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 .
Claims 1-10, 12-20, and 22 are pending in this application and were examined on their merits.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is too short to sufficiently assist readers in deciding whether there is a need for consulting the full patent text for details. Correction is required. See MPEP § 608/01 (b).
The listing of references in the specification is not a proper information disclosure statement. 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 Objections
Claim 1 objected to because of the following informalities: a comma is needed between “viral glycoprotein(s)” and “and are detectable.” Appropriate correction is required.
Claim 3 objected to because of the following informalities: "lymphozyte" should be "lymphocyte". Appropriate correction is required.
Claims 9, 10, 13, and 15 objected to because of the following informalities: "hanta virus" should be "hantavirus". Appropriate correction is required.
Claim 19 objected to because of the following informalities: "epithel" should be "epithelial". Appropriate correction is required.
Claim 22 objected to because of the following informalities: "being" should be "wherein". Appropriate correction is required.
Claim Interpretation
The term "extracellular vesicle" is construed as any structure outside a cell enclosed by a lipid bilayer. This includes enveloped viruses, pseudoviruses, virus-like particles (VLPs), subviral particles (SVPs), exosomes, microvesicles, etc. The prior art cited relates mainly to enveloped pseudoviruses, VLPs, and SVPs. To substantiate this, Nolte-‘t Hoen et al. (PNAS August 16, 2016 vol. 113 no. 33 9155-9161) has been cited which discloses that it is "mission impossible" to distinguish between EVs from virus infected cells and viruses. Thus, there is no clear distinction between EVs and viruses, pseudoviruses, VLPs etc. Of course, some (but not all) independent claims are limited to "noninfectious". However, even this term is open to interpretation. While this reasonably excludes natural viruses, it does not exclude pseuodoviruses, VLPs, SVPs since these have all been disabled such that they are not fully infectious at least in a natural setting. Indeed, the whole point of using pseuodoviruses, VLPs, SVPs etc. is that stringent biosafety measures are not required; some do not even comprise nucleic acid. In short, the claims do not exclude pseudoviruses, VLPs etc.
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 1-10, and 12-20 rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
The instant claims are drawn to a method of determining whether or not virus-neutralizing antibodies are present in a sample, which is a statutory category of invention (STEP 1: YES).
The instant claims are directed to the natural correlation between the uptake of virus-like particles into cells and the ability of virus-neutralizing antibodies to prevent this uptake. The instant claim further encompasses the mental step of appreciating the natural correlation to determine whether or not virus-neutralizing antibodies are present in a sample. As such, the instant claims recite judicial exceptions (JE) in the form of a law of nature and abstract idea (STEP 2A, PRONG ONE: YES).
The crux of the claimed method is the natural correlation and appreciation thereof to determine whether or not virus-neutralizing antibodies are present in a sample. The instant claims do not recite, e.g., any particular treatment or prophylaxis for the virus-neutralizing antibodies detected; rather, the instant claims merely recite insignificant extra-solution activities in the form of obtaining and detecting the natural correlation in a biological sample. As such, the instant claims do not recite additional elements that integrate the JE into a particular application (STEP 2A, PRONG TWO: NO).
As discussed in detail below, it was well-understood, routine, and conventional (WURC) at the time of filing to use extracellular vesicles (EVs) comprising a viral glycoprotein (VLPs), virus-neutralizing antibodies, and cells that are capable of taking up VLPs or other EVs capable of taking up VLPs to determine whether or not virus-neutralizing antibodies are present in a sample (see rejections of record under 35 U.S.C. §102 and §103 below). As such, beyond the JE, the instant claims only recite WURC data-gathering steps. These WURC date-gathering steps constitute insignificant extra-solution activities, which does not reasonably provide an inventive concept. As such, the instant claims do not recite significantly more than JE (STEP 2B: NO).
Accordingly, the instant claims do not constitute patent eligible subject matter under 35 U.S.C. §101.
Claim Rejections - 35 USC § 112
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 7-10, 13, 15, 19, and 20 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.
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, for example, claim 13 recites the broad recitation "wherein the virus-neutralizing antibodies are neutralizing antibodies against a virus selected from the group consisting of a coronavirus", and the claim also recites "optionally a SARS-CoV-virus, the SARS-CoV-2-virus; Epstein-Barr virus, measles virus, influenza virus, parainfluenza virus, human respiratory syncytial virus, Ebola virus, hantavirus and Lassa virus" which is the narrower statement of the range/limitation. The claims 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “tetraspanin” in claims 7 and 8 is used by the claim to mean “CD63, CD40, CD81, CD9, CD37, CD53, CD54, Cd151, CD82, and TSPAN-8,” while the accepted meaning does not include “CD40 and CD54.” The term is indefinite because the specification does not clearly redefine the term. A list of accepted tetraspanins can be found on the “Tetraspanins” page of the HUGO Gene Nomenclature Committee website (https://www.genenames.org/data/genegroup/#!/group/768, with WayBack Machine Publication date of 25 September 2019 having the link: https://web.archive.org/web/20190925191050/https://www.genenames.org/data/genegroup/#!/group/768 and accessed on 02 December, 2025).
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5, 6, 9, 12-16, 19, and 20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hu, et al. (Genes & Diseases (2020) 7, 551-557, hereinafter "Hu").
Regarding claim 1, Hu discloses a method to determine whether or not virus-neutralizing antibodies are present in a sample obtained from a subject, comprising the following steps: providing extracellular vesicles and a label, wherein the extracellular vesicles are non-infectious, comprise one or more viral glycoprotein(s) and are detectable via the label (Production and titration of SARS-CoV-2 S pseudovirus, pg. 553), contacting the sample with said extracellular vesicles and cells, which are capable of taking up said extracellular vesicles, wherein the viral glycoproteins is able to target a receptor of said cells and is fusogenic (Neutralization and inhibition assays, pg. 553), and determining whether or not said cells take up said cells in comparison to a control, wherein said cells and said extracellular vesicles are contacted, but without said sample, is indicative of the presence of virus-neutralizing antibodies (Detection neutralization effect of ACE2-Ig and convalescent COVID-19 patient sera, pg. 554).
Regarding claim 2, Hu further discloses that the label is a luciferase (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 3, Hu further discloses that the receptor is of angiogenin converting enzyme 2 (ACE2) (Cell lines, pg. 552).
Regarding claim 5, Hu further discloses that the extracellular vesicles are detectable via the label, wherein the label is attached to an extracellular vesicle protein comprised in the extracellular vesicles (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 6, Hu further discloses that the extracellular vesicles comprise the extracellular vesicle protein and the label as a fusion protein (Figure 2A, pg. 555, Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 9, Hu further discloses that the extracellular vesicle protein is a viral extracellular vesicle protein (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 12, Hu further discloses that the extracellular vesicles are detectable via the label, wherein the label is attached to one or more viral glycoprotein(s) of the extracellular vesicles (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 13, Hu further discloses that the virus-neutralizing antibodies are neutralizing antibodies against a virus consisting of a coronavirus (Detection neutralization effect of ACE-2 Ig and convalescent COVID-19 patient sera, pg. 554).
Regarding claim 14, Hu further discloses that one or more viral glycoprotein(s) is/are on the surface of the extracellular vesicles (Expression and subcellular localization of SARS-CoV-2 S protein, pg. 553).
Regarding claim 15, Hu further discloses that one or more viral glycoprotein(s) is/are one or more viral glycoprotein(s) from a coronavirus (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 16, Hu further discloses that the viral glycoprotein is the S-protein of the SARS-CoV-virus (Production and titration of SARS-CoV-2 S pseudoviruses, pg. 553).
Regarding claim 19, Hu further discloses that cell is a cell from a cell line (Cell lines, pg. 552).
Regarding claim 20, the Specification (¶0037) discloses that “the cell may be an extracellular vesicle.” As such, the “cell” recited by instant claim 20 was interpreted herein consistent with Specification to include an extracellular vesicle. As discussed above, claim 1 is anticipated by Hu. Since claim 20 only differs from claim 1 in that EVs are used instead of cells as the recipient for the fusion event, and, as defined by applicant, cells are EVs, Hu also reasonably anticipates claim 20.
Accordingly, Hu anticipates the claimed method.
Claim 22 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Roberts, et al. (US 20190290782 A1, hereinafter "Roberts").
Regarding claim 22, Roberts discloses a kit for determining whether or not virus-neutralizing antibodies are present in a sample obtained from a subject, comprising - extracellular vesicles, which comprise one or more viral glycoprotein(s), and a label, being attached to an extracellular vesicle protein of the extracellular vesicles (¶0013).
Accordingly, Roberts anticipates the claimed invention.
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 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 4, 8, 10, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Hu as applied to claims 1-3, 5, 6, 9, 12-16, 19, and 20 above, and further in view of Sasaki, et al. (Virus Research 243 (2018) 69-74, hereinafter "Sasaki").
Claim 4 recites that “the label is a split protein, wherein a first part of the split protein is comprised in the extracellular vesicles and a second part of the split protein is comprised in the cells, and wherein the first and the second part are able to form a complex.” Hu does not teach that the label is a split protein.
However, Sasaki teaches a “split NanoLuc luciferase protein, LgBiT and the small peptide, HiBiT” (Abstract, pg. 69). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the split protein label taught by Sasaki to advantageously allow for detection of the interaction between the EVs, neutralizing antibodies, and cells as “[t]he split luciferase complementation assays are a well-characterized approach to study protein-protein interactions” (Introduction ¶2, pg. 69) with a reasonable expectation of success since the methods of splitting luciferase (a label) into two subunits and transfection to create EVs and cells expressing proteins as well as the ability of these subunit proteins to form a complex are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
In regards to claim 8, Hu does not teach the split protein or where the first part of the split protein is attached. However, Sasaki teaches a sub-viral particle (SVP) that has the HiBiT amino acid sequence attached to the flavivirus E protein (Results 3.1 Generation and detection of WNV SVPs tagged with HiBiT, pg.71, Figure 1A, pg. 71).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the split protein label attached to a viral glycoprotein in the EV taught by Sasaki to advantageously allow for detection of the interaction between the EV’s, neutralizing antibodies, and cells as “[t]he split luciferase complementation assays are a well-characterized approach to study protein-protein interactions” as recognized by Sasaki (Introduction ¶2, pg. 69), with a reasonable expectation of success since the method of attaching a split protein to a viral glycoprotein of an EV is known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Claim 10 recites that “the extracellular vesicles are detectable via the label, wherein the label is attached to a viral capsid-protein or a viral nucleo-protein and wherein the one or more viral glycoprotein(s) and the viral capsid-protein or the viral nucleo-protein are from the same virus.” Hu does not teach wherein the label is attached to a viral capsid-protein or a viral nucleo-protein. However, Sasaki teaches a label (HiBiT) fused to the West Nile Virus capsid protein (Results 3.3 Generation and application of VLPs tagged with HiBiT to quantitative measurement of cellular entry of WNV VLPs, pg. 72). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the split protein label attached to a viral capsid protein taught by Sasaki to advantageously attach labels to a wide range of proteins since it depends on the desired viral protein for detection. Sasaki recognizes that other proteins can be used as the label is also attached to the envelope protein, with a reasonable expectation of success because the method of attaching a split protein to a viral-capsid protein is known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Claim 17 recites that “the one or more viral glycoprotein(s) is/are not the M-, E-, or S-protein of the SARS-CoV-2 virus.” Hu does not teach that the viral glycoprotein(s) are not M-, E-, or S-protein of the SARS-CoV-2. However, Sasaki teaches that the viral glycoprotein is the M-, E-, or C-protein of WNV (Figure 1A, pg. 71 and Results 3.3 Generation and application of VLPs tagged with HiBiT to quantitative measurement of cellular entry of WNV VLPs, pg. 72). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the use of another viral glycoprotein other than the M-, E-, or S-protein of SARS CoV-2 as taught by Sasaki to advantageously allow for more assays and test with many other viruses of interest, with reasonable expectation of success because the use of other viral glycoproteins not from SARS-CoV-2 in extracellular vesicles is known, successfully demonstrated, and commonly used as evidenced by the applied prior art
Accordingly, the claimed method was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hu as applied to claims 1-3, 5, 6, 9, 12-16, 19, and 20 above, and further in view of Cashikar, et al. (PLoS ONE 14(7): e0220007, 2019, hereinafter "Cashikar").
In regards to claim 18, Hu does not teach that the EV protein is a tetraspanin, an integrin, or a type I membrane protein. However, Cashikar teaches a “EV-enriched tetraspanin CD63 fused to the small, ATP-independent reporter enzyme, Nanoluciferase” (Abstract, pg. 1). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the label being attached to a tetraspanin comprised in the EVs as taught by Cashikar. Many proteins can be used to attach labels used to detect EV’s and their entry into cells. Using a fusion protein of a tetraspanin and a label to detect EV’s would have had a reasonable expectation of success because the use of other extracellular vesicle proteins for label attachment is known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
6. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Hu as applied to claims 1-3, 5, 6, 9, 12-16, 19, and 20 above, and further in view of Tscherne, et al. (J Virol Methods. 2010 February; 163.3(2): 336, hereinafter "Tscherne").
In regards to claim 18, Hu does not teach that the label is attached to a viral tegument protein. However, Tscherne teaches “a beta-lactamase reporter protein fused to the influenza matrix protein-1 [M1]” (Abstract, pg. 1). M1 is a viral tegument protein. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hu to incorporate the label being attached to a viral tegument protein as taught by Tscherne to advantageously attach labels to a wide range of proteins, it depends on the desired viral protein for detection. Sasaki recognizes that other proteins can be used as the label is also attached to the envelope protein, with a reasonable expectation of success because the use of viral tegument proteins for label attachment in EVs is known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Accordingly, the claimed method was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Conclusion
NO CLAIMS ARE ALLOWED
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/CASSANDRA SENN GRIZER/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672