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 .
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.
Election/Restrictions
Applicant’s election without traverse of the species 1. First marker, EV associated protein: CD9, 2. Second marker, tissue specific EV associated protein: PODXL, 3. Complement system associated component/protein: iC3b, 4. Disease: IgA Nephropathy (IgAN), in the reply filed on 02/27/2026 is acknowledged.
Claim 50 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention (component that is not iC3b, as elected), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/27/2026.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2021/032241, filed 05/13/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/025,557, filed 05/15/2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed 05/08/2024 is considered, initialed and is attached hereto.
Drawings
The drawings are objected to because Figures 9(A) and 9(B), recite at the x-axis “IgGN” (also IgGN1 and IgGN2). The specification makes no reference to IgGN, it appears that this could be a typographical error (that it should be recited as IgA, see para [0053], which refers to LN and IgA). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
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.
Scope of Enablement
Claims 46-49 and 51-60 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for diagnosis of a complemented-mediated disease in a subject that is IgA nephropathy, the method comprising obtaining a urinary sample comprising extracellular vesicles (EV), contacting a portion of sample with first antibody or antigen binding fragment thereof to capture a first marker that is CD9, contacting a portion with at least a second capture antibody or antigen-fragment thereof to capture at least one second marker on the EVs that is PODXL, and contacting the captured EVs (or membrane bound portions thereof) with at least one detection antibody or an antigen-binding fragment thereof specific for a complement associated component, wherein the component is the protein iC3b, does not reasonably provide enablement for methods for diagnosis or prognostic assessment of a complement mediated disease in a subject (claim 46) or for monitoring response to treatment of a complement mediated disease with a complement modulator (claim 47), wherein the disease is selected from any of those nephrological diseases (atypical haemolytic uraemic syndrome (aHUS), C3 glomerulopathy (C3G), dense deposit disease (DDD), membranoproliferative golumerular nephritis (MPGN), lupus nephritis (LN), IgA nephropathy (IN), lupus nephritis (LN), membranous nephropathy (MN), complications due to hemodialysis in transplant patients, antibody mediated rejection (AMR) and anti-neutrophil cytoplastmic antibody (ANCA) associated vasculitis) and/or heamtological diseases (paroxysmal nocturnal hemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS), secondary HUS due to solid organ transplant or hematopoietic stem cell transplants, Thrombotic microangiopathy (TMA), and cold agglutinin disease (CAD), recited at the claims (claims 46, 47), the method comprising any combination of first and second marker species (or in any sample, with any combination of the claimed first and second markers, and complement protein).
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is "undue" include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
As noted above, Applicant’s elected species are first marker, EV associated protein: CD9, second marker, tissue specific EV associated protein: PODXL, complement system associated component/protein: iC3b, and disease: IgA Nephropathy (IgAN). However, although Applicant’s election correlates the detection of CD9, PODXL and complement component iC3b with the disease/diagnosis IgAN, the claims as recited broadly encompass correlation of any of the claimed complement component proteins with any of the claimed diseases.
The claims (particularly independent claims) broadly encompass any sample, any combination of first and second marker, and complement component that is a protein, and further any nephrological diseases (atypical haemolytic uraemic syndrome (aHUS), C3 glomerulopathy (C3G), dense deposit disease (DDD), membranoproliferative golumerular nephritis (MPGN), lupus nephritis (LN), IgA nephropathy (IN), lupus nephritis (LN), membranous nephropathy (MN), complications due to hemodialysis in transplant patients, antibody mediated rejection (AMR) and anti-neutrophil cytoplastmic antibody (ANCA) associated vasculitis) and/or heamtological diseases (paroxysmal nocturnal hemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS), secondary HUS due to solid organ transplant or hematopoietic stem cell transplants, Thrombotic microangiopathy (TMA), and cold agglutinin disease (CAD), recited at the claims (claims 46, 47, 50).
Regarding the state of the prior art relative to Applicant’s elected species, the prior art recognized that complement system is known to be involved in a wide spectrum of renal diseases including antibody-related glomerulopathies, IgAN recognized as the most common glomerulopathy (Andrighetto et al., Complement and Complement Targeting Therapies in Glomerular Diseases, International Journal of Molecular Sciences, 20, (2019), (15 pages), see at abstract and page 4, last paragraph).
Further, it is known in the prior art that that both the alternate pathway and the lectin pathway are involved in IgA nephropathy, that accumulation of iC3b is a result of complement activation through the alternate pathway (see Maillard et al., Current Understanding of role of Complement in IgA Nephropathy, J. Am. Soc. Nephrol., 26, (2015), p. 1503-1512, e.g., abstract and col. 3, paragraph 3).
Further, regarding complement protein detection and diagnosis of disease, the art (not specific to EV related protein detection) recognized for example, C5b-9 tends to be higher in C3GN (C3 glomerulonephritis) than in DDD (dense deposit disease), however the prior art teaches while C5a and C5b-9 levels may provide a hint in the differential diagnosis between these two diseases, they cannot replace the diagnostic role of renal biopsy (see Angioi et al., Diagnosis of complement alternative pathway disorders, Kidney International, 89, (2016), p. 278-288, at page 282, co1. 1, second to last paragraph). Angioi supports the unpredictability in the prior art related to relying on any one given complement protein for diagnostic accuracy. Further, while C5b-9 levels may be recognized as associated with some species of disease as recited (namely C3GN and DDD), there is nothing that supports the detection of these specific component proteins in relation to other diseases as listed in the claims, or for other complement proteins specific to these diseases
For example, also referring to Angioi, see at page 281, col. 2, para 5, low C3 is taught as found in a substantial number of patients with C3GN, DDD, and atypical postinfectious glomerulonephritis and in some (30-50% patients) with aHUS (a species in the claimed invention), TTP and STEC-HUS (not elevated levels as claimed).
The level of skill in the art is high, as the claimed methods are directed to/involve assay comprising the detection of a combination of 3 markers, one of the markers a component protein marker, in relation to disease. It is not readily predictable that any combination of first, second and detection marker would result in diagnosis of any of (or any combination of) the claimed diseases, or be capable of prognostic assessment of any one of (or any combination of) the claimed diseases.
Even further, regarding the breadth of the claims, in addition to the independent claims being unlimited in terms of the combination of markers and a particular disease, the claims (at least independent claims 46 and 47) are not limited to any particular sample.
Additionally, regarding predictability and Applicant’s actual reduction to practice/the working examples and data provided at the originally filed specification, support that it is not just any combination of detected markers and complement component proteins results in diagnosis of any of the claimed nephrological diseases and/or hematological diseases. See for example, results reported at para [0051], Figure 7, Applicant reports identification of Glomerulus-specific EV, that PODXL can be detected in EV containing CD9 (Applicant’s elected species of first marker) or CD40L, but not CD63 or CD81, see also results referenced at para [0052], Figure 8.
At para [0053], Figure 9, Applicant reports data showing measurement of complement on EV membranes, that C3c and C5b-9 are detected in LN patient urine on both CD9+ and PODXL+ beads, but not CD63+ or CD81+.
Applicant’s own data does not support, for example, the combination of any markers for any of the claimed diseases, for example not CD63+ or CD81+ expressing EVs.
Regarding Applicant’s election of iC3b, at para [0254], Applicant report that in one study, urinary EVs were obtained from healthy volunteers, LN and IgAN patients, that EVs were enriched with a panel of capture beads and then surface phenotyped in duplicate wells using biotinylated-mCLING or complement iC3b using Quidel antibody A710, Applicant indicates Figure 12 as representative of normalized EV data for iC3b (para [0254]). Only Figure 12 supports the positive markers CD9 and PODXL as positively correlating with increased normalized iC3b (see para [0256]).
None of the data or actual reduction to practice provided in the originally filed specification support correlation of any other combination of markers with iC3b for diagnosis or prognostic assessment of patients with any other diseases other than LN and IgAN. Even further, while this data correlates the detection of the elected combination with LN or IgAN, none of the data or examples demonstrate the ability to provide prognostic assessment (nor is there any indication as to what is or is not encompassed by the broadly recited language “prognostic assessment”).
There is insufficient direction or guidance in the originally filed specification regarding how to make and use the claimed invention for diagnosis or prognostic assessment, for monitoring response to treatment of a complemented mediated disease with a complement modulator, for detecting complement activation in a subject’s kidney disease, based on any combination of the recited first (EV-specific) and second (tissue specific) marker, and complement system associated component, that is a protein selected from C3, C5b-9, C4, Clq, C3, C3b, iC3b, TF, CRP, pCRP, MAC, CD59, CD55, CR1, C5aR1 and C5a (claim 58).
Regarding limitations directed to the “prognostic assessment”, it is not readily clear what is an is not encompassed by this limitation. However, when given broadest reasonable interpretation, this limitation appears to encompass, for example, predicting future outcome. There are no working examples or data to support the ability to rely on the claimed combinations of markers for prediction of future outcomes (which would include, for example, predicting future outcomes in those who are not known to have/don’t have disease as claimed).
None of the data or actual reduction to practice provided in the originally filed specification support correlation of any other combination of markers with iC3b for diagnosis or for prognostic assessment of patients with any other diseases other than LN and IgAN (other than Applicant’s elected combination in urinary EVs). Even further, while Applicant’s data correlates the detection of the elected combination with LN or IgAN, none of the data or examples demonstrate the ability to provide prognostic assessment (nor is there any indication as to what is or is not encompassed by the broadly recited language “prognostic assessment”).
Further, regarding unpredictability across the extremely broad scope (claims encompassing any combination of first, second and complement protein marker, for the long list of diseases listed at the claims) of the claimed invention, see also Applicant’s data referenced at para [0053], Figure 9(A) and (B), Applicant report both LN and IgAN samples can have, but are not limited to, C3, C5b-9, C4 and C1q deposition on both PODXL+ and AQP2+ EV compared to controls. However, referring to the figures, along the x-axis, what is shown is “IgGN” and “LN”, and IgGN shows levels comparable to what is indicated as “control” group, only C3c appears to be shown elevated greater than control levels. It does not appear readily predictable that all of these complement components serve as diagnostic, consistent with the claims.
Also notably, Applicant’s examples and figures appear relevant only to LN and IgAN, and not the other recited diseases/conditions recited at the claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Written Description
Claims 46-49 and 51-60 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 claimed methods encompass diagnosis or prognostic assessment of complement mediated disease selected from the species listed at the claims, or further monitoring response to treatment of a complement mediated disease selected from the species listed at the claims. The species in the claims are nephrological diseases (atypical haemolytic uraemic syndrome (aHUS), C3 glomerulopathy (C3G), dense deposit disease (DDD), membranoproliferative glomerular nephritis (MPGN), lupus nephritis (LN), IgA nephropathy (IN), lupus nephritis (LN), membranous nephropathy (MN), complications due to hemodialysis in transplant patients, antibody mediated rejection (AMR) and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis) and/or heamtological diseases (paroxysmal nocturnal hemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS), secondary HUS due to solid organ transplant or hematopoietic stem cell transplants, Thrombotic microangiopathy (TMA), and cold agglutinin disease (CAD). The claims encompass the detection of a first and second EV associated marker, and a third marker that is a complement protein, wherein elevation in the complement protein indicates diagnosis or future risk of developing disease.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Regarding Applicant’s actual reduction to practice, see as discussed in detail Applicant’s data and working examples is limited to those who have disease that is LN or IgAN. There is insufficient support in the originally filed specification to suggest that Applicant’s limited examples (that these particular species) extend to additional diseases and biomarker combinations as encompassed by the extremely broad claim language. The specification supports that it is not just any combination of detected markers and complement component proteins results in diagnosis of any of the claimed nephrological diseases and/or hematological diseases. See for example, results reported at para [0051], Figure 7, Applicant reports identification of Glomerulus-specific EV, that PODXL can be detected in EV containing CD9 (Applicant’s elected species of first marker) or CD40L, but not CD63 or CD81, see also results referenced at para [0052], Figure 8.
At para [0053], Figure 9, Applicant reports data showing measurement of complement on EV membranes, that C3c and C5b-9 are detected in LN patient urine on both CD9+ and PODXL+ beads, but not CD63+ or CD81+.
Applicant’s own data does not support, for example, the combination of any markers for any of the claimed diseases, for example not CD63+ or CD81+ expressing EVs.
Regarding Applicant’s election of species, namely iC3b, see further at para [0254], Applicant report that in one study, urinary EVs were obtained from healthy volunteers, LN and IgAN patients, that EVs were enriched with a panel of capture beads and then surface phenotyped in duplicate wells using biotinylated-mCLING or complement iC3b using Quidel antibody A710, Applicant indicates Figure 12 as representative of normalized EV data for iC3b (para [0254]). Only Figure 12 supports the positive markers CD9 and PODXL as positively correlating with increased normalized iC3b (see para [0256]).
None of the data or actual reduction to practice provided in the originally filed specification support correlation of any other combination of markers with iC3b for diagnosis or prognostic assessment of patients with any other diseases other than LN and IgAN. Even further, while this data correlates the detection of the elected combination with LN or IgAN, none of the data or examples demonstrate the ability to provide prognostic assessment (nor is there any indication as to what is or is not encompassed by the broadly recited language “prognostic assessment”).
See also Applicant’s data referenced at para [0053], Figure 9(A) and (B), Applicant report both LN and IgAN samples can have, but are not limited to, C3, C5b-9, C4 and C1q deposition on both PODXL+ and AQP2+ EV compared to controls. However, referring to the figures, along the x-axis, what is shown is “IgGN” and “LN”, and IgGN shows levels comparable to what is indicated as “control” group, only C3c appears to be shown elevated greater than control levels. It does not appear readily predictable that all of these complement components serve as diagnostic, consistent with the claims.
Regarding the state of the prior art, the prior art recognized that complement system is known to be involved in a wide spectrum of renal diseases including antibody-related glomerulopathies, IgAN recognized as the most common glomerulopathy (Andrighetto et al., Complement and Complement Targeting Therapies in Glomerular Diseases, International Journal of Molecular Sciences, 20, (2019), (15 pages), see at abstract and page 4, last paragraph).
Further, it is known in the prior art that that both the alternate pathway and the lectin pathway are involved in IgA nephropathy, that accumulation of iC3b is a result of complement activation through the alternate pathway (see Maillard et al., Current Understanding of role of Complement in IgA Nephropathy, J. Am. Soc. Nephrol., 26, (2015), p. 1503-1512, e.g., abstract and col. 3, paragraph 3).
However, it is not readily predictable that any combination of first and second marker, and complement protein is diagnostic for any of those diseases/conditions as recited at the claims.
The claim scope is extremely large (regarding the combination of the EV markers and complement protein, and correlation the disease/condition), and in comparison, the description provided at the originally filed specification is extremely narrow. The limited species/combinations disclosed fails to extend and provide support that Applicant was in possession of the entire scope of the claimed method, the limited species do not represent the full scope of the claimed invention.
In conclusion, there is insufficient evidence to support that Applicant was in possession of the full scope of the methods as presently claimed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 46-60 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 46 recites “prognostic assessment”, prognostic generally meaning to predict the likely outcome. It is not readily clear what is and is not encompassed by the limitation “prognostic assessment”, for example, it is unclear if this limitation encompasses future outcome of those with and without disease (i.e., healthy subjects), or if this has to do with future diagnosis or merely just worsening disease (in those already diagnosed). The specification fails to indicate what is meant or encompassed by the terminology “prognostic assessment”.
Claim 46 recites at step (e) “simultaneously detecting…the detection antibody”, the claim language is indefinite because it is unclear if the claim is intended as meaning that all of the contacting/detecting steps a performed simultaneously, or if just steps (d) and (e) are performed simultaneously, or rather if “simultaneously” is referring to some other step/action is to be performed with the “detecting” step of (e). See also this limitation recited at claim 47 (step e).
Claims 46, 47 and 53 each recite the language “extracellular vesicle (EV) or a membrane-bound portion thereof”, the language is indefinite because a membrane bound portion of an EV does not appear to be distinct from an EV (both would be considered EVs).
Claims 46 recites at step (e), “wherein an elevation in the presence or level of the component”; however, the claim language is indefinite because it is not clear how “elevation in presence” is distinct from “elevation in level”, since an elevation in the presence of something appears to be referring to its amount, i.e., level.
Similarly, claim 47 recites at step (e), “an attenuation in the presence or level”, which one given broadest reasonable interpretation, is considered to mean a reduction in the presence or level. A reduction in presence, similarly to above with “elevation in presence”, appears to refer to a change in amount, which would be considered a level. As a result, the language is similarly indefinite because it is not clear how “an attenuation is presence” is distinct from “an attenuation in level”.
Claim 48 recites the limitation "a complement mediator" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 48 recites “the complement mediator is a ..”, and claim 48 depends from claim 47, however, neither claim previously refers to “a complement mediator”. Rather, claim 47 only recites the limitation “a complement system-associated component”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 59 recites the broad recitation “tetraspanins”, and the claim also recites “CD9” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Specifically, claim 59 recites “the first marker is selected from the group consisting of…” and the list includes, for example “CD9” and “tetraspanins”. The claim is indefinite because CD9 is a species of tetraspanin (see for example, as evidence, Brosseau et al., CD9 Tetraspanin: A New Pathway for Regulation of Inflammation, Frontiers in Immunology, 9(Article 2316), (2018), 12 pages).
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677