Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Claims
2. Applicant's preliminary amendment of the instant application, which was originally submitted on 04/06/2023 and later amended on 10/17/2023, is acknowledged by the Examiner. The cancellation of claims 17 – 21, 26 – 32, 36, 37, 41 – 51, and 54 – 59 pursuant to the amendment on 10/17/2023 is acknowledged. Claims 1 – 16, 22 – 25, 33 – 35, 38 – 40, 52, and 53 were examined and subsequently restricted on 11/06/2025.
3. Applicant's election with traverse of Group I for claims 1 – 6, 13 – 16, 22, and 23 with the species of Dengue virus in the reply filed on 12/18/2025 is acknowledged. The traversal is on the grounds that Groups I – VI are linked by common technical features which are neither taught nor suggested by Schreiber, M. and Franzke, K (EP 2980099 A1; Published 03/02/2016; Cited in Applicant’s IDS on 04/06/2023 as Foreign Patent Document Cite No. 1), referred to as Schreiber in the Office Action mailed on 11/06/2025. Applicant further argues that Perez, L. G., et. al. (V1V2-specific complement activating serum IgG as a correlate of reduced human immunodeficiency virus 1 (HIV1) infection risk in RV144, PloS one, 12(7); Published 07/05/2017; Cited in Applicant’s IDS on 04/06/2023 as Non-Patent Literature (NPL) Document Cite No. 3), referred to as Perez in the Office Action mailed on 11/06/2025, does not provide any incentive to modify Schreiber towards the subject matter of Groups I – VI. Applicant contends that Groups I to VI should thus be considered as they are linked by a common technical feature. However, this is not found persuasive because the technical feature, i.e., flavivirus-reactive complement-fixing antibodies, that links the claims of Groups I – VI is known in the art.
Mehlhop, E., et. al. (Complement protein C1q inhibits antibody-dependent enhancement of flavivirus infection in an IgG subclass-specific manner. Cell host & microbe, 2(6), 417–426; Published 12/13/2007), hereby Mehlhop, teaches that IgG activates the complement system pathway through the classical pathway (page 417, right column). It is further taught that the complement component C1q binds to anti-flavivirus IgG in a subclass specific manner, wherein IgG1 and IgG2 were implicated (page 417, abstract; page 418, left column; page 420, right column). Mehlhop goes on to teach that the binding of C1q and IgG plays a key role in the development of antibody-dependent enhancement (ADE) of flavivirus infections, including those caused by Dengue virus and West Nile virus (page 417, abstract; page 419, right column). Taken together, Mehlhop teaches that C1q is part of the complement system and binds to individual subclasses of flavivirus-reactive IgG antibodies (page 420, right column), i.e., flavivirus-reactive complement-fixing antibodies are taught in the art.
Claims 7 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions/species and there being no allowable generic or linking claim. Claims 1 – 6, 13 – 16, 22 and 23 are pending in this application and under examination. Applicant timely traversed the restriction/election requirement in the reply filed on 12/18/2025.
Priority
4. The instant application is a National Stage Entry of International Patent Application No. PCT/US2021/054242 filed on 10/08/2021, which claims priority to United States Provisional Application No. 63/212194 filed on 06/18/2021 and European Patent Application No. 20201091.4 filed on 10/09/2020. Priority is granted to the European Patent Application for claims 1 – 6, 13 – 16, 22 and 23 of the instant application.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 04/06/2023 has been considered by the Examiner. Notably, 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.
Specification
6. The use of the terms MagPlex® on pages 26, 27, 32, and 49 – 51; MicroPlex® on pages 26 and 32; LumAvidin® on page 26; SeroMAP® on page 26; Luminex® on page 32; FLEXMAP 3D® on page 32; MAGPIX® on pages 32 and 33; Thermo Fisher Scientific™ on pages 51 – 53 and 65; BioRad™ on page 53; Tween 20™ on pages 53 and 65; Stamaril® on page 64; Ixiaro® on page 64; Innovator® on page 64; Encepur® on page 64; and possibly others in the specification, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Note that the terms outlined above are merely examples and not an exhaustive list. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
7. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 2. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
8. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Drawings
9. The drawings are objected to under 37 CFR 1.84(u)(1), which states "view numbers must be preceded by the abbreviation "FIG.". In the instant case, the view numbers of Figures 1 – 35 are preceded by the word FIGURE instead of the abbreviation “FIG.”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
10. Claims 5, 13, and 14 objected to because of the following informalities:
There is a typographical error in line 2 of claims 5 and 14. There is a missing hyphen wherein the phrase should read “virus-like particle”;
There is a typographical error in line 5 of claims 5 and 14. There is a missing comma, wherein the phrase should read “non-structural protein 5, and any derivative thereof”;
Applicant is advised that should claim 5 be found allowable, claim 14 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m);
There is a typographical error in claim 13, line 4 and claim 14, line 6. There is a missing period at the end of the sentence.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
11. 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.
12. Claims 6, 13 — 15 and 23 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.
13. Claim 6 is vague and unclear, which renders the claim indefinite. Claim 6 recites “coumarin, and any derivative thereof”. It is not clear if the derivative thereof is for coumarin only or for the entire list of labels. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989).
14. Claims 13, 14, and 23 recite the phrase "preferably", which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. The phrase suggests that the limitation is optional or a preferred embodiment, but is unclear from the claim language itself whether that limitation is essential for infringement or an optional feature. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. See MPEP § 2173.05(d).
15. Claim 15 recites the limitations "an amount of a " in line 2; "an amount of a second microsphere complex..." in line 3; “an amount of a third microsphere complex” in line 4; and “an amount of a fourth microsphere complex” in lines 5 and 6. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of a first, second, third, or fourth microsphere complex in step 1 of claim 1. Additionally, it is not clear if the first, second, third, and fourth microsphere complexes are present in the same sample or different samples? In other words, it is unclear if there is a single population of each microsphere complex per sample, or multiple populations in a sample. The presence of multiple very different interpretations of the same claim language renders the claim indefinite.
16. It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
35 USC § 112(d)
17. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. — Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
18. Claims 3 and 4 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 requires “contacting an amount of a pre-reporter antibody with the C1q...to allow binding of the pre-reporter antibody to the C1q”. Claim 1, which claim 3 is dependent upon, recites “contacting an amount of a ”. The limitation of the reporter antibody binding to C1q in claim 1 is not recited in claim 3. Thus, claim 3 fails to include all the limitations of claim 1. This rejection affects all claims that are dependent upon claim 3, i.e., claim 4. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
35 USC § 112(a)
19. 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.
35 USC § 112(a) – Written Description
20. Claims 5 and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre–AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre–AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
"The purpose of [the written description requirement] is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification"); LizardTech Inc. v. Earth Resource Mapping Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005). This requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement for a claimed genus, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. See In re Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345, 54 USPQ2d 1915, 1917 (Fed. Cir. 2000). “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” See In re Enzo Biochem, Inc. v. Gen–Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002). See also MPEP § 2163.
The written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See In re University of California v. Eli Lilly & Co., 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997); and Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, the applicant must describe a sufficient variety of species to reflect the variation within the genus. See In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See In re Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." See In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. This is because functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.” The description needed to satisfy the written description varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. See In re University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014); In re Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010); and In re Capon v. Eshhar, 418 F.3d at 1357, 76 USPQ2d at 1084.
Claims drawn to a Markush group of the antigen, which is selected from a group consisting of virus like particle (VLP), non-structural protein 1 (NS1), envelope protein (E), pre-membrane protein (prM), membrane protein (M), capsid protein, non-structural protein 2A, non-structural protein 2B, non-structural protein 3, non-structural protein 4A, non-structural protein 4B, and non-structural protein 5, and any derivative thereof. However, the specification only provides sufficient disclosure for Dengue virus (DENV) 1 – 4 NS1 proteins, Zika virus (ZIKV) NS1, DENV1-4 VLPs, and ZIKV VLP, wherein the VLPs are comprised of prM, M, and E proteins (paragraphs 00318 – 00324). It is disclosed that the VLP/NS1 of DENV1, DENV2, DENV3, DENV4, and ZIKV are encoded by the amino acid sequences disclosed in SEQ ID NOs: 1, 2, 3, 4, and 9, respectively (paragraphs 00318 – 00320). At a minimum, the claims encompass any derivative of these sequences, i.e., the VLP. For example, SEQ ID NO: 1 is 3392 amino acids in length and could have anywhere from 1 to 3392 substitutions, deletions, additions, or any combination thereof, along its length and still be a derivative of SEQ ID NO: 1. This corresponds to a massive genus with trillions of sequences, 203392 = 1.2 x 104413 sequences, to be exact, with respect to SEQ ID NO: 1 alone. The same logic applies to SEQ ID NOs: 2, 3, 4, and 9. Moreover, this logic would further apply to any sequence for the other proteins described in claims 5 and 10. In general, any derivative of the disclosed group creates an enormous breadth that becomes innumerable when coupled together with the massive genera of sequences per antigen.
When there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The claims are drawn to several genera that are comprised of innumerable sequences, yet, the specification has only adequately described, and successfully reduced to practice, five constructs, drawn to VLPs for DENV1-4 and ZIKV. This is not representative of the extremely large genus of sequences claimed. One of ordinary skill in the art cannot conclude that Applicant was in possession of the trillions upon trillions of sequences encompassed by the disclosed genera. Absent the disclosed sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, each individual sequence utilized. Thus, it is clear that the breadth of the recited genera in the claims far overreaches the Applicant’s contribution.
In the absence of a representative number of examples, the specification must at least describe the structural features that are required for the claim function. In the instant case, the specification should explain the required component of the antigen to allow coupling with the microspheres. However, the specification fails to describe any such substantive structural limitations as to establish a structure–function relationship. At best, the specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Therefore, one having ordinary skill in the art would readily appreciate that relying on a non–patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
The art teaches that protein chemistry is an extremely unpredictable area of biotechnology, wherein even a single substitution can change the biological property of a peptide. For example, Burgess, W. H., et. al. (Possible dissociation of the heparin–binding and mitogenic activities of heparin–binding (acidic fibroblast) growth factor–1 from its receptor–binding activities by site–directed mutagenesis of a single lysine residue. The Journal of cell biology, 111(5 Pt 1), 2129–2138; Published 11/1990) teaches that replacement of a single lysine residue by a glutamic acid residue can lead to substantial loss of receptor binding and biological activity of a protein (page 2129; abstract). Moreover, Friedberg, I. (Automated protein function prediction––the genomic challenge. Briefings in bioinformatics, 7(3), 225–242; Published 01/25/2006) teaches that homology–based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg, I. also teaches that identification of functionally significant sub–regions is critical to functional annotation, and that often addition, deletion, or re–shuffling of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg, I. teaches that as databased and, thus, diversity of sequences, get larger, sequence–based tools are not sensitive enough to identify functional protein similarity (page 228, first full paragraph). Thornton, J. (Structural genomics takes off. Trends in biochemical sciences, 26(2), 88–89; Published 02/01/2001) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thornton, J. further describes examples of little correlation between specific binding function and overall protein structure (page 992, right column, lines 2 – 10). Thus, when taken with the teachings of Burgess, W. H., et. al., Friedberg, I., and Thornton, J., one having ordinary skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function and their expression would be a result effective parameter requiring optimization in each type of expression system.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. Thus, while Applicant has described a species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One having ordinary skill in the art cannot determine the structures encompassed by the claimed genera. Thus, the described species cannot be considered representative of the entire recited genus.
Overall, the claims as currently written are not adequately described and one of ordinary skill in that art would readily appreciate that Applicant was not in possession of the claimed genera at the time of filing. At present, it is recommended that the recitation of “any derivative thereof” be removed in claims 5 and 14.
Claim Rejections - 35 USC § 103
21. 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.
22. Claims 1, 2, 5, 13, 14, 16, 22, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Tyan, D. B. and Chen, G. (US 2011/0281757, Published 11/17/2011; U.S. National Stage Entry of WO 2010/065425 A1 as Cited in Applicant’s IDS on 04/06/2023 as Foreign Patent Document Cite No. 2), hereby Tyan, and in further view of Mehlhop, E., et. al., (Cell host & microbe, 2(6), 417–426; Published 12/13/2007), hereby Mehlhop.
Tyan teaches a method for determining the presence or absence of complement fixing antibodies in a biological sample using complement factor C1q (abstract; page 1, paragraph 0009; page 6, paragraph 0072; figure 4 [reproduced below]), as recited in instant claim 1. The complement fixing antibodies specifically bind to an antigen of interest that has been immobilized on a solid substrate, wherein the substrate is a microsphere, and C1q in turn binds to the bound antibody (page 1, paragraph 0010; page 6, paragraph 0070), as recited in instant claim 1. Page 7, paragraph 0079 goes on to teach that the C1q binding can be measured directly, i.e., without the use of a detectably labeled anti-C1q antibody, or indirectly, i.e., by contacting the solid substrate with a detectably labeled anti-C1q antibody that specifically binds to the bound C1q, as disclosed in instant claim 1. A signal from the reporter antibody is emitted after exposure of the attached label to its substrate, wherein this signal is detected and indicates the presence or absence of complement fixing antibodies that bind specifically to the antigen of interest in the sample (page 1, paragraph 0010; page 5, paragraph 60), as required in instant claims 1 and 2. The sample itself is obtained from a human source and is heat inactivated prior to testing (sample preparation, pages 8 and 9, paragraphs 0090 – 0095; example 1, page 14,
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paragraph 0162; example 2, page 17, paragraph 0223), as required in instant claims 22 and 23.
Tyan does not explicitly teach that the complement fixing antibody is flavivirus-reactive, as defined in instant claim 1; the antigen is a flavivirus viral protein, as disclosed in instant claims 1, 5, 13, and 14; and that the C1q is purified, as recited in instant claim 16. However, Tyan does teach that a complement fixing antibody is an antibody that specifically binds to an antigen on a pathogen and initiates the complement cascade of the immune system, wherein IgM or IgG antibodies are recognized by C1q (page 4, paragraph 0050). It is further taught that the antigen is any molecule which an antibody can be generated towards, including a pathogen-associated protein, wherein the pathogen may be a virus, that elicits an immune response to protect an animal from disease, or a viral antigen (antigen of interest, pages 7 and 8, paragraphs 0082 – 0085). Page 4, paragraph 0053 goes on to teach that the C1q can be from an exogenous source, meaning it is derived from an organism or system different from the subject sample having complement fixing antibodies. In view of these teachings by Tyan, Mehlhop teaches that the Flavivirus genus is composed of 73 viruses, including West Nile virus (WNV), Yellow Fever virus (YFV), Japanese encephalitis virus (JEV), and DENV (page 417, left column), as disclosed in instant claim 13. It is further taught that IgG activates the complement system, i.e., the complement fixing antibody, wherein C1q specifically binds to the heavy chain constant region of IgG, which has implications in DENV infections (page 417, abstract and right column; page 418, left column), as defined in instant claim 1. The C1q employed in these studies was commercially available, i.e., from an exogenous source, and purified (page 423, right column) as recited in instant claim 16. Mehlhop goes on to teach that the majority of neutralizing antibodies for flaviviruses, i.e., the antigen, are directed against the envelope protein (E), with some recognizing the pre-membrane (prM) and membrane (M) proteins (page 417, right column), as recited in instant claims 5 and 14.
Tyan and Mehlhop are considered to be analogous to the claimed invention because both references are drawn to the interaction of complement fixing antibodies and C1q in antigen detection. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art that the method for determining the presence or absence of complement fixing antibodies in a biological sample using the C1q and detectably-labeled reporter anti-C1q antibody taught by Tyan could be used with the purified C1q to detect complement-fixing membrane protein antibodies, as disclosed by Mehlhop. This obviousness is mainly owed to both references teaching complement system activation with IgG and C1q in the context of viral antigens. The art collectively teaches that the presence of complement fixing antibodies, i.e., the activation of the complement system, plays an important role in the mediation of immune, allergic, immunochemical, and immunopathological reactions, and can provide an indication of many biological disorders (Tyan; page 1, paragraphs 0001 and 0005). Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Tyan and Mehlhop before the effective filing date of the claimed invention with a reasonable expectation of success to detect complement fixing antibodies in a patient sample in a manner that is rapid, sensitive, and specific, particularly with respect to the ability to differentiate accurately and definitively among specific antigens (Tyan; page 1, paragraph 0006). All the claimed elements were known in the prior art. It would have been obvious to a person having ordinary skill in the art to have combined the elements as claimed by known methods with no change in their respective functions. The combination would have yielded nothing more than predictable results to one having ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143A and 2143.02.
23. Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Tyan and Mehlhop as applied to claims 1, 2, 5, 13 – 16, 22, and 23 above, and further in view of Sakamoto, S., et. al., (Enzyme-linked immunosorbent assay for the quantitative/qualitative analysis of plant secondary metabolites. Journal of natural medicines, 72(1), 32–42; Published 11/21/2017), hereby Sakamoto.
Tyan and Mehlhop do not explicitly teach that a pre-reporter antibody is contacted with C1q, which is in turn contacted with a detectably-labeled reporter antibody, as required in instant claims 3 and 4. However, Tyan does teach that direct or indirect ELISA can be used to detect the antigen, wherein the C1q can be measured directly by attaching a label to it or indirectly by introducing a detectably labeled anti-C1q antibody (page 5, paragraph 0061; page 7, paragraph 0079; page 9, paragraph 0103). It is further taught that the anti-C1q antibody can be goat anti-human C1q or sheep anti-human C1q (page 10, paragraph 0106). Tyan also teaches that a secondary binding molecule, i.e., a secondary antibody, can be introduced to the system to bind to the anti-C1q antibody (page 5, paragraphs 0060 and 0061; page 11, paragraph 0111; page 14, paragraph 0160). Sakamoto teaches that indirect ELISA is a two-step process of a primary antibody and labeled secondary antibody binding to a target, wherein the target is indirectly detected by the secondary antibody (page 35, left column), as recited in instant claims 3 and 4. It is further taught any antibody can be used in ELISA, wherein the variable heavy (VH) and variable light (VL) chains of antibodies have become popular probes, and the corresponding secondary antibodies need to be prepared, typically with the Fc region of immunoglobulin is used as the epitope (page 37, left column; page 40, left column). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See also In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960) and In re Ryco, Inc. v. Ag-Bag Corp., 857 F.2d 1418, 8 USPQ2d 1323 (Fed. Cir. 1988). In light of this case law, it would have been obvious to a person having ordinary skill in the art to have employed indirect ELISA instead of direct ELISA to have higher sensitivity, versatility, and signal (Sakamoto; page 35, table 2 [reproduced below]).
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Tyan, Mehlhop, and Sakamoto are considered to be analogous to the claimed invention because both Tyan and Mehlhop are drawn to the detection of complement fixing antibodies using C1q with the indirect ELISA method of Sakamoto being an obvious substitution for the direct ELISA method of Tyan. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to use the ELISA method and antibodies taught by Sakamoto in place of the ELISA method taught by Tyan with the purified C1q for the flaviviruses, as disclosed by Mehlhop to determine the presence or absence of complement fixing antibodies in a biological sample. This obviousness is mainly owed to Tyan and Mehlhop teaching complement system activation with IgG and C1q in the context of viral antigens. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Tyan, Mehlhop, and Sakamoto before the effective filing date of the claimed invention with a reasonable expectation of success to advantageously have higher sensitivity, versatility, and signal than direct ELISA methods to diagnose disease (Sakamoto; page 35, see also table 2 as reproduced above). All the claimed elements were known in the prior art. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143B and 2143.02.
24. Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Tyan and Mehlhop as applied to claims 1, 2, 5, 13 – 16, 22, and 23 above, and further in view of Dianova, (Fluorescent Dyes for Secondary Antibodies; Accessed 10/21/2019), hereby Dianova.
Neither Tyan nor Mehlhop teaches the explicit usage of xanthene, fluorescein isothiocyanate, rhodamine, phycoerythrin, cyanine, coumarin, and any derivative thereof, as the fluorescence label, as disclosed in instant claim 6. However, Tyan does teach that the detectable label is a fluorophore or fluorochrome (page 2, paragraph 0017; page 5, paragraph 0060; claim 15). Dianova teaches that the most often used fluorophores for immunoassays, including ELISA, are fluorescein, rhodamine, phycoerythrin, cyanin, coumarin, and their derivatives (pages 2 – 10). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See also In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960) and In re Ryco, Inc. v. Ag-Bag Corp., 857 F.2d 1418, 8 USPQ2d 1323 (Fed. Cir. 1988). In light of this case law, it would have been obvious to a person having ordinary skill in the art to substitute one known detectable label for another label to arrive at predictable results.
Tyan, Mehlhop, and Dianova are considered to be analogous to the claimed invention because both Tyan and Mehlhop are drawn to the detection of complement fixing antibodies using C1q with fluorophores from Dianova being an obvious substitution. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to use the fluorophores taught by Dianova in the method for determining the presence or absence of complement fixing antibodies in a biological sample using C1q, as taught by Tyan, with the purified C1q for the flaviviruses, as disclosed by Mehlhop. This obviousness is mainly owed to Tyan and Mehlhop teaching complement system activation with IgG and C1q in the context of viral antigens. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Tyan, Mehlhop, and Dianova before the effective filing date of the claimed invention with a reasonable expectation of success to detect complement fixing antibodies in a patient sample in a manner that is rapid, sensitive, and specific, particularly with respect to the ability to differentiate accurately and definitively among specific antigens (Tyan; page 1, paragraph 0006). All the claimed elements were known in the prior art. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143B and 2143.02.
25. Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Tyan and Mehlhop as applied to claims 1, 2, 5, 13 – 16, 22, and 23 above, and further in view of Schreiber, M. and Franzke, K (EP 2980099 A1; Published 03/02/2016), hereby Schreiber as evidenced by Dasso, J., et. al., (A comparison of ELISA and flow microsphere-based assays for quantification of immunoglobulins. Journal of immunological methods, 263(1-2), 23–33; Published 05/01/2002), hereby Dasso.
Tyan teaches that the antigen can be immobilized to a first substrate and a cross-reactive antigen can be immobilized on a second substrate, wherein different epitopes may be present in a sample as a specific antigen of interest and subsequently detected (page 5, paragraph 0059; page 10, paragraph 0109), as recited in instant claim 15. Schreiber teaches that ADE is a complication caused by non-neutralizing, cross-reactive antibodies that were induced by a primary DENV infection, enhancing viral entry when an infection with a second DENV serotype occurs that was different from the primary DENV serotype infection, leading to severe courses of DENV infections (page 2, paragraph 0005). It is further taught by Schreiber that the flavivirus E protein has a high degree of sequence identity (page 3, paragraph 0010). In terms of the assay, Dasso teaches that the beads can be coupled to a different biological probe, wherein the fluorescence of phycoerythrin can be measured independently per bead or in the same coupled set (page 28, left column; page 28, right column). Thus, it would be prima facia obvious to a person having ordinary skill in the art to duplicate/replicate the substrate, i.e., the microsphere complex, to have different epitopes, i.e., different DENV VLPs, present in the same sample to distinguish between different serotypes of DENV (page 3, paragraph 0010). See In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960). It would also be prima facia obvious to a person having ordinary skill in the art to change the order that the microspheres are contacted with the sample. See Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959); In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); and In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930). Moreover, the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See also In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960) and In re Ryco, Inc. v. Ag-Bag Corp., 857 F.2d 1418, 8 USPQ2d 1323 (Fed. Cir. 1988). In light of these case laws, it would have been obvious to a person having ordinary skill in the art to have coupled a specific antigen, i.e., DENV1, to a first microsphere, and a cross-reactive antigen, i.e., DENV2 on a second microsphere, and so forth for DENV3 and DENV4, to separate cross-reactive antibodies in a sample (Tyan, page 10, paragraph 0109), as recited in instant claim 15.
Tyan, Mehlhop, Schreiber, and Dasso are considered to be analogous to the claimed invention because both Tyan and Mehlhop are drawn to the detection of complement fixing antibodies using C1q with the Schreiber teaching the obviousness of duplication for the different DENV serotypes and the method from Dasso being an obvious substitution. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to use the individual beads taught by Dasso in the method for determining the presence or absence of complement fixing antibodies in a biological sample using C1q, as taught by Tyan, with the purified C1q for the flaviviruses, as disclosed by Mehlhop, with the motivation of detecting numerous DENV serotypes to anticipate ADE, as taught by Schreiber. This obviousness is mainly owed to Tyan and Mehlhop teaching complement system activation with IgG and C1q in the context of viral antigens. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Tyan, Mehlhop, Schreiber, and Dasso before the effective filing date of the claimed invention with a reasonable expectation of success to detect complement fixing antibodies in a patient sample in a manner that is rapid, sensitive, and specific, particularly with respect to the ability to differentiate accurately and definitively among specific antigens (Tyan; page 1, paragraph 0006). All the claimed elements were known in the prior art. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143B and 2143.02.
Conclusion
26. Claims 1 – 6, 13 – 16, 22, and 23 are rejected. No claims are allowed.
27. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272-6781. The examiner can normally be reached M-Th 7:30-5:30 ET.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671