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 .
Election/Restrictions
Claims 1 and 2 have been amended in the Response filed 14 November 2025.
Applicant’s election of Group I and the species of: serum, Alzheimer’s disease, quantitative mass spectrometry, both peptides of claim 7, and a monoclonal anti-beta synuclein antibody couples to carboxylates paramagnetic beads; in the reply filed on 14 November 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 9-10 and 13-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or inventions, there being no allowable generic or linking claim.
Claims 1-8 and 11-12 are examined upon their merits.
Priority
This application is the national stage entry of PCT/EP2020/072559 filed 12 August 2020, and claiming the benefit of European Patent EP19191213.8 filed on 12 August 2019.
Claims 1-8 and 11-12 have an earliest effective US filing date of 12 August 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 14 February 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Sequence compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825. Specifically, no sequence identification has been provided for the amino acid sequence presented in Figure 1 and Table 2 of the instant specification. In case these sequences are new, Applicant needs to provide a substitute computer readable form (CRF) copy of a "Sequence Listing" which includes all of the sequences that are present in the instant application and encompassed by these rules, a substitute paper copy of that "Sequence Listing", an amendment directing the entry of that paper copy into the specification, and a statement that the content of the paper and computer readable copies are the same and, where applicable, include no new matter, as required by 37 C.F.R. § 1.821 (e) or 1.821(f) or 1.821(g) or 1.825(b) or 1.825(d). The instant specification will also need to be amended so that it complies with 37 C.F.R. § 1.821(d) which requires a reference to a particular sequence identifier (SEQ ID NO: ) be made in the specification and claims wherever a reference is made to that sequence. See M.P.E.P. 2422.04.
Claim Rejections - 35 USC § 112
Claims 3, 5-9 and 12 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.
Regarding claims 3 and 5-9, the phrases "preferably", “more preferably” and “even more preferably” render the claims indefinite because it is unclear whether the limitation(s) following the phrase(s) are part of the claimed invention. These recitations are further indefinite when the claim recites “preferably” followed by “or alternatively” language. It is unclear what limitations are the alternatives if some are preferred or “even more preferred” over others. See MPEP § 2173.05(d).
Claim 12 is indefinite wherein it recites, “the method is used for discriminating ... Alzheimer’s disease”. MPEP 2173.05(q) states: “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986. Although a claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. See In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975), which discuss the premise that one cannot rely on the specification to impart limitations to the claim that are not recited in the claim.” Claim 12 is indefinite because it recites the method is “used for discriminating” but fails to provide those method steps whereby, the instantly-elected, Alzheimer’s disease is actually differentially diagnosed or discriminated over the other diseases. For purposes of applying prior art, this claim will be interpreted as an intended use of the method of claim 1 comprising determining the concentration of β-synuclein in a sample of a patient, wherein the sample of the patient does not consist of cerebrospinal fluid.
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 and 11-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) diagnosis, determining, which are mental process abstract ideas (MPEP 2106.04(a)(3)), and a natural law/phenomenon/correlation whereby the inherent concentration of beta-synuclein in a sample from a patient is associated with “diseases associated with synaptic degeneration”. This judicial exception is not integrated into a practical application because none of the considerations for integration (see MPEP 2106.05(a-c), (e) and (h)) are present within the additional elements of the claim. Further, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps/elements were well-known, routine and conventional activities in the art prior to filing.
The claims are directed to a method, which is one of the statutory categories of invention (STEP 1:YES). The claims recite a method of diagnosis of a disease or diseases associated with synaptic degeneration, the method comprising determining the concentration of β-synuclein in a sample of a patient, wherein the sample of the patient does not consist of cerebrospinal fluid. The MPEP defines “Mental processes” as “concepts performed in the human mind (including an observation, evaluation, judgment, opinion)”. In this way the “diagnosis” and “determining” of the claim are mental process judicial exceptions. The claims further recite a natural correlation/phenomenon/law whereby the inherent concentration of beta-synuclein in a sample from a patient is associated with “diseases associated with synaptic degeneration” (MPEP 2106.04(b)). Thus, the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
According to Step 2A, Prong Two, the claims are next evaluated with respect to whether the judicial exception(s) is/are integrated into a practical application. This analysis turns to the additional elements recited within the claim. There are no additional steps/elements in claim 1 other than an implicit step of obtaining a sample that is not cerebrospinal fluid. “Determining” in the claims is recited at a high level of generality so as to read upon any means of determining a concentration of β-synuclein, including reading data from a medical chart.
There are no additional elements that reflect any improvement within the technical field (i.e. any new antibody or methodology); there are no additional elements that apply the natural correlation/phenomena judicial exception to any particular treatment or prophylaxis. While depending claim 7 recites “preferably wherein the determination of the concentration of β-synuclein is carried out by means of multiple/selected reaction monitoring or parallel reaction monitoring, even more preferably by measuring the peptides of aa 46 to 58 (EGVVQGVASVAEK (SEQ ID NO: 2)) and/or 61 to 85 (EQASHLGGAVFSGAGNIAAATGLVK (SEQ ID NO: 3)) of β-synuclein, this does not limit the method to a particular machine. There are no additional elements that effect a transformation; and there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, disease associated with synaptic degeneration. In this way the claims, as a whole, amount to nothing more than a drafting effort designed to monopolize the natural correlation itself. ((STEP 2A, Prong Two: NO).
As stated above determining is recited at a high level of generality so as to encompass any means for determining the concentration of beta-synuclein in a sample other than CSF. In accordance with Berkheimer Memo III.A.1, in the specification indicates that the additional elements are sufficiently well-known that the specification does not need to describe the particulars thereof. In other words, the disclosure describes no new technology, but merely refers to techniques and elements that were known in the art at the time of filing.
While the broadest claims do not require any specific methodology, Applicant has elected the methodology of quantitative mass spectrometry for depending claim 7, but this was well-established in the art prior to filing. The following prior art teaches it was well-established in the art prior to the effective filing date of the application that the specific epitope of peptides 46 to 58 of beta-synuclein (EGVVQGVASVAEK; SEQ ID NO: 2 of the instant claims) was known to be a biomarker for brain damage in hemorrhagic stroke patients (see Table 3, Martinez-Morillo et al., J of Proteome Research, 13: 969-981, 2014). Also methods comprising determining the concentration of β-synuclein by quantitative mass spectrometry in the context of Alzheimer’s disease (Oeckl et al., 2016 cited on the IDS filed 14 February 2022), albeit in CSF samples. Thus, in accordance with Berkheimer Memo III.A.III. the examiner cites publications within the field of technical expertise, that demonstrate the well-understood, routine, conventional nature of the additional element(s). Therefore, the steps/elements recited in addition to the judicial exception were all well-understood, routine, conventional activities in the field of Neurology prior to filing the application at hand (STEP 2B: NO). The claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to data-gathering or mere observation of the natural phenomenon itself, by any means known, with the words “apply it” in order to append it to the field of synaptic degeneration and, specifically, to Alzheimer’s disease.
For all of these reasons, Claims 1-8 and 11-12 are directed to the judicial exception without significantly more and are rejected.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-4, 7-8 and 11-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sriwimol et al., Hindawi BioMed Res Internatl, Vol. 2018, Article ID 4503871, 7 pages.
It should be noted that the instant specification fails to explicitly define “diseases associated with synaptic degeneration”. Rather, the specification discloses preferred embodiments but these are not limiting definitions. The court in Merck KGaA v. Integra LifeSciences Ltd, 50 USPQ2d 1846 (DC SCalif, 1999) held that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discover of a particular property of the material used in the process.
Regarding claim 1, the Sriwimol et al. reference teaches determining the concentration of β-synuclein in a sample of a patient, wherein the sample of the patient does not consist of cerebrospinal fluid. Specifically, Sriwimol discloses measurement of plasma 𝛽-Synuclein levels by double-antibody sandwich ELISA, using commercial kits according to the manufacturers’ instructions (Human Beta-Synuclein ELISA Kit-FIVE photon Biochemicals, Part Number hSNCB-Biotin (96T)) in samples collected from Autism and pervasive developmental disorder-not otherwise specified (PDD-NOS). Table 1 and Figure 2b of the reference demonstrates significantly increased levels in autism spectrum disorder patients over controls.
Regarding claims 2 and 3, the Sriwimol et al. reference teaches the sample of the patient does not comprise cerebrospinal fluid (CSF) – the samples are serum.
Regarding claim 4, the method of Sriwimol et al., is not carried out on the human or animal body itself, rather, measurement of plasma 𝛽-Synuclein levels is carried out ex vivo by double-antibody sandwich ELISA.
Thus, the method of the invention fails to distinguish over the methods disclosed in the prior art reference.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sriwimol et al. as applied to claims 1-4 above, and further in view of Martinez-Morillo et al., J of Proteome Research, 13: 969-981, 2014.
The teachings of Sriwimol as they anticipate claims 1-4 are outlined in the art rejection above. Sriwimol et al. is silent only with respect to the limitations of claim 5 (wherein the disease or diseases associated with synaptic degeneration are one or more of Alzheimer's disease, Creutzfeldt-Jakob disease, traumatic brain injury, stroke, glioma, hypoxia, intoxication, infections, inflammation, or alcoholism); claim 6 (wherein the method is for assessing the status of the disease or diseases associated with synaptic degeneration, or alternatively a method of predicting response to therapy of a patient diagnosed with or suspected of having the disease or diseases associated with synaptic degeneration, or alternatively a method of classifying a stage, preferably a prognostic stage, of a patient diagnosed with or suspected of having the disease or diseases associated with synaptic degeneration, or alternatively a method of selecting the mode of treatment of a patient diagnosed with or suspected of having the disease or diseases associated with synaptic degeneration, or alternatively a method of monitoring disease progression in patients diagnosed with or suspected of having the disease or diseases associated with synaptic degeneration); and claim 7 (wherein the determination of the concentration of β-synuclein involves quantitative mass spectrometry, preferably multiple/selected reaction monitoring (MRM/SRM) or parallel reaction monitoring (PRM), more preferably wherein the determination of the concentration of β-synuclein is carried out by means of multiple/selected reaction monitoring or parallel reaction monitoring, even more preferably by measuring the peptides of aa 46 to 58 (EGVVQGVASVAEK (SEQ ID NO: 2)) and/or 61 to 85 (EQASHLGGAVFSGAGNIAAATGLVK (SEQ ID NO: 3))).
The Martinez-Morillo et al. prior art, however, remedies these deficiencies.
Regarding claim 5, Martinez-Morillo et al. teaches selected reaction monitoring (SRM) assays in which the levels of 68 “brain-specific” proteins were measured by SRM in 36 age-matched patients, including individuals with HS (n = 15), ischemic stroke (n = 11), and controls (n = 10)(Abstract). Seven proteins, including β-Syn, showed significantly higher CSF levels in patients with hemorrhagic stroke than in patients with ischemic stroke and controls (pg. 977, second column, fourth paragraph). Thus the prior art teaches determining the concentration of β-Syn in a sample of a patient with a disease associated with synaptic degeneration, and specifically teaches “stroke” and “hypoxia” of the instant claims.
Regarding claim 6, Martinez-Morillo teach β-Syn showed a rebound in its increased concentration after a secondary event (rebleeding and hydrocephalus) (pg. 978, last paragraph of first column). Thus, the prior art teaches classifying a stage or monitoring disease progression comprising determining β-Syn concentrations.
Regarding claim 7, The authors teach, “Mass spectrometry has emerged as a technology that can overcome some of the limitations of traditional immunoassays. [Selected reaction monitoring] SRM assays require shorter times for method development and have multiplexing capabilities. These advantages make this technology a good alternative for biomarker discovery” (pg. 978, first paragraph of second column). Table 3 (pg. 974) discloses the peptide within the beta-synuclein protein that was assessed was EGVVQGVASVAEK, which is identical to SEQ ID NO. 2 of the instant claims.
The only element that Martinez-Morillo et al. does not disclose is the not CSF limitation of the instant claims. It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, that beta-synuclein could have been measured in serum, as taught by the Sriwimol et al. prior art. Motivation to look in serum is explicit in the teachings of Sriwimol wherein it states, “The detection of synaptic proteins, including 𝛼-synuclein and 𝛽-synuclein, in cerebrospinal fluid (CSF), blood plasma, and serum of both healthy persons and patients has been reported” (pg. 2, second paragraph). The authors state that two possible mechanisms of synuclein clearance have been proposed for maintain the normal levels in the healthy brain; one via the blood-brain and the other via blood-CSF barriers. Serum conveys the distinct advantage over CSF because it is easier to obtain a sample from a patient. Given the guidance and direction in the prior art references, a person having ordinary skill in the art would have been able to use serum samples instead of CSF samples the method of Martinez-Morillo with predictable success of determining the concentration of 𝛽-synuclein in a sample that does not consist of CSF.
Thus, the invention of claims 5-7 is obvious in view of methods that were disclosed in the art prior to filing.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675