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 .
Claims Status
Claim(s) 1-3, 6-7, 18, 22, 24, 26-32, 43-44, 46, 49, and 52 is/are currently pending and presented for examination on the merits.
Response to Amendment
The objection(s) to the specification have been withdrawn in view of the Amendment filed on 22Aug2025.
All previously presented rejection(s) are maintained for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Maintained Rejections
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.
Claim(s) 1-3, 7, 18, 22, 24, 26-28, 30-31, 43-44, 46, and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. (WO 2017/205101 A1, published 30 Nov 2017), hereinafter “O’Brien”.
The applied reference has common Assignee and Inventors with the instant application. Based upon the publication date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1).
Regarding Claims 1, 7, 27, and 30, O’Brien claim 1 teaches “a method of treating refractory generalized myasthenia gravis in a patient in need thereof comprising administering a therapeutically effective amount of eculizumab to the patient; wherein the patient is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR) and shows marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST) and requires chronic plasma exchange or chronic IVIg to maintain clinical stability…” [e.g., pg. 99, claim 1]. O’Brien further teaches “the course of treatment with eculizumab lasts for 26-52…weeks or more… for greater than…51, 52… weeks…for greater than 1… or more years…” [e.g., pg. 27, paragraph 2]. O’Brien teaches improvement after at least 4 weeks [e.g., pg. 119, Fig. 15]. O’Brien teaches MG clinical state is assessed using the MGFA Post-Intervention Status and that change in categories of Improved…and Minimal Manifestation (MM) can be assessed.” [e.g., pg. 26, paragraph 3]. O’Brien further teaches the categories (e.g., Improved) as well as MM are assessed and recorded at week 4 [e.g., pg. 69, 5.5.2]. While O’Brien does not expressly teach achieving MM status after at least 4 weeks of treatment, MPEP § 2112 (II) provides “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference…”. As the method of the instant claim is identical to the method of O’Brien through week 26, the achievement of MM status (a response of the method of treatment) after a specified number of weeks (e.g., at least 4, after 12) of treatment is considered inherent to the method when the MM status is achieved in less than or equal to 26 weeks of treatment. Specifically, the clinical response (e.g., MM status) is a mechanistic property of a method and would therefore flow naturally from the method. O’Brien teaches “…the patient has a clinically meaningful improvement (reduction) in at least two measurements of generalized myasthenia gravis severity selected from the group consisting of MG-ADL, QMG, MGC, MG-QOL, and Neuro-QOL.” [e.g., pg. 101, claim 18], and “the patient has a clinically meaningful improvement (reduction) in five measurements of generalized myasthenia gravis severity, wherein the five measurements of generalized myasthenia gravis severity are a reduction in MG-ADL of at least 3 points, a reduction of QMG of at least 4 points, a reduction in MGC of at least 6 points, a reduction in MG-QOL of at least 6 points, and a reduction in Neuro-QOL of at least 8 points.” [e.g., pg. 1, claim 19].
Regarding claims 2, 28, and 31, which depends from claim 1 (claim 2), 27 (claim 28), or 30 (claim 31), the teachings of O’Brien as recited above apply for claims 1 and 27. O’Brien further teaches eculizumab is administered using a phased dosing schedule with an induction phase comprising administering a 900 mg induction dose of eculizumab on day 1, administering 900 mg doses of eculizumab on days 7, 14, and 21, and administering 1200 mg of eculizumab as a fifth induction dose on day 28. [e.g., pg. 99, claim 2]. O’Brien claim 3 teaches “wherein the 28 day induction phase of eculizumab treatment is followed by a maintenance phase comprising administering 1200 mg of eculizumab 14 days after the fifth induction dose and administering 1200 mg of eculizumab every 14 ± 2 days thereafter.” [e.g., pg. 99].
Regarding claim 3, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien further teaches “…performing plasmapheresis on the patient and administering eculizumab at a dose of between 300 mg and 1200 mg to the patient within 4 hours of completion of plasmapheresis” [e.g., pg. 99, claim 4], “…performing plasmapheresis on the patient and administering eculizumab at a dose of between 600 mg and 900 mg to the patient within 90 minutes of completion of plasmapheresis.” [e.g., pg. 99, claim 5], and “…performing plasmapheresis on the patient and administering eculizumab at a dose of 600 mg to the patient within 1 hour of” [e.g., pg. 99, claim 6].
Regarding claim 18, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches wherein the patient experiences a clinically meaningful improvement (reduction) in a measurement of generalized myasthenia gravis severity after 26 weeks of treatment selected from the group consisting of Myasthenia Gravis Activities of Daily Living (MG-AOL) score [e.g., pg. 100, claim 7], quantitative Myasthenia Gravis (QMG) [e.g., pg. 100, claim 9], score and Myasthenia Gravis Composite (MGC) score [e.g., pg. 100, claim 11], wherein the clinically meaningful improvement the patient experiences is an at least a 3 point reduction in the patient's MG-ADL score [e.g., pg. 100, claim 8] after 26 weeks of treatment, is an at least a 4 point reduction in the patient's QMG score [ e.g., pg. 100, claim 10] after 26 weeks of treatment, or is an at least a 6 point reduction in the patient's MGC score [e.g., pg. 100, claim 12] after 26 weeks of treatment.
Regarding claim 22, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches the patient experiences a clinically meaningful improvement (reduction) in quality of life as measured by Myasthenia Gravis Quality of Life (MG-QOL-15) score after 26 weeks of treatment [e.g., pg. 100, claim 13], and the clinically meaningful improvement the patient experiences is an at least a 6 point reduction in the patient's MG-QOL-15 score after 26 weeks of treatment [e.g., pg. 100, claim 14].
Regarding claim 24, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches the patient experiences a clinically meaningful improvement (reduction) in neuro-fatigue as measured by Neuro-QOL Fatigue score after 26 weeks of treatment [e.g., pg. 101, claim 15], and that the clinically meaningful improvement the patient experiences is an at least an 8 point reduction in the patient's Neuro-QOL score after 26 weeks of treatment [e.g., pg. 101, claim 16].
Regarding claim 26, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches the patient experiences a clinically meaningful improvement (increase) in health status as measured by EQ-5D health status score after 26 weeks of treatment [e.g., pg. 101, claim 17].
Regarding claim 43, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches eculizumab is administered by intravenous infusion [e.g., pg. 102, claim 21].
Regarding claim 44, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches eculizumab is administered subcutaneously [e.g., pg. 102, claim 22].
Regarding claim 46, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches the patient has failed treatment over one year or more with two or more ISTs in sequence or in combination [e.g., pg. 103, claim 25].
Regarding claim 49, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien teaches the patient experiences a reduction in the administration of one or more IST following at least 26 weeks of treatment [e.g., pg. 103, claim 28].
Response to Arguments
Applicant argues O'Brien does not teach or suggest administration of eculizumab to a subject to treat myasthenia, wherein the patient is treated for at least 52 weeks and achieves a Myasthenia Gravis Foundation of America (MGFA) post-intervention status of Improved or Minimal Manifestations (MM) after at least 4 weeks of treatment. In fact, O'Brien does not teach or suggest any improvement after any particular amount of time. The Office is relying on inherency to allege that the claimed feature of wherein the patient "achieves a Myasthenia Gravis Foundation of America (MGFA) post-intervention status of Improved or Minimal Manifestations (MM) after at least 4 weeks of treatment" is disclosed by O'Brien and/or is routine in the field of treatment/management of gMG. However, based on the teachings of O'Brien one of skill in the art would not be able to predict that the method would provide, after at least 4 weeks of treatment, a post-intervention status of Improved or MM as demonstrated in the specification as filed. Accordingly, Applicant asserts that independent claims 1, 27, and 30, which each stipulate that the patient achieves a MGFA post-intervention status of Improved or MM after at least 4 weeks of treatment, along with dependent claims 2, 3, 7, 18, 22, 24, 26, 28, 31, 43, 44, 46, and 49, are nonobvious over O'Brien. Thus, Applicant respectfully requests the rejection be withdrawn.
Briefly, as provided in the Office Action mailed 25Mar2025 (hereinafter “FAOM”), O’Brien teaches "a method of treating refractory generalized myasthenia gravis in a patient in need thereof comprising administering a therapeutically effective amount of eculizumab to the patient…” [e.g., claim 1], and further teaches "the course of treatment with eculizumab lasts for 26-52...weeks or more... for greater than...51, 52...weeks...for greater than 1... or more years..." [e.g., pg. 27, paragraph 2]. Given the above, O’Brien teaches administration of eculizumab to a subject to treat myasthenia, wherein the patient is treated for at least 52 weeks.
Further, as provided in the FAOM, while O’Brien does not expressly teach achieving MM status after at least 4 weeks (e.g., 4+ weeks) of treatment, the method of the instant claim is identical to the method of O’Brien through week 26 (e.g. teaches the same active steps as the instant claims), therefore any observed therapeutic results observed through week 26 are considered to flow from the identical treatment method (e.g., MM status at 4+ weeks). Additionally, the clinical response (e.g., MM status at 4+ weeks) is a mechanistic property of the method and would therefore flow naturally from the method. As provided in MPEP § 2112(II), ““There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference…”. Given the above, a person having ordinary skill in the art not being able to predict one or more specific outcome(s) at the time of filing is not required, and the subject matter (e.g., MM at 4+ weeks) is considered to flow from the active steps because (1) the active steps of the instant method through week 26 are identical to the active steps of the method that taught by O’Brien, and (2) the claimed outcome(s) (e.g., week 4+ MM status) occur within the timeframe in which the instant method and that of O’Brien recite identical active method steps.
All of the Applicant’s arguments have been fully considered and were not found persuasive. The 35 USC 103 rejections claims 1-3, 7, 18, 22, 24, 26-28, 30-31, 43-44, 46, and 49 have been maintained.
Claim(s) 6, 29, and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. (WO 2017/205101 A1, published 30 Nov 2017), hereinafter “O’Brien”, in view of Summary of Product Characteristics (Soliris, Wayback Machine Archive of Alexion Pharma UK Ltd SmPC webpage, 02 Oct 2018), hereinafter “SmPC”.
Regarding claim 6, 29, and 32, which depends from claim 1 (claim 6), 27 (claim 29), or 30 (claim 32), the teachings of O’Brien as recited above apply for claims 1, 27, and 30. O’Brien does not teach body weight dosing of eculizumab.
SmPC teaches IV infusions of standardized doses (by phase) of eculizumab (Soliris) in aHUS and gMG adult subjects, as well as body weight dosing in pediatric aHUS. Although aHUS and gMG are distinct indications, the common use of eculizumab for both suggests that body weight dosing may be used in gMG as well (as the reference does not expressly teach away from body weight in gMG) [e.g., pg. 1-2, 4.2 Posology and method of administration].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of eculizumab administration in MG taught by O’Brien (Alexion Pharmaceuticals, Inc.), with the eculizumab methods of administration for taught by SmPC (Alexion Pharma UK, Ltd.), in the context of assessing potential additional methods of eculizumab administration.
This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143). Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that SmPC does not remedy the deficiencies of O'Brien acknowledged by the Office as SmPC fails to teach or suggest dosing of eculizumab to treat gMG in a subject based on body weight. SmPC discloses weight-based dosing for SOLIRIS® in the treatment of aHUS exclusively. SmPC provides no specific disclosure or even a suggestion that dosing of SOLIRIS® in gMG patients is or would be based on the weight of the subject. In fact, the SmPC clearly outlines that for patients with gMG, SOLIRIS® therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter.
The cited product label for SOLIRIS® in gMG made no mention of weight-based dosing for gMG patients. Instead, the product label for SOLIRIS® expressly requires that flat dosing, irrespective of patient weight, be used for the treatment of gMG patients. Accordingly, SmPC in fact teaches that weight was not considered a primary factor in determining optimal dosage. Unlike in the case of a nephrology indication such as aHUS, the effectiveness and safety of SOLIRIS® would not have been considered to be significantly impacted by variations in body weight within the patient population. Therefore, there is no motivation for one of skill in the art to deviate from the SmPC and instead dose-adjust the treatment regimen to be based on weight of the patient.
The Office's suggestion that SmPC would have motivated one of skill in the art to administer to the subject eculizumab based on the weight of the subject relies on impermissible hindsight reconstruction.
Neither of the cited references whether considered alone or in combination, would have provided the necessary motivation to pursue the claimed subject matter of weight based dosing as neither provides one of skill in the art any reasonable motivation to deviate from the known flat dosing regimen. Accordingly, Applicant submits that claims 6, 29, and 32 are nonobvious in view of the O'Brien and SmPC and respectfully requests the rejection be withdrawn.
Briefly, as provided in the Office Action mailed 25Mar2025 (hereinafter “FAOM”), it was acknowledged that SmPC teaches flat dosing for Soliris (eculizumab) for gMG therapy, and that the use of body weight dosing of eculizumab in another indication (aHUS) suggests that body weight dosing may be used in gMG as well because the prior art doesn’t teach away from body weight dosing. The FAOM additionally provides the context for body weight administration of eculizumab is to assess potential additional methods of administration (e.g., the motivation), and that the principle of applying a known technique (e.g., routine optimization of mAb dosing) to a known method (e.g., O’Brien’s method) to yield predictable results (e.g., dose optimization), supports a conclusion of obviousness. Additionally, a person having ordinary skill in the art (PHOSITA) would understand that monoclonal antibodies may be administered in different ways (e.g., flat dose, body weight dosing). As taught by Bai et al. (A Guide to Rational Dosing of Monoclonal Antibodies, Clin Pharmacokinet 2012; 51 (2): 119-135), it was common practice in the art at the time of filing to optimize the dosing of monoclonal antibodies (mAbs), and further it was recommended to administer mAbs with flat dosing regimen(s) first and then body weight dosing regimen(s) to determine optimal dosing for a given mAb [e.g., Abstract].
Further still, in regard to the specific dosage and interval amounts recited in the instant claims "[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), and see M.P.E.P. § 2144.05 II.A. 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). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and 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 intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious. In summary, considering the above, the FAOM rejection of claims 6, 29, and 32 is based on the art not teaching away and the common practice in the art of routine optimization, not hindsight.
The Applicant’s arguments have been fully considered and are not considered persuasive. For the reasons provided above, the 35 USC 103 rejection(s) of claims 6, 29, and 32 are maintained.
Claim(s) 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over O’Brien et al. (WO 2017/205101 A1, published 30 Nov 2017), hereinafter “O’Brien”, in view of Estruch (Neurología. 2013;28:169-78).
Regarding claim 52, which depends from claim 1, the teachings of O’Brien as recited above apply for claim 1. O’Brien does not expressly teach switching from one anti-C5 antibody or antigen binding therapy to eculizumab (an anti-C5 antibody).
Estruch reviews safety profiles and practical considerations of monoclonal antibody (mAb) treatments [e.g., pg. 1, title]. Estruch teaches general side effects of mAbs [e.g., pg. 3, table 1 and discloses that these side-effects are largely manageable [e.g., pg. 1, development]. Estruch further teaches that mAbs are proteins that behave like antigens and therefor may trigger an immune response to those antigens by generating Abs to the mAbs being delivered [e.g., pg. 6, development of neutralizing antibodies]. Two such types of mAb-response Abs have been described: the first type doesn’t impact the pharmacological properties of the drug; the second includes neutralizing antibodies (NAb) which can decrease and even eliminate the drug’s effects [e.g., pg. 6, development of neutralizing antibodies]. The development and percentage of patients with NAb varies as it is specific to a given therapeutic mAb (e.g., one mAb may result in NAb in a patient while another mAb for the same target antigen may not) [e.g., pg. 6, development of neutralizing antibodies].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by O’Brien, with the possible NAb-mediated side effects (e.g., eliminating mAb effects) taught by Estruch, and determine that a prospective patient may have failed one or more antibody therapies (e.g., due to NAb), thereby arriving at the instant invention allowing a patient to switch from a previous mAb antibody or antigen binding fragment thereof to another (e.g. from and anti-C5 mAb to eculizumab), in the context of treating MG with mAbs.
This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143). Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that the Office acknowledges that O'Brien does not expressly teach switching from one anti-C5 antibody or antigen binding therapy to eculizumab, but argues that Estruch allegedly teaches general side effects of mAbs, and thus, one of skill in the art could determine that "a prospective patient may have failed one or more antibody therapies (e. g., due to NAb), thereby arriving at the instant invention allowing a patient to switch from a previous mAb antibody or antigen binding fragment thereof to another" Office Action, page 9. Applicant respectfully disagrees with the Office's rejection in view of the arguments set forth above with respect to the deficiencies of O'Brien. Applicant contends that Estruch fails to remedy the deficiencies of O'Brien as Estruch is entirely silent with respect to weight based dosing for treating gMG.
Briefly, O’Brien is not considered deficient in the manner(s) claimed by Applicant arguments for the reasons provided above (as arguments and response thereto are the same, please see above for details). Rather, regarding instant claim 52, O’Brien was used to teach a method of treating gMG in a patient in need thereof comprising administering a therapeutically effective amount of eculizumab to the patient and associated active steps thereof (see 35 USC 103 rejection of claim 1 above for details), but O’Brien did not expressly teach switching from one anti-C5 antibody or antigen binding therapy to eculizumab (an anti-C5 antibody). To cure this deficiency, Estruch was used to teach rational to modify the method of O’Brien for treating gMG to include that gMG patients may have failed a previous anti-C5 antibody therapy and may benefit by switching to another anti-C5 antibody such as eculizumab (see 35 USC 103 rejection above for details).
Applicant arguments have been fully considered and are not found to be persuasive. The 35 USC 103 rejection of claim 52 has been maintained.
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.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643