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
Applicant's election with traverse of Group II and the species of flow cytometry, fluorescent antibody and Tau, including phosphorylated Tau, in the reply filed on 5 January 2026 is acknowledged. The traversal is on the ground(s) that Groups I and II are basically the same and prior art for one would be applicable to the other. This is not found persuasive because Group II requires measuring biomarker inside of or on the cell surface of neutrophils. Measuring markers inside a cell requires materially distinct processes relative to the method of Group I. Additionally, for purposes of the initial requirement, a serious burden on the examiner may be prima facie shown by appropriate explanation of separate classification, or separate status in the art, or a different field of search as defined in MPEP § 808.02.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 8-14 are examined upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 or 120 as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos:
This application is a CIP of 17/719,243 04/12/2022 which is a CIP of 17/228,416 04/12/2021 and is a CIP of 16/872,064 05/11/2020 ABN which claims benefit of 62/845,670 05/09/2019 This application is a CIP of PCT/US22/24457 04/12/2022 which is a CIP of 17/228,416 04/12/2021 This application is a CIP of 17/719,177 04/12/2022 which is a CIP of 17/228,416 04/12/2021 which is a CIP of 16/271,186 02/08/2019 ABN and said 17/719,177 04/12/2022 is a CIP of 16/872,064 05/11/2020 ABN. This application claims benefit of 63/487,429 02/28/2023 and said 16/872,064 05/11/2020 is a CIP of 16/271,186 02/08/2019 ABN which is a CIP of 15/472,066 03/28/2017 ABN which is a CIP of 14/721,250 05/26/2015 ABN which is a CIP of 14/704,791 05/05/2015 ABN which is a CIP of PCT/US13/68465 11/05/2013 which claims benefit of 61/722,441 11/05/2012 and said 14/721,250 05/26/2015 claims benefit of 62/086,948 12/03/2014 and is a CIP of 13/852,889 03/28/2013 ABN which claims benefit of 61/650,947 05/23/2012 and is a CIP of 12/325,035 11/28/2008 PAT 8,506,933 which claims benefit of 60/991,594 11/30/2007 and claims benefit of 61/007,728 12/14/2007 and claims benefit of 61/020,820 01/14/2008 and claims benefit of 61/042,407 04/04/2008 and said 14/721,250 05/26/2015 is a CIP of 13/645,266 10/04/2012 ABN which is a CIP of 12/853,203 08/09/2010 ABN which claims benefit of 61/232,605 08/10/2009 and said 13/645,266 10/04/2012 is a CIP of 12/954,396 11/24/2010 ABN which claims benefit of 61/264,763 11/27/2009 and said 14/721,250 05/26/2015 is a CIP of 12/954,505 11/24/2010 ABN and said 14/704,791 05/05/2015 is a CIP of 12/954,505 11/24/2010 ABN which claims benefit of 61/264,760 11/27/2009 and claims benefit of 61/371,122 08/05/2010 and claims benefit of 61/393,254 10/14/2010.
Each of these applications fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. These provisional and non-provisional applications all fail to disclose “neutrophils” which are a key element of the instantly-elected claims. The first mention of neutrophils occurs in Application No. 17/228,416 filed 12 April 2021. Therefore, claims 8-14 have an earliest effective filing date of 12 April 2021, which is the filing date of the ‘416 Non-provisional Application.
Information Disclosure Statement
The references cited within the specification is not a proper information disclosure statement (see for example Yin and Marshall and Spiller et al. cited on page 5 of the specification). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
Claim 14 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of Claim 14 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The biomarkers listed in Claim 14 share no structural similarity but are directed to structurally and functionally distinct proteins that have no common structure, nor a common use stemming from this common structure.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 8-14 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 the specific detecting disclosed in Table 1 of the specification in which elevated neuromelanin is detected in recirculating phagocytes from patients with Multiple Sclerosis (MS), Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Traumatic Brain Injury (TBI); elevated Tau in circulating phagocytes from patients with MS, PD, and TBI; decreased Tau in circulating phagocytes from AD; increased UCH-L1 in recirculating phagocytes from MS, AD, PD and TBI patients; FIG. 1 shows about 1.7% of CD14+ cells were GFAP+ (0.19% of total); FIG. 2 shows about 8.7% of CD14+ cells were TAU+; the specification does not reasonably provide enablement for detecting any other biomarker in circulating phagocytes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The broadest reasonable interpretation of the claimed method is that it provides for staining and detecting, in a sample from a subject comprising neutrophils, any labeled first binding moiety specific for neutrophils, and any labeled second binding moiety specific for any target biomarker derived from central nervous system tissue that is within or displayed on the cell surface of the neutrophils. Depending claims recite a vast list of target biomarkers, many of which are not described in the working examples of the disclosure: Tau, phosphorylated Tau, hippocalcin-1, 14-3-3 protein, MBP, UCH-L1, TDP-43, superoxide dismutase(SOD), neuromelanin, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), neurofilament heavy chain (NFH), neurofilament medium chain (NFM), phosphorylated NFL, phosphorylated NFH, phosphorylated NFM, internexin (Int), peripherin, UCH-L1, amyloid beta, alpha-synuclein, apo A-I, Apo E, Apo J, a viral antigen, a JC viral antigen, TGF-beta, VEGF, dopamine-beta-hydroxylase (DBH), vitamin D binding protein, histidine-rich glycoprotein, cDNA FLJ78071, apolipoprotein C-II, immunoglobulin heavy constant gamma 3, alpha-1-acid glycoprotein 1, alpha-1-acid glycoprotein 2, haptoglobin-related protein, leucine-rich alpha-2- glycoprotein, erythropoietin (EPO), C-reactive protein, tyrosinase EC 1.14.18.1, tyrosine hydroxylase, tyrosinase EC 1.14.16.2, PSD-95 protein, neurogranin, SNAP-25, TDP-43, transketolase, NS1 associated protein 1, major vault protein, synaptojanin, enolase, alpha synuclein, S-100 protein, Neu-N, 26S proteasome subunit 9, ubiquitin activating enzyme ZE1, ubiquitin B precursor, vimentin, 13-3-3 protein, NOGO-A, neuronal-specific protein gene product 9.5, proteolipid protein; myelin oligodendrocyte glycoprotein, neuroglobin, valosin-containing protein, brain hexokinase, nestin, synaptotagmin, myelin associated glycoprotein, myelin basic protein, myelin oligodendrocyte glycoprotein, myelin proteolipid protein, annexin A2, annexin A3, annexin A5, annexin A6, annexin All, ubiquitin activating enzyme ZE1, ubiquitin B precursor, vimentin, glyceraldehyde-3-phosphate dehydrogenase, 14-4-4 protein, rhodopsin, all-spectrin breakdown products (SBDPs), or a breakdown product thereof.
A skilled artisan would not know how to use the method with a reasonable expectation of success commensurate in scope with the breadth of the claims, based solely on what is disclosed in the specification because in contrast to what is claimed, what is enabled by the specification is more limited. As stated above, Table 1 (pg. 26 of the specification) discloses only seven specific markers (Tau, GFAP, NFL, UCH-L1, Amyloid Beta, Alpha-Synuclein, and Neuromelanin) as being elevated or decreased in specific diseases. Within Table 1 only those results designated as “R” are biomarkers that were detected in recirculating phagocytes, as recited by the claims (“neutrophils”). Lastly, Figures 1 and 2 demonstrate the use of only one binding moiety specific for neutrophils, namely, CD14 in combination with GFAP or Tau binding only. Thus, what is enabled by the guidance in the specification is narrow compared to the breadth of the invention claimed.
Absent specific guidance with respect to the breadth of the claims, a person having ordinary skill in the art would have to make a substantial inventive contribution in order to use the method commensurate in scope with the breadth of the claims. Given that the nature of the invention is ex vivo sample analysis, a person having ordinary skill in the art would have to perform multiple experiments in order to demonstrate each of the biomarkers could be detected in samples comprising neutrophils with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ laboratory methods, and constitutes undue further experimentation in order to use the method with a reasonable expectation of success. Therefore, Claims 8-14 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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 8-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gabbita et al., (2015) Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model. PLoS ONE 10(10): e0137305. doi:10.1371/journal.pone.0137305.
It should be noted that the instant specification states: “[0021] The present invention is not limited to humans. As used herein, a patient or subject may refer to an animal such as but not limited to a mammal. Mammals may include but are not limited to primates (e.g., a human, non-human primates), a mouse, a rat, a llama, a rabbit, a dog, a primate, a guinea pig, a cat, a hamster, a pig, a goat, a horse, or a cow. The present invention is not limited to the aforementioned subjects or patients.” Therefore, the method comprising staining neutrophils in the sample from the subject reads upon any sample comprising neutrophils from any mammal.
Regarding claim 8, the Gabbita et al. prior art teaches methods comprising assessing neutrophils in 3xTgAD mice, which is an art-accepted model for Alzheimer’s disease (AD). Gabbita et al. teach staining neutrophils in the sample from the mouse subject with a labeled first binding moiety specific for neutrophils. Gabbita and colleagues teach CD45Hi+/Cd11b+/GR1+/1A8+ neutrophils increase in a dose-dependent manner with IDT administration (pg. 11, last paragraph). The authors perform flow cytometry to isolate the neutrophils (see Figure 4). The prior art further teaches performing amyloid and tau ELISAs (pg. 5, ELISA section). The prior art teaches paired helical filament (PHF) tau and fibrillar amyloid were reduced while cognitive abilities were improved by IDT administration (see Figure 11). The authors postulate CNS neutrophilia improves clearance of amyloid and tau pathology by microglia/macrophages (pg. 2, third full paragraph). Therefore, the prior art teaches staining at least one target biomarker molecule with a labeled second binding moiety specific for the target biomarker, the first binding moiety can be differentiated from the second binding moiety, the target biomarker being a compound derived from central nervous system tissue that is within or displayed on the cell surface of the neutrophils; and detecting the first binding moiety and the second binding moiety, wherein the relationship between the amount or distribution of the neutrophil binding moiety and the Tau binding moiety is indicative of an amount of target biomarker molecules inside or displayed on the cell surface of said neutrophils (Figure 11).
Regarding claim 9, the prior art teaches blood samples were collected (pg. 3, section on Cmax and Brain/Plasma ratio).
Regarding claim 10, the prior art teaches both flow cytometry (pg. 6, Flow Cytometry) and ELISA (pg. 5 ELISA for ….Tau) detecting methods.
Regarding claim 11, the prior art teaches the use of Siloam Biosciences Optimiser™ Microfluidic ELISA Plates, which teaches immobilization before detecting (pg. 5, ELISA). For flow cytometry by magnetic separation, cells were passed through MACS LS Columns (Miltenyi Biotec) and placed on the MACS separator (Miltenyi Biotec). Each sample was resuspended in 3
ml of AutoMACS buffer and passed through 70 μm filters (Miltenyi Biotec) on LS Columns (1
mL for each column) (pg. 6, second to last paragraph). Thus, the prior art teaches immobilization on columns prior to detection by flow cytometry.
Regarding claim 12, the prior art also teaches AT8 (phospho-Tau; 1:1000, Thermo Scientific) detection comprising fluorescence microscopy (pg. 4, Immunohistochemistry). Thus the prior art teaches the labels are fluorescent labels.
Regarding claims 13 and 14, Applicant has elected the target biomarker molecule of Tau, and the prior art teaches Tau as a factor in AD pathology and reduction of paired helical filament (PHF) tau leads to improved cognitive abilities (pg. 2, third full paragraph).
Therefore, the method of the invention fails to distinguish over those methods disclosed in the prior art, and Claims 8-14 are anticipated.
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 8-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/719,177 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to a method comprising introducing to a whole blood sample obtained from outside central nervous system (CNS) tissue of a subject a first detectable binding moiety specific for circulating phagocytes and a second detectable binding moiety specific for a CNS-derived molecule, the first detectable binding moiety being differentially detectable from the second detectable binding moiety; subjecting the preparation to single-cell analysis for detecting the first detectable binding moiety and second detectable binding moiety; and analyzing the CNS-derived molecules in the preparation. Depending claims read upon wherein the circulating phagocytes are neutrophils (claims 7 and 13) and the CNS-derived molecule is Tau (claims 9, 15-16, and 19-20).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 8-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-10, 12-14, 16, and 20 of copending Application No. 17/228,416 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to a method comprising introducing to a sample obtained from outside central nervous system (CNS) tissue of a subject a first detectable binding moiety specific for circulating phagocytes and a second detectable binding moiety specific for a CNS-derived molecule, the first detectable binding moiety being differentially detectable from the second detectable binding moiety; and analyzing the CNS-derived molecules in the preparation, wherein said analyzing comprises flow cytometry. Depending claims recite the circulating phagocytes are neutrophils (claim 14) and the biomarker is Tau (claim 20).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675