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 III, claims 60-65, and the required species of blood, in the reply filed on 5/11/2026 is acknowledged. The traversal is on the ground(s) that there is no burden on searching all of the groups and species as set forth by the Examiner. This is not found persuasive because this application is a 35 U.S.C. §371 application, and the restriction requirement was due to a lack of unity between the groups identified by the examiner in the restriction requirement filed on 4/28/2026. The restriction is proper because the standard for unity of invention is whether the groups share a special technical feature, which the instant groups do not, as demonstrated by the restriction requirement filed on 4/28/2026. Accordingly, Applicant’s argument regarding the search burden is not relevant when determining whether a restriction requirement for an application under 35 U.S.C. §371 is proper.
The requirement is still deemed proper and is therefore made FINAL.
Claims 51-59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 5/11/2026.
Applicant failed to elect species from group A) of the election of species component of the restriction requirement filed on 4/28/2026: a specific composition comprising a specific sensitizer and a specific chemiluminescent compound. In Applicant’s next response to this action, please respond with respect to the species election requirement of a specific chemiluminescent compound by name/or chemical structure. Because biotin-specific binding partner is present in the composition comprising a sensitizer of claim 63, the examiner will examine that species at present.
Claims 60-65 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 9/22/2023, 6/13/2024, 11/21/2024, 5/13/2024, and 1/9/2026 are in compliance with 37 CFR 1.97. Accordingly, the references listed in the IDSs are being considered by the examiner.
Claim Interpretation
The specification indicates that the term “antibody” is used in the broadest sense and refers to, for example, intact monoclonal antibodies and polyclonal antibodies, multi-specific antibodies, antibody fragments and conjugates thereof that exhibit the desired biological activity of analyte binding, antibody substitute proteins or peptides, and combinations or derivatives thereof (spec., para. [0026]).
Claim Objections
Claims 60 and 63 are objected to because of the following informalities: the claims recite “activating the sensitizer to generate a singlet oxygen, wherein activation of the sensitizers present in the complex” at lines 17-18 and 19-20, respectively. To put the claims in better form, it is suggested that “sensitizers” is changed to “sensitizer”. Appropriate correction is required.
Claims 60 and 63 are objected to because of the following informalities: the claim contains a typographical mistake on line 13, where it recites “allowing the binding of (b) and (c) to antibodies to the SARS-COV-2 present in (a)”, but (a) contains antibodies to SARS-COV-2, not necessarily SARS-COV-2. It appears that the claim should instead recite “allowing the binding of (b) and (c) to antibodies to SARS-COV-2 present in (a)”, where “the” is removed. Claim 60 has the same issue on line 22. Claim 63 has the same issue on line lines 16, 17, and 24. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
Claims 60-65 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 a method for detecting the presence and/or concentration of antibodies to a microorganism in a human biological sample shown to have measurable amounts of antibodies in it, does not reasonably provide enablement for a method for detecting the presence and/or concentration of antibodies to a microorganism in any and all human biological samples with the specific methods claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 60.
The nature of the invention is a method for detecting the presence and/or concentration of antibodies to a microorganism in a human biological sample, the method comprising the steps of: (1) combining, either simultaneously or wholly or partially sequentially: (A) the human biological sample suspected of containing antibodies to SARS-CoV-2; (b) a composition comprising a singlet oxygen-activatable chemiluminescent compound having at least one antigen of SARS-CoV-2 directly or indirectly bound thereto; and (c) a composition comprising a sensitizer capable of generating singlet oxygen in its excited state and at least one anti-human immunoglobulin antibody directly or indirectly bound to the sensitizer; (2) allowing the binding of (b) and (c) to antibodies to the SARS-COV-2 present in (a), wherein the binding of (b) and (c) to the antibodies to the SARS-COV-2 results in the formation of a complex in which the sensitizer is brought into close proximity to the chemiluminescent compound; (3) activating the sensitizer to generate singlet oxygen, wherein activation of the sensitizers present in the complex causes the activation of the chemiluminescent compound present in each complex; and (4) determining the amount of chemiluminescence generated by the activated chemiluminescent compound in the complex to determine the presence and/or concentration of antibodies to the SARS-CoV-2 present in the sample (claim 60). In other embodiments, the at least one anti-human immunoglobulin antibody of (c) specifically binds to human IgA, human IgG, and human IgM (claims 61 and 64), or the human biological sample is selected from the group consisting of whole blood or any portion thereof, urine, saliva, sputum, cerebrospinal fluid, skin, intestinal fluid, intraperitoneal fluid, cystic fluid, sweat, interstitial fluid, extracellular fluid, tears, mucus, bladder wash, semen, fecal, pleural fluid, nasopharyngeal fluid, and combinations thereof (claims 62 and 65).
The level of skill of one skilled in this art is high.
The specification teaches detection of anti-RBD antibodies in COVID-19 positive samples using the assay format of the present disclosure (para. [0090] and Figs. 1-2). The assay format represented by Figure 2 resulted a positive result for anti-SARS-CoV-2 antibodies in all 15 of the COVID-19 positive samples. Figure 2 indicates that the sample is from serum or plasma (Fig. 2). These teachings do not enable the full breadth of the claims because they do not demonstrate detection of antibodies specific for SARS-CoV-2 from all sample types. The claimed assays utilize at least one antibody and so would have sensitivity similar to other antibody-based assays in tested sample types.
The state of the art is such that it is well established in the art that antibodies are not detectable in all tissues and fluids of a human subject. For example, Singh (Sensing and Bio-Sensing Research 50 100914, 2025) demonstrates that so far, no study has found the therapeutic antibody adalimumab in non-invasive biofluids like sweat (p. 2, col. 2, para. 1), and that previously reported methods for detecting adalimumab in serum or plasma have a linear ranges from 5 ng/ml to 100,000 ng/ml, and the concentrations of biomarkers in sweat are about 1:1000 of those in serum (p. 2, col. 2, para. 2). Furthermore, “although the presence of immunoglobulins and other serum components has been reported in the past [in sweat], these findings may have to be reexamined with the use of uncontaminated human sweat, because other studies have failed to confirm the presence of serum components other than albumin in human sweat collected over a white petrolatum (Vaseline) barrier on the skin to minimize epidermal contamination” (Sato, et al. J Am Acad Dermatol. 1989 Apr;20(4):537-63, p. 554, col. 2, para. 2). Additionally, antibody isotyping arrays on sweat from 50 individuals found that the antibodies were not universally present, were in the pg/ml concentration range when present, and exhibited high variable ranges (Katchman, et al. Proteomics Clin Appl. 2018 Nov;12(6):e1800010. doi: 10.1002/prca.201800010. Epub 2018 Jun 28. PMID: 29882373; Fig. 2B). These low levels and high variability add to the unpredictability of detection with an antibody assay that generally binds in the ng/mL range.
Thus, the state of the art recognized that it would be highly unpredictable to detect antibodies in samples such as sweat, even if antibodies may occasionally be present at low levels. One of skill in the art would neither expect nor predict the appropriate functioning of the method as broadly as currently claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Singh, Sato, and Katchman, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to detect the presence and/or concentration of antibodies to a microorganism, or SARS-CoV-2 specifically, in tissue or fluid samples where antibodies are not present in detectable quantities, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Written Description
Claims 61 and 64 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 instant claims above are drawn to a genus of at least one anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and human IgM. The specification indicates that the term “antibody” is used in the broadest sense and refers to, for example, intact monoclonal antibodies and polyclonal antibodies, multi-specific antibodies, antibody fragments and conjugates thereof that exhibit the desired biological activity of analyte binding, antibody substitute proteins or peptides, and combinations or derivatives thereof (spec., para. [0026]). Thus, the claimed invention encompasses a single monoclonal antibody that binds specifically to human IgA, human IgG, and human IgM.
Even if the prior art is aware of such anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM, the totality of known anti-human immunoglobulin antibodies would not be representative of the entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he 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.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have incomplete CDR sets, one must describe a sufficient variety of species to reflect the variation within the genus. 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 Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “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.” One of skill in this art cannot envision the structure of every anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM. The specification refers to “anti-human AMG, an anti-human antibody that specifically binds to all of IgA, IgM, and IgG, and thus provides for detection of total anti-SARS-CoV-2 antibodies in COVID-19 patient samples, where “total” refers to the sum of IgG, IgM, and IgA; Table 1” (spec., para. [0091]). However, the specification does not provide structural information (complete CDR set and VL/VH domains) about “anti-human AMG”. The specification does not disclose the structural information for a single antibody that specifically binds to human IgA, human IgG, and IgM, which would impart the function of binding specifically to IgA, IgG, and IgM. Therefore, since limited species are provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
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. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, 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. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Zero species is certainly not adequate. The disclosure does not provide examples with structural information (complete CDR set and VH/VL chains) of anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM that confer the required function.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
A representative number of species has not been taught to describe these genera; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and IgM, including full CDRs, specific, and full-length heavy and light variable chain domains.
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 60-65 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.
The term “wholly or partially sequentially” in claims 60 and 63, line 4, is a relative term which renders the claim indefinite. The term “wholly or partially sequentially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “wholly or partially sequentially” renders the claims indefinite because the metes and bounds of the action of “combining” are unclear. The term is confusing because, it is not clear how components could be partially sequentially added, whether that means a part of each component, or all of one component in a step-wise manner. Claims 61-62 and 64-65 are also indefinite because they depend from claims 60 or 63 and do not resolve the lack of clarity.
The term “close proximity” in in claims 60 and 63, lines 15-16 and 18, respectively, is a relative term which renders the claim indefinite. The term “close proximity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “close proximity” renders the claims indefinite because the metes and bounds of the proximity of the sensitizer to the chemiluminescent compound sufficient to be “close” are unclear. Claims 61-62 and 64-65 are also indefinite because they depend from claims 60 or 63 and do not resolve the lack of clarity.
Claim 63 recites the limitation "the microorganism present in the sample" in line 24. There is insufficient antecedent basis for this limitation in the claim. It appears that claim 60 and 63 have swapped the antibody targets relative to their preambles (claim 60’s preamble indicates microorganism and yet states SARS-CoV-2 at line 22, while claim 63’s preamble indicates SARS-CoV-2 and yet states microorganism at line 24).
Claim 64 recites “The method of claim 63, wherein the at least one anti-human immunoglobulin antibody of (c) specifically binds to human IgA, human IgG, and human IgM.” However, claim 63, part (c) does not recite an anti-human immunoglobulin antibody. Part (d) of claim 63 recites “at least one anti-human immunoglobulin antibody”. Accordingly, there is insufficient antecedent basis for the term “anti-human immunoglobulin antibody of (c)”, and the claim is further indefinite because it is unclear if claim 63, part (c) is supposed to have another anti-human immunoglobulin antibody, or if claim 64 has a typographical mistake, and is meant to refer to claim 63, part (d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 60-65 are rejected under 35 U.S.C. 103 as being unpatentable over Ullman (Clinical Chemistry 42:9 1518-1519. 1996, on IDS) in view of Amanat, et al. (Nat Med. 2020 Jul;26(7):1033-1036, cited in restriction requirement) and Zmuda (US Patent No. 8,124,348 B2, issued 2/28/2012).
The claimed invention encompasses method for detecting the presence and/or concentration of antibodies to a microorganism in a human biological sample, the method comprising the steps of: (1) combining, either simultaneously or wholly or partially sequentially: (A) the human biological sample suspected of containing antibodies to SARS-CoV-2; (b) a composition comprising a singlet oxygen-activatable chemiluminescent compound having at least one antigen of SARS-CoV-2 directly or indirectly bound thereto; and (c) a composition comprising a sensitizer capable of generating singlet oxygen in its excited state and at least one anti-human immunoglobulin antibody directly or indirectly bound to the sensitizer; (2) allowing the binding of (b) and (c) to antibodies to the SARS-COV-2 present in (a), wherein the binding of (b) and (c) to the antibodies to the SARS-COV-2 results in the formation of a complex in which the sensitizer is brought into close proximity to the chemiluminescent compound; (3) activating the sensitizer to generate singlet oxygen, wherein activation of the sensitizers present in the complex causes the activation of the chemiluminescent compound present in each complex; and (4) determining the amount of chemiluminescence generated by the activated chemiluminescent compound in the complex to determine the presence and/or concentration of antibodies to the SARS-CoV-2 present in the sample (claim 60).
The Prior Art
Ullman teaches a homogenous immunoassay method capable of rapid, quantitative determination of a wide range of analytes, including high and very low concentrations of large and small molecules, and specific IgM (Abstract). One particle has dissolved in it a photosensitizer that produces singlet oxygen when exposed to light, and the second particle has dissolved in it an olefin that, upon reaction with singlet oxygen, produces chemiluminescent emission, wherein the reaction with singlet oxygen with the subsequent emission is strongly dependent on the formation of particle pairs (pp. 1518-19, bridging para.). Ullman discloses an assay to detect IgM specific for HAV (anti-HAV IgM; HAV is hepatitis A virus, see footnote 1 on p. 1518), wherein a serum sample is combined with a chemiluminescer particle coated with HAV antigen and soluble biotinylated anti-human IgM antibody, incubated for 7 minutes, then streptavidin-coated sensitizer particles are added, and chemiluminescence read after an additional 7-min incubation (p. 1524, col. 2, para. 3). Ullman’s method exhibited high sensitivity, such that the samples could be diluted sufficiently to avoid interference from competitive binding by specific anti-HAV IgG for the limited amount of HAV Ag (Id.). Additionally, Ullman teaches that irradiation causes photosensitized formation of singlet oxygen, which migrates to a bound particle and activates the chemiluminscer, thereby initiating a luminescence emission (Abstract). Ullman discloses that the detection unit was designed to expose the sample alternately to a light source and then to a photomultiplier tube, where each chemiluminescence determination involved 3 to 10 sequential periods of 1s of irradiation and 1s of photon counting, and the signal was recorded as the total counts detected, an amount (p. 1519, cols. 1-2, bridging para.).
However, Ullman does not teach SARS-CoV-2 or a composition comprising a singlet oxygen-activatable chemiluminescent compound having at least one antigen of the SARS-COV-2 directly or indirectly bound thereto. Nor does Ullman disclose combining simultaneously or wholly or partially sequentially, the human biological sample, singlet oxygen-activatable chemiluminescent compound having at least one SARS-CoV-2 antigen directly or indirectly bound thereto, sensitizer capable of generating singlet oxygen in its excited state and at least one anti-human immunoglobulin antibody directly or indirectly bound to the sensitizer (as in claim 60), or combining simultaneously or wholly or partially sequentially, the human biological sample, singlet oxygen-activatable chemiluminescent compound having at least one SARS-CoV-2 antigen directly or indirectly bound thereto, sensitizer capable of generating singlet oxygen in its excited state and a biotin-specific partner directly or indirectly bound thereto, and at least one anti-human immunoglobulin (as in claim 63).
Amanat teaches ELISAs for screening and identification of human SARS-CoV-2 seroconversion, which are of critical importance to help define previous exposure to SARS-CoV-2 in populations and identifying highly reactive human donors for convalescent plasma therapy (Abstract). Amanat’s assays measure antibodies specific for SARS-CoV-2 spike protein and its receptor binding domain (Fig. 1). Amanat further discloses an ELISA protocol where the SARS-CoV-2 spike protein or RBD is coated onto 96-well plates, blocked with 3% non-fat milk, serial dilutions of sera and antibody samples in 1% non-fat milk added, the plates washed, and goat anti-human IgG-HRP conjugated secondary antibody added (p. 1037, col. 2, para. 2). The plates were then washed, substrate added, and stopped after 10 min, then optical density at 490 nm measured using a plate reader (p. 1037, col. 2, para. 2). Amanat also specifically discloses use of goat anti-human IgG-HRP conjugated secondary antibody in its ELISA protocols (p. 1037, col. 2, para. 2).
Accordingly, Amanat teaches at least one antigen of SARS-CoV-2 being the target for binding assays to detect antibodies specific for SARS-CoV-2.
It would have been obvious to one of ordinary skill in the art to modify the method disclosed by Ullman to detect the presence and/or concentration of antibodies to SARS-CoV-2 in a human biological sample. Ullman teaches that its immunoassay is capable of rapid, quantitative determination of a wide range of analytes, including high and very low concentrations of large and small molecules, and specifically virus-specific antibodies, and Amanat teaches that screening and identification of human SARS-CoV-2 seroconversion, which are of critical importance to help define previous exposure to SARS-CoV-2 in populations and identifying highly reactive human donors for convalescent plasma therapy.
Ullman discloses the structural components of a chemiluminescent compound and sensitizer complex formed in the method of the instant claims. Specifically, Ullman discloses a singlet oxygen-activatable chemiluminescent particle coated with HAV virus antigen, it would have been obvious to one of ordinary skill in the art, that in order to detect SARS-CoV-2 specific antibodies, the SARS-CoV-2 spike protein or RBD should be coated, because Amanat’s assays utilized those antigens to detect and measure SARS-CoV-2 specific antibodies. Ullman also discloses a biotinylated anti-human IgM antibody, which binds the virus-specific IgM in the sample, and then forms a complex with the streptavidin-coated sensitizer particles, due to the high affinity of biotin and streptavidin. Thus bringing the photosensitizer into close proximity of the chemiluminescer particle, which upon reaction with a singlet oxygen generated by irradiation, produces chemiluminescence that can be quantified.
Although Ullman’s sequence of combining the sample, chemiluminescent compound, sensitizer, and biotinylated antibody compositions is slightly different from the instant claims 60 and 63, the instant claims’ orders of mixing and specific compositions are obvious variant to those disclosed by Ullman. For instance, it would have been obvious to add the biotinylated anti-human antibody to the streptavidin-coated sensitizer composition disclosed by Ullman prior to adding that to the serum sample and SARS-CoV-2-antigen-bearing chemiluminescent compound (as in claim 60), and it would also have been obvious to add the antigen-particle complex, incubate, then add the with sensitizer, incubate, and then add the biotinylated anti-human antibody (as in claim 63) to arrive at the predictable results. Then, it would have been obvious to determine the amount of chemiluminescence generated by the chemiluminescent compound in the complex, as taught by Ullman’s method.
One of ordinary skill in the art would have been motivated to screening and identification of human SARS-CoV-2 seroconversion, which are of critical importance to help define previous exposure to SARS-CoV-2 in populations and identifying highly reactive human donors for convalescent plasma therapy. There would be a reasonable expectation of success because Ullman discloses use of similar assays to detect and quantify analytes for various substances, including sera samples containing virus-specific antibodies, and Amanat teaches use of SARS-CoV-2 spike protein or its RBD to detect and quantify SARS-CoV-2 specific antibodies in sera. Therefore, claims 60, 62-63, and 65 were prima facie obvious before the priority date of the instant invention.
However, Ullman and Amanat fail to disclose an antibody that specifically binds to human IgA, human IgG, and human IgM.
Zmuda teaches a method to detect hepatitis C virus-specific antibodies in oral fluid (Abstract). Zmuda evaluated whether the detection of multiple classes of anti-HCV antibodies, instead of IgG alone, could increase the sensitivity of an ELISA in a modified format (col, 5, last para.). Zmuda utilized a cocktail of peroxidase-labeled goat anti-human IgG+IgM+IgA antibodies instead of a monoclonal anti-human IgG, and resulted in all oral fluid samples from HCV positive individuals that were initially scored negative using anti-IgG alone were subsequently scored positive when detected using the anti-IgG+IgM+IgA cocktail (col. 6, paras. 1-2; Table II).
Accordingly, Zmuda teaches at least one anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and human IgM.
It would have been obvious to one of ordinary skill in the art to modify the teachings of Ullman and Amanat to incorporate use of a cocktail of anti-human IgG+IgM+IgA. Ullman discloses use of biotinylated anti-human antibodies and their use in chemiluminescence assays to detect virus-specific antibodies in serum. Zmuda discloses that use of the detection of multiple classes of anti-HCV antibodies, instead of IgG alone, could increase the sensitivity of an immunoassay. The specification indicates that the term “antibody” refers to combinations of monoclonal antibodies and polyclonal antibodies. It would have been obvious to one of ordinary skill in the art to and utilize a cocktail of biotinylated anti-human IgA+IgG+IgM antibodies to detect SARS-CoV-2 specific antibodies in samples from human subjects. One of ordinary skill in the art would have been motivated to increase the sensitivity of the immunoassay. There would be a reasonable expectation of success because Zmuda discloses use of an antibody cocktail of anti-human IgA+IgG+IgM in virus-specific antibody immunoassays. Therefore, claims 60-65 were prima facie obvious before the priority date of the instant invention.
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 60-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37 and 40-44 of copending Application No. 18/681,351 (published as PGPub US20250138011A1) in view of Zmuda (US Patent No. 8,124,348 B2, issued 2/28/2012).
Although the instant and copending claims are not identical, they are not patentably distinct from each other. Each set of claims is drawn to a method for detecting the presence and/or concentration of anti-SARS-CoV-2 antibodies in a sample, wherein simultaneously or wholly or partially sequentially, a sample suspected of containing SARS-CoV-2 antibodies is combined with a composition comprising a singlet oxygen-activatable chemiluminescent compound having at least one antigen of SARS-CoV-2 directly or indirectly bound thereto, a composition comprising a sensitizer capable of generating singlet oxygen in its excited state and a biotin-specific binding partner directly or indirectly bound thereto, allowing binding of the compositions to form complexes, activating the sensitizer to generate singlet oxygen, and determining the amount of chemiluminescence generated by the activated chemiluminescent compound (instant claims 60 and 63, copending claim 37), and at least one biotinylated anti-human immunoglobulin (Ig) antibody (instant claims 60 and 63, copending claim 37).
The claims differ in that the copending claims are drawn to a method of detecting the presence and/or concentration of multiple anti-SARS-CoV-2 antibodies specific to first and second SARS-CoV-2 proteins (copending claim 37), the instant claims do not require detection of multiple target-specific antibodies or utilize first and second target antigens (instant claims 60-65). Each set of claims also encompass embodiments wherein the sample is a biological sample of whole blood or any portion thereof (instant claims 62 and 65, copending claim 44.
Therefore, claims 60, 62-63, and 65 were obvious in view of ‘351.
However, ‘351 does not disclose at least one anti-human immunoglobulin antibody that specifically binds to human IgA, human IgG, and human IgM (claims 61 and 64).
The teachings of Zmuda are described above in the rejection under 35 U.S.C. §103.
It would have been obvious to one of ordinary skill in the art to modify the method of ‘351 to utilize a cocktail of anti-human IgG+IgM+IgA, as taught by Zmuda. One of ordinary skill in the art would have been motivated to increase the sensitivity of the immunoassay. There would have been a reasonable expectation of success because Zmuda discloses that use of anti-human IgG+IgM+IgA resulted in increased specificity relative to anti-human IgG alone.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is 571-272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights