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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/26/2026 has been entered.
Election/Restrictions
The restriction requirement mailed on 11/7/2024 is moot in view of the cancellation of claims 1-32 and newly submitted claims on 1/6/2025.
Claims 33-54 are under consideration in the instant Office Action.
Terminal Disclaimer
The terminal disclaimers filed on 2/25/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of 11,079,396 and 11,959,927 have been reviewed and are accepted. The terminal disclaimers have been recorded.
Maintained Rejections
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 33-43 and 45-54 are rejected under 35 U.S.C. 103 as being unpatentable over Estrada et al., US 2008/0118938 A1 (IDS) in view of Giehm et al., 2011 (instant PTO-892), Foulds et al., 2011 (1/30/2025 PTO-892) and Allsop et al., US 2005/0176078 A1 (1/30/2025 PTO-892).
Estrada discloses methods for detecting protein aggregation in biological samples wherein such methods can be used for diagnosis and/or for identification of a misfolded protein in a subject (see [0009]). The misfolded protein may comprise abnormally folded protein that is wild type, variant, or mutant of alpha-synuclein (see [0030]), and the method can be used to diagnose Parkinson's disease (PD) (see [0058]). Such teachings are on point to the -synuclein recited in claims 33, 48-49, and 54 given that wild-type -synuclein is a 140-amino acid protein.
The method is discussed, for example, at paragraphs [0012]-[0021] and is termed protein misfolding cyclic amplification (PMCA) (see [0009]), wherein the method is taught to comprise:
(a) Mixing a sample with substrate protein to make a reaction mixture, wherein substrate protein refers to a preparation of protein or protein fragments that are not present in aggregates of the protein, and they are termed seed-free or low molecular weight form of the protein (i.e., contacting a sample with a monomeric -synuclein protein to form an incubation mixture);
(b) an amplification step comprising: (i) incubating the reaction mix, (ii) disrupting the reaction mix, and (iii) repeating steps (b)(i) and (b)(ii) one or more times (i.e., conducting an incubation cycle two or more times…each incubation cycle comprising incubating…and…physically disrupting the incubation mixture);
(c) performing serial amplification comprising: (i) removing a portion of the reaction mix and incubating it with additional substrate protein, (ii) repeating amplification steps (b), and (iii) repeating steps (c)(i) and (c)(ii) one or more times;
(d) detecting misfolded or aggregated proteins or protein fragments in the serially amplified reaction mix (i.e., determining the presence of soluble, misfolded -synuclein protein in the sample by detecting at least a portion of the amplified portion of misfolded -synuclein protein).
Estrada further elaborates that the substrate protein refers to a protein or protein fragment that is homologous in all or part to the amino acid sequence of a misfolded or aggregated protein, has a structural conformation that is typically not identified in biological aggregates of the protein, and is generally capable of being converted into a misfolded or aggregated protein and may further have a higher propensity for aggregation under typical biological conditions (see [0024]). Thus, the substrate protein referred to by Estrada is directly on point to the monomeric, folded -synuclein protein of the instant claims. The soluble, misfolded -synuclein protein that is detected according to Estrada’s method thus would comprise -synuclein aggregate.
Estrada teaches that the misfolded protein is detected by a Thioflavin T (ThT) binding assay (see [0042] and claim 23 at p. 16), which provides for the indicators of Thioflavin T as in instant claims 33 and 49. Estrada indicates that detection can also be performed using a Western blot assay, ELISA, a sedimentation assay, an electron microscopic assessment, a spectroscopic assay, or atomic force microscopy (see, for instance, [0042]).
Estrada teaches that the disclosed methods have a high sensitivity and specificity, which a specificity of greater than 90%, and are capable of detecting less than 500 attograms (ag) or less of misfolded protein in a 10 l sample (see [0045]).
Estrada teaches that incubation of the reaction mixture may be at 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C or 35°C (see [0034]), which temperatures each fall with the recited range of about 8°C to about 50°C as in instant claim 43.
Estrada teaches that the method of detecting misfolded protein in a sample can be used in the diagnosis of Parkinson’s disease (PD) in a subject (see [0058] and [0155]) and therefore, teaches a method of determine levels of fluoresces to indicate increase in alpha synuclein aggregation.
Estrada discloses that the sample comprise blood, lymph, cerebrospinal fluid, urine, milk, tears and/or saliva (see [0031] and[0080]), and the subject may be a human, cow (i.e., cattle), sheep, pig, cat, deer or elk (see [0029] and [0058]) as required in the instant claims 33 and 49.Estrada discloses that the disruption may be accomplished by physical methods such as sonication or homogenization (see [0025] and [0032]).
A method for detecting misfolded protein comprising the use of fluorometric Thioflavin T assay and shaking of the incubation mixture is described, for example, at [0150] as well as at [0042] as noted above, which is on point to claims 33 and 49.
Estrada teaches that the misfolded protein can be separated from the sample with the use of ligands that specifically bind and precipitate the misfolded form of the protein, including conformational antibodies (see [0084]). At paragraph [0152] for instance, Estrada demonstrates an immunoprecipitation assay of plasma samples to extract misfolded protein to amplification and detection. The immunoprecipitation of misfolded protein using conformational antibodies that specifically bind the misfolded form of the protein, wherein the captured, soluble, misfolded S would include misfolded S monomer and/or misfolded S aggregate.
In particular, Estrada provides for a method of determining the presence or amount of a misfolded S protein within a biological sample, such a sample obtained from a subject (see [0009]), using a protein misfolding cyclic amplification (PMCA) assay. Estrada further teaches that immunoprecipitation with antibodies specific for the misfolded conformation of S may be used to separate and concentrate misfolded S protein in samples prior to amplification and detection (see [0084] and [0152]).
Thus, although Estrada teaches concentrating soluble, misfolded S protein in a sample prior to incubation/amplification by way of an immunoprecipitation procedure using an antibody specific for S, the reference does not teach the use of specific anti-S antibodies such as 211, N-19, FL-140 and LB509, etc. as in claim 42, nor that the antibodies are coupled to a solid phase such as a silica or magnetic bead, as in claims 33, 39-42, 49, 51-52. Estrada indicates that the PMCA methods can be used to screen for modulators of protein misfolding (see [0121]) but does not teach use of beads of aggregation or the claimed antibodies.
Giehm teaches different assays for the incubation and production of alpha synuclein aggregation. Giehm teaches that an important way to induce aSN fibrillation is by agitation and agitation increase the collision of monomeric and oligomeric species interacting with fibril ends (see page 297, 1st column, 3rd paragraph) as required by instant claims 33 and 49. Giehm teaches the use of Thioflavin T (ThT) is commonly used to verify aSN fibrillation because ThT is a cheap and easy fibril (aggregation) detecting tool and does not interfere with the kinetics of aSN fibrillation (see page 29, 2nd column, 2nd paragraph) as in instant claims 33 and 49. Giehm teaches that aSN fibrillation is consistently reproducible when using a plate reader assay where small glass beads in combination with agitation is crucial to obtain good reproducibility (see page 301, 1st column, section 7). Giehm teaches that the beads can be 1.2-1.4 mm (diameter). Giehm teaches that the aggregation of aSN fibrillation depends upon given conditions such as temperature, degree/type of agitation and pH (see page297, bottom of 2nd column). Therefore, one of ordinary skill would be able to determine the best temperature, agitation rate and pH to produce the optimal results through routine optimization of the detection assay and meets the limitations of instant claims 35-36, 38, 43 and 49-50.
Foulds teaches methods for detection of alpha-synuclein in blood plasma (see page 4128, 1st column, 2nd paragraph) as in instant claims 33 and 49. Foulds teaches combining recombinant alpha-synuclein in buffers that include 20 mM Tris-HCl (pH7.5) 50mM KCl, 10mM MgCl2 at 30°C (see page 4129, 1st column, 2nd paragraph) as in instant claims 34-35, 37, 45-48 and 53-54. Foulds teaches using Dynabeads covalently coupled to N19 antibody and incubated with plasma samples (See page 4130, 1st column, 3rd paragraph) as in instant claims 33-42, 49 and 51-52.
Allsop teaches methods for diagnosing a synucleinopathy in a patient as well as methods for monitoring the effectiveness of a therapeutic agent that has been administered for the purpose of treating a synucleinopathy, the methods comprising analyzing a sample taken from the patient for the presence and/or amount of soluble synuclein (see abstract, [0012] and [0014]). The synuclein is soluble -synuclein (see [0021]).
Allsop teaches that prior to determining the amount of S in a sample, a pre-concentration step may be performed using a capture antibody specific forS and attached to a solid phase, such as a magnetic bead (i.e., an immunoprecipitation step) (see [0027]-[0028]), which is on point to the determining steps of claims 33 and 49, the antibodies being coupled to solid phase being a magnetic bead in claims 40-41 and 51-52. Antibodies suitable for this step are taught to include the S -specific antibodies 211, N-19, FL-140 and LB509 (see [0029]-[0035]), which notably addresses some of the recited antibodies of claim 42.
It would have been obvious to one of ordinary skill in the art at the time of filing to have incorporated a pre-concentration immunoprecipitation (IP) step comprising the use of specific anti-S capture antibodies coupled to magnetic beads, as taught by Giehm, Foulds and Allsop, prior to performing the PMCA assay of Estrada and thereby arrive at the presently claimed method. Given teachings of by Giehm, Foulds and Allsop, the artisan would have been aware that S in a sample could be concentrated prior to further analysis by using specific anti-S antibodies coupled to magnetic beads and performing an immunoprecipitation assay. And given the demonstrated use of such a technique by Giehm, Foulds and Allsop, the artisan would have had a reasonable expectation that such an IP-PMCA method would have been successful.
Claims 33--54 are rejected under 35 U.S.C. 103 as being unpatentable over Estrada et al., US 2008/0118938 A1 (IDS) Giehm et al., 2011 (instant PTO-892), Foulds et al., 2011 (1/30/2025 PTO-892) and Allsop et al. US 2005/0176078 A1 (1/30/2025 PTO-892) in view of Naik et al., (1/30/2025 PTO-892).
Estrada, Giehm , Foulds and Allsop fail to teach the limitation of claim 44. While Giehm teaches the use of fluorimeters, all the references fail teach the required excitation and emission for the detection of ThT.
Naik teaches that ThT properties where observed in different environmental conditions and the emissions bands ais observed at 485nm and excitations can range from 390-420nm as in instant claim 44. Therefore, one of ordinary skill in the art would use these known ranges of ThT to determine the best emissions and excitation band to measure the ThT with a fluorimeters in the alpha synuclein assay with a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed 2/26/2026 have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant argues that Giehm does not teach the instantly claimed invention. Applicant argues that the glass beads taught by Giehm teach away from the instant inventions since they are used to produce self-aggregated a-synuclein monomers and that is not the use of the instantly claimed beads. This is not found persuasive because Giehm is not depended upon to teach the method and that requirement is met by the Estrada reference and all of the other references that are combined provide clear motivating that all of the modifications are known in the prior art and are obvious to one of ordinary skill in the art to combine and produce the required effects. It is pointed out that Estrada teaches detecting misfolded or aggregated proteins or protein fragments in the serially amplified reaction mix (i.e., determining the presence of soluble, misfolded -synuclein protein in the sample by detecting at least a portion of the amplified portion of misfolded -synuclein protein). Applicant argues that the Giehm reference when combined with the Estrada reference would destroy the operability of Estrada. It is unclear how this is the case since Giehm is only depended upon to show that one may use beads, silica or magmatic, to detect a-syn aggregation and that one can further issue the beads in the assistance of immunoprecipitation and isolation of the aggregated protein. Estrada already teaches that one would want to serially amplify the reaction mix to be able to properly detect the presence of a-synuclein aggregates. Therefore, Giehm’s teaching of glass/silica beads to induce aggregation is a teaching that would motivate one of ordinary skill to uses these beads to help in the serail amplification of the a-synuclein aggregates. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also >Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). One of ordinary skill in the art does not have to take every aspect of the teaching in a reference but may use it to provide obvious reasons to why on element would be useful outside the instant teaching it is supporting. In other words, one does not take very element of the Giehm reference and apply to the Estrada reference, but rather the reasonable expectation that glass beads are an effective support system to provide a serially amplified reaction mix to help in the detection of at least a portion of the amplified portion of misfolded -synuclein protein.
Applicant also ignores the Foulds teaching of Dynabeads covalently coupled to N19 antibody and incubated with plasma samples (See page 4130, 1st column, 3rd paragraph) as further showing that beads are used successfully in the this type of assay. The combination of references clearly set forth a reasonable expectation of success in producing the claimed method.
Applicant also argues that Foulds never teaches that sufficient quantities of protein are captured by the DynaBeads to perform immunoprecipitation. This not found persuasive because all of the requirements are taught or obvious over the references of record. Estrada teaches the instantly claimed method except for the requires beads, and other references teach the claimed limitations and the motivation of why one of ordinary skill in the art would de be motivated to use the claimed beads with a reasonable expectation of success and why these modifications are an improvement on the disclosed Estrada method. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
Therefore, applicant’s arguments are not found persuasive and rejections are maintained.
New Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 33-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-46 of copending Application No. 18/596,310. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘310 claims methods claims methods of detecting alpha synuclein in biological samples using the same buffers and beads. Since biological samples encompass blood plasma, the ‘310 reads on the instantly claimed limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to AURORA M. FONTAINHAS whose telephone number is 571-272-2952. The examiner can normally be reached on Monday - Friday (8AM - 4PM).
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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