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 .
Status of the Claims
Claims 1-8 and 18 are pending in the application and are the subject of this office action.
Claim Rejections - 35 USC § 112(a)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-8 and 18 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 written description requirement. The claim(s) contains 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP lists factors that can be used to determine if sufficient evidence of possession
has been furnished in the disclosure of an application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art.
Claim 1 recites “a method for identifying a patient having a complement-mediated disease as likely to benefit from treatment with a Factor D inhibitor”.
Claim 1 encompasses identifying a patient who would benefit from a treatment wherein the patient may have any “complement-mediated disease” which is a very broad genus including a diverse array of conditions, as indicated by the instant specification which lists numerous complement-mediated diseases at Pg. 6-8.
In contrast to the broad genus encompassed by each independent claim, the specification provides specific description and reduction to practice for very limited species, and does not provide or establish evidence of predictability of results across the genus of complement-mediated diseases. Such predictability is not provided by the prior art, which does not establish a predictable relationship between observed reduction of C5b-9 deposition ex vivo and efficacy of treatment across the whole genus of complement-mediated disease.
For example, while many complement-mediated diseases are associated with a lack of regulation and overactivity of the complement system, some diseases are associated instead with a deficiency of the complement system (wherein these diseases are understood to fall within the genus of complement-mediated disease insofar as they are specifically mediated and known to be associated with particular deficiencies of the complement system). For example, Lewis et al (Meningococcal disease and the complement system. Virulence. 2014 Jan 1;5(1):98-126.) teaches that recurrent meningococcal infection is particularly associated with and mediated by complement deficiency (Abstract; Introduction), wherein such complement deficiency makes a subject more vulnerable to infection with Neisseria meningitidis in particular (Abstract; Introduction), such that further suppression of the complement system and decreased deposition of C5b-9 would not be expected to be predictably beneficial in patients with this complement-mediated disease.
Further, there are many diseases which are considered complement mediated, but for which the specific complement associated pathological mechanisms are unclear, and as such in these diseases there is not an established or predictable relationship between the level of deposition of C5b-9 and pathology or treatment outcomes, since the role of C5b-9 in the pathology is unclear. For example, see Table 1 of Brandwijk et al (Pitfalls in complement analysis: A systematic literature review of assessing complement activation. Front Immunol. 2022 Oct 18;13:1007102) which teaches the following regarding Parkinson’s Disease: “PD is characterized by dopamine deficiency at the basal ganglia and deposition of a-synuclein that forms Lewy bodies. However, the exact neuropathologic mechanisms remain elusive. Studies regarding the role of complement in PD are controversial. Some reported the involvement of the classical complement pathway by recognizing anti C3d, C4d, C7, and C9 antibodies in the substantia nigra or by the aggregation of iC3b and C9 in Lewy bodies of PD patients. Other studies failed to correlate complement activation with cortical Lewy Bodies. Clusterin and complement C1r were decreased compared to controls and have been proposed as useful biomarkers of disease progression”. And further teaches the following regarding hypocomplementemic urticarial vasculitis syndrome (HUVS): “exact pathophysiology is unknown. Rare immune complex mediated small vessel vasculitis characterized by urticaria, hypocomplementemia (low C1q, C3, and C4), and systemic manifestations, and it is also associated with circulating anti-C1q autoantibodies”. Wherein one of ordinary skill in the art cannot conclude from these teachings of the art that at the time of filing there was a predictable or consistent relationship between levels of C5b-9 deposition and efficacy of treatment for all members of the genus of complement mediated disease.
Examples provided in the specification which reflect the method steps of claim 1 discuss only a single type of complement-mediated disease (APS) (i.e. serum from a patient with APS/catastrophic APS), a single type of GPI-AP deficient cell (PIGA-null TF-1 cells), a single type of terminal complement inhibitor (anti-C5 mAb eculizumab), and a single type of Factor D inhibitor/APC inhibitor (ACH-4471) (see Specification, Pg. 4, Ln. 20-Pg. 5, Ln. 13; Pg. 19, Ln. 26-Pg. 20, Ln. 7; Pg. 17, Ln. 11-24). The specification further indicates that the cohort of patients studied may not be fully representative of APS, much less of the entire range of complement-mediated diseases encompassed by the instant claims (Pg. 27, Ln. 15-17: limitations of the described study include that a highly selected group of patients who were referred to tertiary care centers that may not be fully representative of all APS patients was evaluated).
The specification further does not provide reduction to practice or specific data on treatment of complement mediated diseases which links observed trends in C5b-9 deposition measured by flow cytometry with beneficial outcomes in patients with any complement-mediated disease.
Accordingly, given the breadth of the claims, the lack of predictability in the art, and the limited disclosure and reduction to practice provided in the application, the specification fails to describe a representative number of species to support the methods as claimed. While the dependent claims (claims 2-8 and 18) provide some further limitation, they do not limit the claims sufficiently such that the scope of the claims aligns with what is supported and disclosed by the specification, and notably none of the dependent claims limits the genus of complement mediated disease.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 depends from claim 1. However, claim 18 which is directed to a method of treating a patient identified using the method of claim 1 does not further limit the method of claim 1 itself. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The claims recite an abstract idea (i.e. the step of identifying a patient as likely to benefit from treatment amounts to drawing a conclusion based on gathered data, a mental step/abstract idea).
The judicial exception is not integrated into a practical application because the claim as a whole is directed to the judicial exception itself (i.e. identifying a patient), and all actively recited method steps of independent claim 1 are performed in support of that judicial exception. The limitations of dependent claims 2-8 provide further limitation on the assays performed and reagents used in claim 1, but do not serve to integrate the judicial exception into a practical application.
The claims as a whole do not amount to significantly more than the judicial exception because all additional limitations of the claims and all actively recited method steps of the claims amount to necessary data-gathering in support of the judicial exception (i.e. in the methods of claim 1, one cannot perform the judicial exception (drawing a mental conclusion about whether a subject would benefit from a treatment) without performing the method steps (a)-(c) and evaluating the data obtained from these steps). As such, these limitations of the claims amount to necessary data gathering activities required for implementing the judicial exception, wherein steps which amount to data gathering in conjunction with a judicial exception are considered to be adding insignificant extra-solution activity to the judicial exception, and are not considered enough to qualify as “significantly more” when recited in a claim with a judicial exception. See MPEP 2106.05(g). The additional limitations of the dependent claims serve only to limit the reagents and conditions of the data gathering steps and therefore are also insufficient to amount to significantly more than the judicial exception.
Therefore, claims 1-8 as a whole do not amount to significantly more than the judicial exceptions when the claim elements are considered individually or in combination.
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.
Claims 1-8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Galbusera et al (US 2020/0057046 A1; previously cited) in view of Brodsky et al (US 2018/0246082 A1; previously cited), as evidenced by Yuan et al (Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica. 2017;102(3):466-475.; IDS entered).
Regarding claims 1-8, and 18, Galbusera teaches a method for identifying a patient having a complement mediated disease as likely to benefit from a treatment (Abstract): comprising the steps of:
Performing assays, wherein each of the assays comprises: incubating serum obtained from a patient with a plurality of disease relevant cells; staining the cells with an anti-C5b9 monoclonal antibody, and measuring C5b9 deposition on the cell membrane (Par. 6-19, 89).
Galbusera further teaches that the assays performed may comprise a control assay (i.e. similar to instant assay (a), wherein serum and cells are incubated in the absence of any therapeutic) and an assay performed to assess the efficacy or likelihood of efficacy of a particular treatment which may include an assay which comprises incubation of patient serum with a terminal complement inhibitor such as eculizumab (i.e. instant assay (b)) (Par. 10-11; Par. 175-190) and an assay which comprises incubation of patient serum with a different therapeutic that in some way inhibits C5 (i.e. instant assay (c)) (Par. 10-11; Par. 175-190; Par. 131, 133).
Galbusera teaches that the disclosed methods may be used to assess whether a patient would be likely to benefit from treatment with eculizumab, and/or whether a patient would be likely to benefit from treatment with a different inhibitor of C5 (wherein an inhibitor of C5 as defined by Galbusera would encompass a Factor D inhibitor and/or and APC inhibitor) (Par. 131: suitable inhibitors of human complement component C5 for use in the methods described herein can include any inhibitor or any molecule that binds to or otherwise blocks the generation of C5b-9 and/or activity of C5; Par. 133: in some embodiments, the inhibitor inhibits formation or assembly of the C3 convertase and/or C5 convertase of the alternative and/or classical pathways of complement).
Galbusera teaches that the disease-relevant cells on which C5b-9 deposition is measured can include a variety of different cells types including endothelial cells and erythrocytes and teaches that the complement-mediated disease of interest may be any of a wide variety of complement-mediated diseases (Par. 76-77, 80).
Galbusera teaches that a measured reduction in C5b9 deposition on the treated cells (i.e. assays (b) and (c)) as compared to the control cells indicates that the patient from whom the sample was taken is likely to benefit from the tested treatment (Par. 104, 116).
Though Galbusera does not explicitly teach the exact combination of instantly claimed assays (a), (b), and (c) in claim 1, (i.e. Galbusera teaches one method for evaluating C5b-9 deposition with and without the addition of eculizumab and another method for evaluating C5b-9 deposition with and without the addition of a different C5 inhibitor) it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform these assays in the specifically claimed combination. One of ordinary skill in the art would be motivated to make this modification in order to compare C5b-9 deposition and results of a known and approved treatment such as eculizumab with C5b-9 deposition and results of different or newer therapeutics in order to evaluate their comparative efficacy or promise as treatments of complement mediated disease. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Galbusera teaches methods of evaluating C5b-9 deposition with and without the addition of a terminal complement inhibitor such as eculizumab and methods of evaluating C5b-9 deposition with and without the addition of a different inhibitor of C5.
Galbusera differs from the instant claim in that it does not specifically teach that the disease relevant cells are GPI-AP deficient cells; that C5b-9 deposition is measured by flow cytometry; or that the non-eculizumab C5 inhibitor is specifically a Factor D inhibitor (claim 1).
Regarding claim 18, Galbusera further teaches that once a patient having a complement-associated disorder is identified (by a reduction in C5b-9 deposition) as being likely to benefit from treatment with a particular inhibitor of C5 using the disclosed methods, that treatment may be administered to the patient for treatment of the disease (Par. 116-117).
Brodsky discloses compositions and methods useful for diagnosing disorders of the complement system (Abstract).
Brodsky further teaches that the methods may comprise measurement of C5b-9 deposition on GPI-AP/disease relevant cells after exposure to a serum sample from a patient with a complement-mediated disease, and teaches that the cells use may comprise either PIPLC-treated endothelial cells (i.e. chemically treated to remove GPI-AP, claim 2) (Par. 80) or cells of a PIGA null mutant cell line (i.e. PIFA-null TF-1 cells, Par. 82), wherein such measurement is conducted via flow cytometry (Par. 68).
Brodsky teaches that the disclosed methods can be used to identify patients who should be treated with a complement inhibitor, wherein the complement inhibitor may comprise a Factor D inhibitor such as ACH-4471 (Par. 14).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Galbusera to comprise the use of GPI-AP deficient cells such as PIPLC-treated endothelial cells or PIGA-null TF-1 cells, as taught by Brodsky. Galbusera teaches the disclosed method may be performed with any disease-relevant cells, wherein the cells may comprise endothelial cells, while Brodsky teaches specific types of disease-relevant endothelial cells on which deposition of C5b-9 may be measure (wherein GPI-AP deficient cells such as those taught by Brodsky are understood to be disease-relevant to the method of Galbusera in that GPI-AP deficiency is a common component of complement-mediated disease). As such, substitution for the cells taught by Galbusera for the cells taught by Brodsky amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Galbusera to comprise the use of flow cytometry to measure the deposition of C5b-9, as taught by Brodsky. The methods of both Galbusera and Brodsky comprise measuring C5b-9 deposition by staining the cells with an antiC5b-9 antibody and a detectable fluorescent label and quantifying deposition by measuring the fluorescent label such that substitution for the flow cytometry method of Brodsky for the detection methods taught by Galbusera amounts to simple substitution of known methods to achieve predictable results with a reasonable expectation of success.
Further, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Galbusera such that the alternative C5 inhibitor tested in addition to eculizumab comprised a Factor D inhibitor such as ACH-4471, as taught by Brodsky. Galbusera teaches that the disclosed methods can be used to evaluate the efficacy of any treatment which inhibits C5 in any way (Galbusera Par. 131, 133), which would include a Factor D inhibitor such as ACH-4471. Brodsky teaches that a similar method can be used to evaluate the suitability of a number of different complement inhibitors, and explicitly includes the Factor D inhibitor ACH-4471. One would be motivated to use a Factor D inhibitor such as ACH-4471, because this inhibitor acts upstream of the anti-C5 antibody eculizumab, and therefore may have different therapeutic results and impacts, such as the potential to avoid or reduce extravascular hemolysis resulting from C3 fragment deposition in patients treated with eculizumab, as evidenced by Yuan (Abstract; Pg. 467, Col. 2, Par. 2; Pg. 470, Col. 2, last Par.-Pg. 471, Col. 1, first Par). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the specific species of Factor D inhibitor taught by Brodsky falls within the genus of C5 inhibitors disclosed by Galbusera.
Response to Arguments
Applicant’s arguments filed 9 February 2026 have been fully considered.
Prior objections to the specification are withdrawn in view of the amendments to the specification.
Regarding the 112(a) rejections of claims 1-8 and 18, Applicant argues that the claims are not directed to treating a patient having any complement-mediated disease and are instead directed to identifying a patient who would benefit from treatment with a Factor D inhibitor. This argument is not persuasive to overcome the rejection because, as discussed in the rejection above, the application as originally filed does not provide sufficient evidence to prove that the inventor had possession of the full scope of the invention claimed. That is, the evidence provided in the application does not support that a practitioner could use the claimed method to reliably identify a patient with any complement mediated disease who would benefit from treatment with a Factor D inhibitor. The 112(a) rejections of claims 1-8 and 18 are maintained.
Applicant’s arguments regarding the prior rejection of claim 5 under 112(b) are persuasive in view of the amendment of the claim, and the 112(b) rejection is withdrawn.
Regarding the 112(d) rejection of claim 18, applicant argues that claim 18 further limits the method of claim 1 by adding a treatment step. This argument is not persuasive because claim 18 is presented as a separate method of treatment that depends from the method of identification of claim 1. The step of treating a patient within a separate method of treatment does not further limit the method of identification of claim 1. The rejection is maintained.
Regarding the 101 rejections, applicant argues that the method steps provided in the claim are sufficient to comprise “significantly more” than the judicial exceptions recited in the claims. This argument is not persuasive because all additional elements of the claim provided in addition to the judicial exception amount to mere data gathering in support of the judicial exception. That is, the claims are directed to the judicial exception of drawing a conclusion about whether a patient is likely to benefit from a treatment (i.e. an abstract idea) and all the actively recited method steps are performed in order to gather the data used to draw that conclusion, and therefore do not amount to significantly than the judicial exception.
Regarding the 103 rejection, applicant argues that Galbusera does not sufficiently teach that one would use both an assay using eculizumab and an assay that would use a Factor D inhibitor, and that Brodsky and Yuan do not cure this deficiency. This argument is not persuasive because this point is addressed in the 103 rejection and Applicant’s arguments do not specifically address or rebut the rationale of the rejection. The 103 rejections of claims 1-8 and 18 are maintained.
Conclusion
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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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677