the antibody in treating a myasthenia gravis patient. Kakehi provides a range of dosages and body weights well within the claimed ranges such that one of ordinary skill in the art could easily foresee lowering the dose to 180mg in a patient with a body weight of more than 100kg. Further, while Kakehi does not explicitly teach providing at least 4 doses, one of ordinary skill in the art could readily glean that such dosages would be provided based on the weekly schedules of shorter and routine dosages taught by Kakehi. MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at a 180 mg dose (body weight of more than 100 kg) or provided for at least 4 doses of the pharmaceutical composition through the process of routine optimization.
Claim(s) 25 and 31-32 are further rejected under 35 U.S.C. 103 as being unpatentable over US 20210017286 (Kakehi et al., published January 21, 2021) in view of Evoli et al. (Neurological Sciences, 40, 2019).
Kakehi et al. teach as set forth above but does not specifically teach pre-determining that the patient is positive for one or more of certain serum antibodies: anti-acetylcholine receptor (AChR) antibody, anti-muscle-specific tyrosine kinase (MuSK) antibody, and anti-low density lipoprotein receptor-related protein 4 (Lrp4) antibody (Claim 25). Kakehi et al. also do not teach combining the antibody therapy with an anticholinesterase inhibitor, an oral corticosteroid, and an immunosuppressant wherein the therapy comprises one or more of the following immunosuppressants: azathioprine, mycophenolate mofetil, cyclosporin A, and tacrolimus. (Claims 31-32).
Evoli et al. teach that Myasthenia gravis (MG) is a well-treatable disease, in which a prompt diagnosis and an adequate management can achieve satisfactory control of symptoms in the great majority of patients. When myasthenia gravis is suspected on clinical grounds, diagnostic confirmation relies mainly on the detection of specific antibodies (abstract). Anti-AChR and -MuSK Abs are routinely tested by a radio-immunoprecipitation assay (RIPA). When MG is suspected on clinical ground, anti-AChR Abs are the first to be tested. Anti-MuSK should be assayed in all AChR-negative cases. Anti-AChR and anti-MuSK are very specific, and, in practice, their detection in patients with congruous symptoms confirms the diagnosis (page 1116, 1st column) Common treatments include administration of cholinesterase inhibitors (pyridostigmine). Immunosuppression is used in all patients with disabling symptoms not adequately controlled with cholinesterase inhibitors. Azathioprine is the first-choice immunosuppressant in MG. Both cyclosporine and tacrolimus have also proven effective (page 1117).
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have modified the teachings of Kakehi et al. so as to include a diagnostic step prior to treating a patient with myasthenia gravis because a doctor/neurologist would want to first confirm a clinical diagnosis of the disease in advance of treatment. Further, one would have been motivated to test for serum antibodies such as AChR or MuSK because Evoli et al. teach that when myasthenia gravis is suspected on clinical grounds, diagnostic confirmation relies mainly on the detection of specific antibodies, and anti-AChR and anti-MuSK antibodies are routinely tested by a radio-immunoprecipitation assay (RIPA). Further, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to have combined the antibody (satralizumab) therapy with conventional therapies such as cholinesterase inhibitors, oral corticosteroids, or immunosuppressants such as azathioprine for the expectation of additional therapeutic efficacy. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claim(s) 26-30 is/are further rejected under 35 U.S.C. 103 as being unpatentable over US 20210017286 (Kakehi et al., published January 21, 2021) in view of Thomsen et al. (Front. Neurol., vol 11., December 2020)
The claims are broadly drawn to identifying patients according to the Myasthenia Gravis Foundation of America Clinical Classification or assessing patients’ disease severity according to standards using the Myasthenia Gravis (MG) Activities of Daily Living (MG-ADL) prior to and after treatments. The method further includes assessing the patient's scores or points on at least one of the following questionnaires, Quantitative Myasthenia Gravis (QMG), 15-item Myasthenia Gravis Quality of Life scale (revised)(MG-QOL 15r), Neurology Quality-of-Life Fatigue Short Form (Neuro-QOL Fatigue), and Myasthenia Gravis Composite (MGC) compared to the patient's scores or points on the at least one questionnaire prior to beginning the treatment.
Thomsen et al. teach that MG is a heterogenous disease with several possible classifications and that symptom distribution may be used to classify MG as “generalized MG” or ocular MG (page 2, 1st column). Although subpopulations of MG are distinguishable, patients are often classified according to the severity of deficits using the Myasthenia Gravis Foundation of America (MGFA) Classification. Patients are classified according to level of overall severity, spanning ocular-only (I), mild (II), moderate (III), severe (IV) and intubation (V), with additional subclassification related to axial/extremity (a) or bulbar (b) predominance (page 2, 1st column). Currently, the QMG, the MGC, the MG-ADL, and the QOL15(r) are the most widely used scales in clinical trials. The Quantitative Myasthenia Gravis (QMG) scale was introduced in 1998, serving as an objective measure of disease severity. The MG Activity of Daily Living (MG-ADL) scale is a patient-reported outcome developed in 1999 as a quickly administered set of questions examining frequency and severity of key MG symptoms. The MG Composite (MGC) scale was developed in 2008. It was constructed using the top performing items of the QMG, the MG-ADL and the Manual Muscle Test during a trial of mycophenolate. Six physician-assessed examinations evaluate ocular, neck and proximal limb muscles. Furthermore, four patient-reported items assess speech, chewing, swallowing and respiratory function. The MG Quality of Life 15-items (QOL15) was developed in 2008 as a patient-reported outcome. It was based on a large 60-item MG questionnaire. The current 15 questions were based on feedback from patients and on responsiveness of the individual items during a trial of mycophenolate.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to combine the methods of treating MG as taught by Kakehi et al. with the standards of measuring outcomes of patients with MG as taught by Thomsen et al. For example, prior to administering the therapeutic antibody, the patient should be properly classified according to the Myasthenia Gravis Foundation of America (MGFA) Classification. Accordingly, one would reasonably expect that from a sample of patients there would be patients diagnosed with MG with generalized muscle weakness within Class II, III, or IV. Further, it would be obvious to have patients fill out the MG Activities of Daily Living (MG-ADL) and report a score both before and after treatment to assessing treatment efficacy as this is a common patient reported outcome questionnaire. It would be expected that some patients would score 5 or higher and that at least half of the score would be related to non-ocular symptoms as Thomsen et al. teach that “Using a recall period of a few weeks, eight questions assess ocular function, speech, chewing, swallowing, respiratory function, and strength of proximal upper and lower extremities. Each item is scored from 0 to 3, which results in an unweighted total score of 0–24 points. A higher score indicates more severe symptoms”. Hence, following treatment with the antibody, one of ordinary skill in the art would expect or might observe a reduction in patient scores or points on the known MG questionnaires as taught by Thomsen et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 10774148 in view of Evoli et al. (Neurological Sciences, 40, 2019) and Thomsen et al. (Front. Neurol., vol 11., December 2020).
Claim 1 of the ‘148 patent is drawn to a method of treating an IL-6-related disease with an anti-IL-6 receptor antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2, the method comprising: administering, during an initial period, two to five sequential doses of the antibody to a human patient who has the IL-6-related disease, wherein the doses administered during the initial period are spaced by a first dosing interval that is in the range of one to two weeks, and wherein each dose is a selected dosage amount of the antibody that does not vary and is in the range of 50 mg to 800 mg; after the final dose administration of the initial period, waiting a second dosing interval that is twice the length of the first dosing interval and then administering a dose of the antibody in the selected dosage amount. SEQ IDs 1 and 2 anticipate the CDRs of Claim 1 of the instant application and are identical to claim 14 of the instant application. The dosing intervals and amounts described above are an obvious variation of Claims 18-20 and 22-24 of the instant application.
Claims 19 and 25 of the ‘148 patent indicate that the IL-6 related disease is “myasthenia gravis”.
Claim 4 and 28 of the ‘148 patent further defines the heavy and light chains as comprising SEQ ID NO:3 and SEQ ID NO:4 which are identical to current claim 15.
Claim 9 and 23 of the ‘148 patent identifies the antibody as “SA237” which is the same antibody as satralizumab (current claim 16).
While the patented claims do not teach treating the patient with a therapy comprising one or more of an anticholinesterase inhibitor, an oral corticosteroid, and an
immunosuppressant, wherein the therapy comprises one or more of the following immunosuppressants: azathioprine, mycophenolate mofetil, cyclosporin A, and tacrolimus (current claims 31-32) or that clinical diagnosis of serum antibodies such as AchR are essential (current claim 25), such diagnosis and combinatorial therapy is obvious in view of Evoli et al. (Neurological Sciences, 40, 2019) as set forth in the obviousness rejection above.
Further, while the patented claims do not include identifying patients according to the Myasthenia Gravis Foundation of America Clinical Classification or assessing patients’ disease severity according to standards using the Myasthenia Gravis (MG) Activities of Daily Living (MG-ADL) prior to and after treatments. Or, further assessing patient's scores or points on at least one of the following questionnaires, Quantitative Myasthenia Gravis (QMG), 15-item Myasthenia Gravis Quality of Life scale (revised)(MG-QOL 15r), Neurology Quality-of-Life Fatigue Short Form (Neuro-QOL Fatigue), and Myasthenia Gravis Composite (MGC) compared to a patient's scores or points on the at least one questionnaire prior to beginning the treatment (Current claims 25-30), the inclusion of such clinical assessments is obvious in view of Thomsen et al. (Front. Neurol., vol 11., December 2020). See obviousness rejection above.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643