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 .
Status of the Claims
Claims 1-4, 8-9, 12-22, and 37-38 are pending in the application.
Claims 22 and 37-38 are withdrawn.
Claims 1-4, 8-9, and 12-21 are the subject of this office action.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 8-9, and 12-21 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 claims encompass a broad genus of fluorophores which may be used as the first fluorophore and the second fluorophore within the claim method. The species of fluorophores are not explicitly limited except in claims 8 and 9 which provide a list of species for the first and/or second fluorophore. Claim further recites a wherein clause which requires a specific interaction between the first fluorophore and the second fluorophore within the claimed method (i.e. wherein the fluorescent emission from the first and the second fluorophore is proportionally reduced based on the target antibody concentration in the sample as compared to a sample lacking the target antibody).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The claimed invention is directed to a ratiometric bioassay method for detecting a target antibody in a sample.
The claims encompass a broad genus of fluorophores which may be used as the first fluorophore and the second fluorophore within the claim method. The species of fluorophores are not explicitly limited except in claims 8 and 9 which provide a list of species for the first and/or second fluorophore. Claim 1 further recites a wherein clause which requires a specific interaction between the first fluorophore and the second fluorophore within the claimed method (i.e. wherein the fluorescent emission from the first and the second fluorophore is proportionally reduced based on the target antibody concentration in the sample as compared to a sample lacking the target antibody).
The method described in the disclosure indicates that in the presence of the target antibody, the first fluorophore and second fluorophore are brought into proximity to one another via binding of the antigen and the antibody-binding moiety to the target antibody. This increase in proximity of the first fluorophore and the second fluorophore then causes a decrease in total fluorescence emission from the first fluorophore and second fluorophore which is thereby indicative of the presence of the target antibody in the sample (as described by the final wherein clause of instant claim 1) (see, e.g. Fig. 2; specification Par. 49.
Thus, the detection mechanism of the claimed bioassay relies on a quenching relationship between the first fluorophore and the second fluorophore when they are brought into proximity to one another by binding to the target antibody (specification Par. 49: molecular proximity results in ratiometric quenching of fluorescence emission of the first and second fluorophores; Par. 52: the results provided herein demonstrate that the mechanism underlying the bioassays of the present disclosure involve fluorescence quenching, reliant on the labelling of the antigen and PrL as an acceptor-donor pair. The decrease in fluorescein emission with mAb concentration is not due to a traditional FRET mechanism, since the rhodamine signal does not concurrently increase).
The specification provides reduction to practice for this quenching relationship with examples which comprise the use of fluorescein (Fl) and rhodamine (Rh) or AlexaFluor 350 and Rh as the first and second fluorophore. This reduction to practice demonstrates a quenching relationship between Fl and Rh with increasing antibody concentration within a certain range when the first fluorophore is Fl and the second fluorophore is Rh (see Figs. 3-4, 6-8). Fig. 5 indicates quenching of AF350 by Rh with increasing antibody concentration within a certain range when the first fluorophore is AF350 and the second fluorophore is Rh.
While these examples provide reduction to practice for three different fluorophores in two different pairings, the instant specification itself acknowledges that not all pairings of first and second fluorophores will function in this manner (Par. 49: control experiments conducted with two tags labeled with equal fluorophore, or two tags labeled with fluorophores of discrete absorbance and emission bands exhibited significantly reduced effect; Par. 142: experiments were conducted to evaluate whether other quenching phenomena occur, such as self-quenching, that drive the linear decrease in fluorescence emission. To this end, the fluorescence emission of the affinity complex formed using two Rh-labeled affinity tags (i.e. Rh as both the first fluorophore and the second fluorophore) was measured. No fluorescence quenching was observed with mAb concentration). Thus there is explicit admission that not all fluorophore pairings will produce the required quenching relationship, as fluorophores with either too much spectral overlap or two little spectral overlap will not exhibit this relationship. As such, the quenching relationship appears to require some amount of spectral overlap (as Par. 49 indicates that first and second fluorophores with discrete abs/em spectra will not exhibit quenching) but not too much (as Par. 49 and 142 indicate that fluorophores with equal abs/em spectra will not exhibit quenching).
This is further indicated by the discussion of high and low energy fluorophores in the disclosure (Par. 52: the results provided herein demonstrate that the mechanism underlying the bioassays of the present disclosure involve fluorescence quenching, reliant on the labelling of the antigen and PrL as an acceptor-donor pair; Par. 91: in some embodiments the antigen is coupled to a first fluorophore that is a high-energy fluorophore, and the antibody-binding moiety is coupled to a second fluorophore that is a low-energy fluorophore. A high-energy fluorophore generally has an excitation spectra bathochromically shifted from the excitation spectra of a low-energy fluorophore; Par. 143: the fluorescence quenching observed in these results consistently favors the quenching of the high-energy fluorophores, yet it requires the presence of a low-energy fluorophore). Thus, some specific relationship between the first fluorophore and the second fluorophore is required to produce the quenching relationship, but the metes and bounds of that relationship are unclear. That is, the metes and bounds of what constitutes a high-energy fluorophore and a low-energy fluorophore are unclear and the particular relationship between the first fluorophore and the second fluorophore required to meet the claim is unclear (i.e. how much spectral overlap between fluorophores is too much? how little is too little?).
The state of the art in this area is unpredictable, especially since many combinations of fluorophores in a similar arrangement would be expected to participate in a traditional FRET mechanism such that increased proximity of the fluorophores by binding to the target antibody would result in an increase in fluorescence emission rather than a decrease as required by the instant claim. For example, Nicolaides et al (US 2021/0285960 A1; previously cited) discloses an assay which is similar to the one instantly claimed. In one embodiment, the assay comprises detection of an antigen in a sample wherein a first affinity tag labeled with a first fluorophore binds the Fc region of an antibody, and a second affinity tag labeled with a second fluorophore binds the Fab region of the antibody. Binding of the antibody to the target antigen produces a conformational change in the antibody which brings the first fluorophore and the second fluorophore into closer proximity to one another, such that they participate in a FRET reaction, and fluorescence emission increases with increasing concentration of antigen in the sample (Fig. 1; Par. 4, 7; Par. 141-142: an increased FRET signal would indicate the antigen causing the first and second fluorophores to become closer in proximity, while a decreased FRET signal would indicate the antigen causing them to become more distal). Nicolaides provides a specific example where AF488 and AF555 are used as the first and second fluorophore.
Claims 8 and 9 further limit the species of the first and second fluorophore, but also explicitly encompass fluorophore pairing that will increase in fluorescence emission with increased proximity (e.g. multiple fluorophore pairings which could be made from the listings of species in claims 8 and 9 are known in the art to participate in traditional FRET mechanisms wherein an increase in proximity of the fluorophores would result in an increase in emission rather than a decrease, such as AF488 and AF55 as demonstrated in Nicolaides, or AF546 and AF594, as demonstrated in Ko et al ("Development of a novel FRET immunosensor for detection of listeria," SENSORS, 2003 IEEE, Toronto, ON, Canada, 2003, pp. 288-292 Vol.1)).
Thus, it is unclear how one of ordinary skill in the art would be able to recognize and select fluorophore pairings that participate in the quenching relationship required by the instant claims and differentiate them from those that do not (e.g. those that may have a relationship such as the one demonstrated in Nicolaides, wherein fluorescence emission would increase with proximity rather than decrease).
Therefore, the examples and the information provided in the disclosure as a whole are not sufficient to prove that the inventors had possession of the full scope of the method as claimed at the time of filing, because one of ordinary skill cannot, as one can do with a fully described genus, visualize or recognize the identity of all members of the genus that would exhibit the claimed functional relationship (i.e. the particularly recited quenching relationship). That is, the claims (with the exception of claims 8-9) do not limit the first and second fluorophores except by indicating that they must exhibit the desired quenching relationship, however, the disclosure and the prior art do not provide sufficient information for one of ordinary skill in the art to recognize and determine which pairings of fluorophores will exhibit this relationship or not, thus the information provided in the disclosure does not support the full scope of the claims, even for claims 8 and 9 which provide some limitation on the species of fluorophores.
Claims 1, 3-4, 8-9, and 12-21 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 an embodiment wherein the antigen is capable of being bound by the target antibody in the sample (i.e. claim 2), does not reasonably provide enablement for any other antigen (i.e. antigen which is not capable of being bound by the target antibody. 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.
A determination of enablement involves the consideration of the following factors: the breadth of the claims; the nature of the invention; the state of the prior art; level of one or ordinary skill; level of predictability in the art; amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Claims 1, 3-4, 8-9, and 12-21 all encompass any species of antigen which is not specifically limited. However, the disclosure indicates that the claimed method of detecting a target antibody relies on binding of the antigen coupled to a first fluorophore and an antibody-binding moiety coupled to a second fluorophore both binding to the target antibody, such that the first fluorophore and the second fluorophore are brought into proximity to one another when the target antibody is present in the sample. As such, binding of the antigen to the target antibody is critical to the function of the claimed assay. An antigen which is not capable of being bound by the target antibody will not bind to the target antibody and thus the first and second fluorophore will not be held in proximity to one another and will not produce a signal/change in signal which is indicative of the presence of the target antibody in the sample.
As such, the quantity of experimentation needed to make or use the full scope of the claimed invention based on the content of the disclosure is undo. Enablement requires that the disclosure provide a reasonable level of detail which would enable one of ordinary skill in the art to understand and carry out the full scope of the invention as claimed. In the instant case, such reasonable detail is lacking. There are numerous embodiments within the scope of the instant claims which are not reasonably supported or enabled by the instant disclosure or by the prior art.
For these reasons, when taken together with the breadth of the claims, the specification fails to teach one of ordinary skill in the art how to make and use the claimed invention in its full scope without undue experimentation.
Claim Rejections - 35 USC § 112(b)
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 1-4, 8-9, and 12-21 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.
Claim 1 is rejected as indefinite over the recitation “wherein the fluorescence emission from the first and the second fluorophore is proportionally reduced based on the target antibody concentration”, wherein the phrasing “based on” does not indicate a definite or defined relationship between fluorescence emission and antibody concentration, such that the metes and bounds of the claim are unclear.
Claim 3 is rejected as indefinite over the recitation “the ratiometric bioassay method is not FRET-based”. This is unclear because the metes and bounds of the term “FRET-based” are unclear, i.e. it is not clear what particular aspects or elements are required for an assay to be considered “FRET-based” such that the metes and bounds of the claim are unclear.
Claims 8-9 recite a list wherein the fluorophores listed all appear to be identified by trademarks/ trade names. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe particular species of fluorophores and, accordingly, the identification/description is indefinite.
Claim 12 is rejected as indefinite over the recitation “determining the target antibody concentration in the sample based on the proportionally reduced fluorescence emission” because the phrasing “based on” does not create a clear and defined relationship between the antibody concentration and the fluorescence emission such that the metes and bounds of the claim are unclear.
Dependent claims 2-4, 8-9, and 12-21 are rejected as indefinite because they depend from an indefinite claim and fail to remedy its deficiencies
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 8-9, 12-19, are rejected under 35 U.S.C. 103 as being unpatentable over Vallee-Belisle et al (CA 2818556 A1; IDS entered).
Regarding claims 1-2, Vallee-Belisle teaches a method comprising:
Combining an antigen coupled to a first fluorophore, an antibody-binding moiety coupled to a second fluorophore, and a sample comprising or suspected of comprising a target antibody; wherein the antigen is capable of being bound by the target antibody in the sample (Pg. 2, Ln. 5-19: a system for detecting one or more targets in a sample. The system includes a probe configured to produce a detectable signal when contacted by the one or more targets. The probe includes: a first target binding moiety and a second target binding moiety and a first signaling moiety and a second signaling moiety; Pg. 3, Ln. 22-23: the first signaling moiety and second signaling moiety may be fluorophores; Pg. 11, Ln. 20-21: the probes may recognize targets by specific binding of the target to the probe at a target binding moiety include on the probe; Pg. 14, Ln. 20-26: the target binding moieties may be any molecule that specifically binds to a target of the present disclosure. These include but are not limited to proteins, peptides, carbohydrates, nucleic acids, lipids, small molecules, and the like. The target binding moiety may be an antigen. The probe may include two different target binding moieties, and the target may be an antibody);
Exposing the antigen coupled to the first fluorophore, the antibody-binding moiety coupled to the second fluorophore, and the sample to fluorescent light comprising an excitation wavelength of the first and/or the second fluorophore; and detecting fluorescence emission from the first and/or the second fluorophore (Pg. 30, Ln. 20-35: fluorophore signal detected by a detector; Pg. 44, Ln. 25-30: fluorescence measurements obtained using a Cary Eclipse Fluorimeter; wherein it is generally understood in the art that measurement of a signal from a fluorophore comprises exposure to fluorescent light comprising an excitation wavelength of the first and/or second fluorophore);
Wherein the fluorescence emission from the first and the second fluorophore is reduced, and wherein the reduced fluorescence emission is proportional to the antibody concentration in the sample (Pg. 16, Ln. 27-30: under conditions in the presence of target, the distance the first signaling moiety moves away from the second signaling moiety. In some embodiments, this change in distance leads to a detectable decrease in signal; Pg. 20, Ln. 28-32: specific binding will allow an increase (or decrease) in signal with increasing amount of target contacted with the probe).
Though Vallee-Belisle does not explicitly recite a configuration wherein the probe comprises both the cognate antigen of the target antibody and an antigen-binding moiety comprising a polypeptide capable of binding a region of the target antibody that does not comprise the antigen-binding site, it is strongly implied by the teachings of the reference. The teaching of a target binding moiety comprising the cognate antigen of the target antibody is discussed above. Additionally, Vallee-Belisle teaches that the probe may comprise first and second target binding moieties that are explicitly different from one another, and suggests this configuration in the figures; further Vallee-Belisle’s discussion of cognate antigens as target binding moieties is presented as a non-limiting example of an target binding moiety that specifically binds to a target antibody, and this necessarily implies that there are additional species of target binding moiety that could be used to bind to regions of the antibody other than the antigen-binding site (Pg. 31, Ln. 10-19; Pg. 14, Ln. 20-33: in some cases, the probe includes two target binding moieties, wherein the first target binding moiety may be different from the second target binding moiety, for example in embodiments where the target is capable of binding to two or more different target binding moieties; Figs. 1 and 8 show oligonucleotide probes comprising two target binding moieties which each bind to a different region of the target antibody).
As such, although Vallee-Belisle shows exemplary use of a probe where both target binding moieties bind to an antigen binding site, and does not explicitly discuss an example wherein one target binding moiety is the cognate antigen and the second target binding moiety binds to a region of the target antibody other than the antigen binding site, it would have been obvious to one of ordinary skill in the art before the effective filing date to arrive at this probe configuration from the teachings of Vallee-Belisle which strongly suggest such a probe configuration, and which indicate that both a probe comprising two cognate antigens as the first and second target binding moieties or a probe comprising a cognate antigen as a first binding moiety and a second target binding moiety which binds to a region of the target antibody other than the antigen-binding region would be successful within the disclosed method of target antibody detection. As such, substitution of one configuration for the other amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success.
Regarding claim 3, the assay of Vallee-Belisle in view of Nicolaides is considered not FRET-based in that antibody is detected by a lack of energy transfer between the acceptor and donor fluorophores rather than a presence of energy transfer between the acceptor and donor fluorophores.
Regarding claims 8-9, Vallee-Belisle teaches the method wherein the first and/or the second fluorophore comprise the species recited in claims 8 and 9 (Pg. 18, L. 11-16, 26-29; Pg. 19, Ln. 15-21).
Regarding claim 12, Vallee-Belisle further teaches the method comprising determining the concentration of the target antibody in the sample based on the reduction in fluorescence emission of the first and second fluorophore (Pg. 20, Ln. 12-13: the probes are capable of identifying nanomolar to picomolar concentrations of targets in a sample; Pg. 33, Ln. 18-28: the subject systems and methods find use in a variety of applications wherein quantification of one or more targets in a sample is desired. The presence or absence of a target in a sample or significant changes in the concentration of a target over time can be used to diagnose disease risk or presence in an individual; Pg. 30, Ln. 30-35: the signal detected by the detector may be optionally compared to control readouts for control samples that contain a known amount of target; under conditions in the presence of target, the distance the first signaling moiety moves away from the second signaling moiety is sufficient to lead to a detectable change in the signal. In some embodiments, this change in distance leads to a detectable decrease in signal).
Regarding claims 13-14, Vallee-Belisle teaches the method further comprising incubating the sample comprising or suspected of comprising the target antibody, the antigen coupled to the first fluorophore, and the antibody-binding moiety coupled to the second fluorophore for 30min or less or 10 min or less prior to measuring the fluorescent emission of the first and/or second fluorophore (Pg. 30, Ln. 20-35; though Vallee-Belisle does not explicitly recite an incubation step of a particular length, the reference teaches combining the probe and sample to facilitate binding of the probe to the target in the sample, followed by detecting a fluorescent signal from the probe fluorophores. It is assumed, therefore, that some amount of time elapses between combining the probe and sample and detecting fluorescence in order to allow binding of probe and target to occur. Since there is no lower limit to the time required to meet the incubation step, any period of time that elpases between combining the sample and probe and detecting fluorescence (even if it is only a matter of seconds or a fraction of a second) is understood to read on the incubation steps recited in claims 13-14).
Regarding claims 15-17, Vallee-Belisle teaches the method of claim 1 as described above. Vallee-Belisle does not explicitly teach the particular ratio of antigen to first fluorophore, antibody-binding moiety to second fluorophore, or first fluorophore to second fluorophore, though the figures appear to suggest that these may generally all be present in about a 1:1 ratio, which would meet the limitations of the instant claims.
The prior art differs from the claimed invention only with respect to the particular ratios of antigen to first fluorophore, antibody-binding moiety to second fluorophore, and first fluorophore to second fluorophore, wherein the prior art does not explicitly teach a particular ratio, but appears to suggest a baseline ratio of about 1:1 for each of these components. The Court has stated that, generally, such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the claims present a relatively broad range of ratios, while the specification suggests that there is room for optimization within the claimed ratios (see, e.g. specification Par. 85).
As such, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at ratios for each of these reagents that meet the claimed limitations as a result or routine optimization. One of ordinary skill in the art would be motivated to optimize these ratios in order to optimize performance for the particular combinations of fluorophores, antigens, antibody-binding moieties, target antibody, and sample type used in a given assay. For example, one of ordinary skill might be motivated to change the ratio of the first fluorophore to the second fluorophore based on the particular interactions of the fluorophores chosen; one might be motivated to change the ratio of antigen to first fluorophore or antibody-binding moiety to second fluorophore based on the expected concentration of the target antibody in the sample (i.e. one might desire to increase or decrease the amount of fluorophore based on the concentration of the target in order to extend the limits of detection and quantification of the assay to the appropriate range for the chosen sample and target). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because such modification amounts to routine optimization which would yield predictable results in the disclosed assay.
Regarding claim 18, Vallee-Belisle teaches that the method may comprise use of a wide variety of different sample types (Pg. 33, Ln. 22-25), but does not explicitly teach the use of an undiluted sample.
The prior art differs from the claimed invention only with respect to the particular level of dilution of the sample. The Court has stated that, generally, such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification indicates that samples may be either diluted or undiluted (specification Par. 94).
As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Vallee-Belisle to specifically include the use of an undiluted sample. One of ordinary skill in the art would be motivated to modify and optimize the concentration (i.e. level of dilution) of a sample based on the sample type and expected concentration of the target antibody in order to ensure that concentration of the target antibody in the sample falls within the limits of quantification and detection of the disclosed method. For example, one of ordinary skill would be motivated to use an undiluted sample in a case where the expected concentration of the target antibody is low and is close to the limit of detection and quantification of the assay, such that further dilution of the sample would decrease the concentration of the target antibody to an undetectable level in the sample. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because such optimization of sample dilution is common practice in the art and because Vallee-Belisle teaches that the method may be used to detect a variety of different targets in a variety of different sample types, such that optimization of sample dilution would be an expected and routine practice in the use of the disclosed method.
Regarding claim 19, Vallee-Belisle further teaches the method wherein the sample is a whole blood sample, a plasma sample, a serum sample, a urine sample, a saliva sample, a tissue sample, a cell culture sample, a cell lysate sample, or a cell culture media sample (Pg. 31, Ln. 6-9).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Vallee-Belisle et al (CA 2818556 A1; IDS entered). as applied to claim 1 above, and further in view of Nicolaides et al (US 2021/0285960 A1; previously cited).
Regarding claim 4, Vallee-Belisle teaches the method wherein the antibody-binding moiety comprises a polypeptide capable of binding a region of the target antibody that does not comprise the antigen-binding site. Vallee-Belisle specifically teaches that the binding moiety may be a protein (Pg. 14, Ln. 20-26: the target binding moieties may be any molecule that specifically binds to a target of the present disclosure. These include but are not limited to proteins, peptides, carbohydrates, nucleic acids, lipids, small molecules, and the like).
Vallee-Belisle differs from the instant claim in that it does not explicitly teach that the antibody-binding moiety comprises Protein A, Protein L, or Protein G.
Nicolaides discloses protein probes that bind to target antibodies (Abstract). Nicolaides teaches that the probes may comprise a first antibody binding moiety coupled to a first fluorophore, and a second antibody binding moiety coupled to a second fluorophore, wherein the first and second antibody binding moieties bind to different regions of the antibody (Fig. 1; Par. 4: a first fluor-labeled protein or aptamer that specifically binds to the Fab domain of the antibody and a second fluor-labeled protein or aptamer that specifically binds to the Fc domain of the antibody). Nicolaides further teaches that the antibody-binding protein or aptamer may comprise a polypeptide that is capable of binding a region of the target antibody that does not comprise the antigen binding site, and teaches that these polypeptides may be used in combination with a fluor-labeled cognate antigen of the antibody (Par. 19: One protein or aptamer may be protein A and one may be protein L. Alternatively, one may be protein A and one may be the cognate antigen to which the antibody binds).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Vallee-Belisle such that the antibody binding moiety which binds to a region of the antibody other than the antigen-binding site comprises Protein A, as taught by Nicolaides. Vallee-Belisle teaches a dual affinity probe which may comprise two different target binding moieties for the detection of a target antibody, wherein one of the target binding moiety may be a cognate antigen, and the second target binding moiety may be different from the first target binding moiety, and may bind a different region of the target antibody. Vallee-Belisle also specifically teaches that the target binding moiety may comprise any molecule that binds to the target, including a protein (Pg. 14, Ln. 20-26). Additionally, Figs. 1, 8 and/or 10 of Vallee-Belisle appear to show target binding moieties which bind to the Fc region of an antibody. However, Vallee-Belisle is generic regarding the particular species of protein target-binding moiety used or the specific species of target binding moiety which might be used to bind the Fc region of the target antibody. As such, one would be motivated to use an appropriate species of protein target binding moiety for binding the target antibody, such as the species Protein A, taught by Nicolaides. Additionally, such modification of a protein target binding moiety taught by Vallee-Belisle for the particular species of protein target binding moiety taught by Nicolaides amounts to simple substitution of known elements to achieve predictable results. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Vallee-Belisle teaches a method comprising a fluor-labeled target binding moiety which may be a protein target binding moiety that binds to a target antibody, while Nicolaides similarly teaches a fluor-labeled target binding moiety which may be a protein target binding moiety that binds to a target antibody (Protein A).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Vallee-Belisle et al (CA 2818556 A1; IDS entered), as applied to claim 1 above, and further in view of Funari et al (Detection of antibodies against SARS-CoV-2 spike protein by gold nanospikes in an opto-microfluidic chip. Biosens Bioelectron. 2020 Dec 1;169:112578. Epub 2020 Sep 3.).
Regarding claim 20, Vallee-Belisle teaches the method of claim 1, as described above, and teaches that the target detected may be a target antibody which may be detected via a probe comprising a cognate antigen of the target antibody, wherein the particular type of target antibody and cognate antigen used are not particularly limited. Vallee-Belisle differs from the instant claim in that it does not explicitly teach an embodiment wherein the antigen comprises the spike protein of SARS-CoV-2 or a fragment thereof.
Regarding claim 20, Funari teaches a immunoassay method for the detection of antibodies against SARS-CoV-2 spike protein (Abstract) wherein the method comprises a SARS-CoV-2 spike protein antigen which is used to capture and facilitate detection of the antibody against SARS-CoV-2 spike protein (Abstract; Pg. 2, Col. 2, last Par.: functionalization of gold nanospikes with SARS-CoV02 S peptide). Funari teaches that detection of antibodies against SARS-CoV-2 spike protein is important for uses such as identifying false negative qRT-PCR responses, tracking how effectively a patient’s immune system is fighting the infection, and plasma transfusion therapies (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Vallee-Belisle to specifically comprise use of a SARS-CoV-2 spike protein or a fragment thereof as the antigen. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper antigen for the detection of the chosen target antibody. Specifically, one would be motivated to use a SARS-CoV-2 spike protein or fragment thereof for the detection of antibodies against SARS-CoV-2 spike protein because Funari teaches that detection of antibodies against SARS-CoV-2 spike protein is important for uses such as identifying false negative qRT-PCR responses, tracking how effectively a patient’s immune system is fighting the infection, and plasma transfusion therapies (Abstract). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Vallee-Belisle teaches an immunoassay wherein detection of a target antibody may comprise use of a cognate antigen of that target antibody, wherein the antigen and antibody are not particularly limited, and Funari teaches that antibodies against SARS-CoV-2 spike protein may be detected by immunoassay methods which comprise the use of SARS-CoV-2 spike protein or a fragment thereof.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Vallee-Belisle et al (CA 2818556 A1; IDS entered), as applied to claim 1 above, and further in view of Falese et al (Strategy to detect pre-existing immunity to AAV gene therapy. Gene Ther. 2017 Dec;24(12):768-778.).
Regarding claim 21, Vallee-Belisle teaches the method of claim 1, as described above, and teaches that the target detected may be a target antibody which may be detected via a probe comprising a cognate antigen of the target antibody, wherein the particular type of target antibody and cognate antigen used are not particularly limited. Vallee-Belisle differs from the instant claim in that it does not explicitly teach an embodiment wherein the antigen comprises the capsid protein of a viral vector for gene therapy or a fragment thereof.
Regarding claim 21, Falese teaches that AAVs are a promising viral vector for gene therapy, but that the efficacy may be limited in individuals with pre-existing immunity to AAVs (Abstract). Falese discloses in vitro assays for the study of pre-existing AAV5 immunity in humans which can be used to identify individuals who are more or less likely to response to AAV5-directed gene therapy (Abstract).
Falese teaches an immunoassay for the detection of anti-AAV5 antibodies which involves using AAV5 capsid proteins to capture and detect anti-AAV5 antibodies (Fig. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Vallee-Belisle to specifically comprise use of a AAV capsid protein or a fragment thereof as the antigen. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper antigen for the detection of the chosen target antibody. Specifically, one would be motivated to use an AAV capsid protein or fragment thereof for the detection of antibodies against AAV because Falese teaches that detection of antibodies against AAVs is important for uses such as identifying patients who are more or less likely to benefit from gene therapies that use AAV as viral vectors (Abstract). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Vallee-Belisle teaches an immunoassay wherein detection of a target antibody may comprise use of a cognate antigen of that target antibody, wherein the antigen and antibody are not particularly limited, and Falese teaches that antibodies against AAV capsid protein may be detected by immunoassay methods which comprise the use of AAV capsid protein or a fragment thereof.
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 1, 3, 8-9, and 12-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-6, 11, and 14-17 of copending Application No. 18/713,047 in view of Vallee-Belisle et al (CA 2818556 A1; IDS entered).
All limitations of instant claims 1-2 are taught by reference claims 1 and 3 with the exception that reference claim 1 does not specifically teach that the altered emission which is proportional to the antibody concentration in the sample is specifically a reduction in emission.
Regarding instant claims 1, Vallee-Belisle teaches:
Combining an antigen coupled to a first fluorophore, an antibody-binding moiety coupled to a second fluorophore, and a sample comprising or suspected of comprising a target antibody (Pg. 2, Ln. 5-19: a system for detecting one or more targets in a sample. The system includes a probe configured to produce a detectable signal when contacted by the one or more targets. The probe includes: a first target binding moiety and a second target binding moiety and a first signaling moiety and a second signaling moiety; Pg. 3, Ln. 22-23: the first signaling moiety and second signaling moiety may be fluorophores; Pg. 11, Ln. 20-21: the probes may recognize targets by specific binding of the target to the probe at a target binding moiety include on the probe; Pg. 14, Ln. 20-26: the target binding moieties may be any molecule that specifically binds to a target of the present disclosure. These include but are not limited to proteins, peptides, carbohydrates, nucleic acids, lipids, small molecules, and the like. The target binding moiety may be an antigen. The probe may include two different target binding moieties, and the target may be an antibody);
Exposing the antigen coupled to the first fluorophore, the antibody-binding moiety coupled to the second fluorophore, and the sample to fluorescent light comprising an excitation wavelength of the first and/or the second fluorophore; and detecting fluorescence emission from the first and/or the second fluorophore (Pg. 30, Ln. 20-35: fluorophore signal detected by a detector; Pg. 44, Ln. 25-30: fluorescence measurements obtained using a Cary Eclipse Fluorimeter; wherein it is generally understood in the art that measurement of a signal from a fluorophore comprises exposure to fluorescent light comprising an excitation wavelength of the first and/or second fluorophore);
Wherein the fluorescence emission from the first and the second fluorophore is reduced, and wherein the reduced fluorescence emission is proportional to the antibody concentration in the sample (Pg. 16, Ln. 27-30: under conditions in the presence of target, the distance the first signaling moiety moves away from the second signaling moiety. In some embodiments, this change in distance leads to a detectable decrease in signal; Pg. 20, Ln. 28-32: specific binding will allow an increase (or decrease) in signal with increasing amount of target contacted with the probe).
As such, it would have been obvious to one of ordinary skill in the art to have modified the method of the reference claim such that the change in emission is specifically a reduction in emission, as taught by Vallee-Belisle. One of ordinary skill in the art would be motivated to make this modification because the reference claims teach an assay wherein a change in emission is proportional to the antibody concentration in the sample, but is generic regarding how the emission is altered. One of ordinary skill in the art would recognize that such an alteration would be dependent upon the specific fluorophores used in the assay, wherein Vallee-Belisle teaches that such an assay may comprise the use of a combination of two fluorophores, wherein the fluorophores interact such that a reduction in emission is proportional to the antibody concentration in the sample. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claim and Vallee-Belisle are directed to similar assays wherein a change in emission is proportional to the antibody concentration in the sample.
Regarding instant claims 8-9, reference claims 5-6 teach that one fluorophore may be high energy while the other may be low-energy, but the reference claims do not specify the particular species of fluorophore used.
Regarding instant claims 8-9, Vallee-Belisle teaches that the high energy fluorophore may be Alexa488 while the low energy fluorophore may be Alexa555 (Pg. 19, Ln 15-20).
It would have been obvious to one of ordinary skill in the art to have modified the reference claims such that the specific high energy fluorophore used is Alexa488 while the specific low energy fluorophore used is Alexa555, as taught by Vallee-Belisle. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper reagents for the disclosed assay, wherein the reference claims teach a combination of a high energy fluorophore and a low energy fluorophore, but are generic regarding the particular species of fluorophore used, while Vallee-Belisle teaches specific species of fluorophores (Alexa488 and Alexa555) which may be used for the disclosed method. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claims and Vallee-Belisle are both directed to similar bioassays comprising the use of a high energy fluorophore and a low energy fluorophore.
All additional limitations of instant claim 12 are taught by reference claim 11.
All additional limitations of instant claims 15-18 are taught by reference claims 14-17.
Regarding instant claims 13-14, the reference claims do not explicitly teach the inclusion of an incubation step in the disclosed method.
Regarding instant claims 13-14, Vallee-Belisle teaches the method further comprising incubating the sample comprising or suspected of comprising the target antibody, the antigen coupled to the first fluorophore, and the antibody-binding moiety coupled to the second fluorophore for 30 minutes or less or 10 minutes or less prior to measuring the fluorescent emission of the first and/or the second fluorophore (Pg. 30, Ln. 20-35; though Vallee-Belisle does not explicitly recite an incubation step of a particular length, the reference teaches combining the probe and sample to facilitate binding of the probe to the target in the sample, followed by detecting a fluorescent signal from the probe fluorophores. It is assumed, therefore, that some amount of time elapses between combining the probe and sample and detecting fluorescence in order to allow binding of probe and target to occur. Since there is no lower limit to the time required to meet the incubation step, any period of time that elapses between combining the sample and probe and detecting fluorescence (even if it is only a matter of seconds or a fraction of a second) is understood to read on the incubation steps recited in claims 13-14).
It would have been obvious to one of ordinary skill in the art to modify the method of the reference claims to specifically include an incubation step. One of ordinary skill in the art would be motivated to make this modification because such incubation would allow time for the labeled binding reagents to bind to the target in the sample, which would increase the accuracy and efficacy of the assay. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because incubation steps to facilitate time for binding to occur are common practice in immunoassay methods.
Regarding instant claim 19, the reference claims do not specifically teach the sample type used in the method.
Regarding instant claim 19, Vallee-Belisle teaches that the sample type used with the disclosed method may be a whole blood sample, a plasma sample, a serum sample, a urine sample, a saliva sample, a tissue sample, a cell culture sample, a cell lysate sample, or a cell culture media sample (Pg. 22-25).
It would have been obvious to one of ordinary skill in the art to modify the method of the reference claims to include the sample types taught by Vallee-Belisle. One of ordinary skill in the art would be motivated to make this modification because the reference claims are generic regarding the type of sample used, while Vallee-Belisle teaches a variety of appropriate sample types which may be used with the disclosed method. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claims and Vallee-Belisle are directed to similar bioassays comprising the use of a biological sample.
This is a provisional nonstatutory double patenting rejection.
Claims 3-4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 18/713,047 in view of Vallee-Belisle et al (CA 2818556 A1; IDS entered), as applied to claim 1 above, and further in view of Nicolaides et al (US 2021/0285960 A1).
Regarding instant claims 3-4, reference claim 3 teaches that the antibody binding moiety is capable of binding a region of the target antibody that does not interfere with the antigen binding. The reference claims do not specifically teach that the antibody binding moiety is specifically a polypeptide.
Regarding instant claims 3-4, Vallee-Belisle teaches that the antibody binding moiety may comprise a polypeptide that is capable of binding the target antibody outside the antigen binding region (Pg. 31, Ln. 15-17).
Nicolaides discloses protein probes that bind to target antibodies (Abstract). Nicolaides teaches that the probes may comprise a first antibody binding moiety coupled to a first fluorophore, and a second antibody binding moiety coupled to a second fluorophore, wherein the first and second antibody binding moieties bind to different regions of the antibody (Fig. 1; Par. 4: a first fluor-labeled protein or aptamer that specifically binds to the Fab domain of the antibody and a second fluor-labeled protein or aptamer that specifically binds to the Fc domain of the antibody). Nicolaides further teaches that the antibody-binding protein or aptamer may comprise a polypeptide that is capable of binding aregion of the target antibody that does not comprise the antigen binding site, and teaches that these polypeptides may be used in combination with a fluor-labeled cognate antigen of the antibody (Par. 19: One protein or aptamer may be protein A and one may be protein L. Alternatively, one may be protein A and one may be the cognate antigen to which the antibody binds).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of the reference claims such that the antibody binding moiety comprises a polypeptide capable of binding a region of the target antibody that does not comprise the antigen binding site, such as Protein A, as taught by Vallee-Belisle and Nicolaides. One of ordinary skill in the art would be motivated to make this modification because the reference claims teach probes which may comprise two different fluor-labeled target-binding moieties, wherein the target may be an antibody, and one of the target binding moieties may be the cognate antigen of the target antibody. As such, since the cognate antigen binds to the antigen binding site of the antibody, one would be motivated to choose a second target-binding moiety that binds to a different region of the antibody (such as Protein A which is known to bind to the Fc region of an antibody) in order to prevent the two target-binding moieties from interfering with one another. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claims teach a method comprising a first fluor-labeled target binding moiety and a second fluor-labeled target binding moiety, wherein one target binding moiety may comprise a cognate antigen of a target antibody and one target binding moiety may comprise an antibody binding moiety that binds to a target antibody, while Nicolaides similarly teaches a first fluor-labeled target binding moiety which may comprise a cognate antigen of the antibody and a second fluor-labeled target binding moiety which may comprise a polypeptide that specifically binds to the antibody in a region of the antibody that does not comprise the antigen binding site. Wherein both the method of the reference claims and the method of Nicolaides comprise characterizing and/or detecting an antibody based on fluorescent signals produced by the two different fluor-labeled target binding moieties.
It would have been obvious to one of ordinary skill in the art to have modified the invention of the reference claims such that the antibody binding moiety capable of binding a region of the target antibody that does not interfere with antigen binding is a polypeptide. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper reagents for the chosen assay. That is, the reference claims teach an antibody-binding moiety but are generic regarding the particular species and structure of the antibody binding moiety, while Vallee-Belisle teaches that appropriate antibody binding moieties for the disclosed method may include polypeptides that bind to the target macromolecule. One of ordinary skill in the art would be motivated to make this modification because both the reference claims and Vallee-Belisle are directed to similar bioassays comprising the use of labeled antibody binding moieties.
This is a provisional nonstatutory double patenting rejection.
Claim 20 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/713,047 in view of Vallee-Belisle et al (CA 2818556 A1; IDS entered), as applied to claim 1 above, and further in view of Funari et al (Detection of antibodies against SARS-CoV-2 spike protein by gold nanospikes in an opto-microfluidic chip. Biosens Bioelectron. 2020 Dec 1;169:112578. Epub 2020 Sep 3.).
Regarding instant claim 20, reference claim 1 teaches that the method comprises an antigen coupled to a first fluorophore, but is generic regarding the specific identity of the antigen.
Regarding claim 20, Funari teaches an immunoassay method for the detection of antibodies against SARS-CoV-2 spike protein (Abstract) wherein the method comprises a SARS-CoV-2 spike protein antigen which is used to capture and facilitate detection of the antibody against SARS-CoV-2 spike protein (Abstract; Pg. 2, Col. 2, last Par.: functionalization of gold nanospikes with SARS-CoV02 S peptide). Funari teaches that detection of antibodies against SARS-CoV-2 spike protein is important for uses such as identifying false negative qRT-PCR responses, tracking how effectively a patient’s immune system is fighting the infection, and plasma transfusion therapies (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by the reference claims to specifically comprise use of a SARS-CoV-2 spike protein or a fragment thereof as the antigen. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper antigen for the detection of the chosen target antibody. Specifically, one would be motivated to use a SARS-CoV-2 spike protein or fragment thereof for the detection of antibodies against SARS-CoV-2 spike protein because Funari teaches that detection of antibodies against SARS-CoV-2 spike protein is important for uses such as identifying false negative qRT-PCR responses, tracking how effectively a patient’s immune system is fighting the infection, and plasma transfusion therapies (Abstract). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claim teaches an immunoassay wherein detection of a target antibody may comprise use of a cognate antigen of that target antibody, wherein the antigen and antibody are not particularly limited, and Funari teaches that antibodies against SARS-CoV-2 spike protein may be detected by immunoassay methods which comprise the use of SARS-CoV-2 spike protein or a fragment thereof.
This is a provisional nonstatutory double patenting rejection.
Claim 21 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/713,047 in view of Vallee-Belisle et al (CA 2818556 A1; IDS entered), as applied to claim 1 above, and further in view of Falese et al (Strategy to detect pre-existing immunity to AAV gene therapy. Gene Ther. 2017 Dec;24(12):768-778.).
Regarding instant claim 21, reference claim 1 teaches the method comprising comprises an antigen coupled to a first fluorophore, but is generic regarding the specific identity of the antigen.
Regarding claim 21, Falese teaches that AAVs are a promising viral vector for gene therapy, but that the efficacy may be limited in individuals with pre-existing immunity to AAVs (Abstract). Falese discloses in vitro assays for the study of pre-existing AAV5 immunity in humans which can be used to identify individuals who are more or less likely to response to AAV5-directed gene therapy (Abstract).
Falese teaches that these assays include an immunoassay for the detection of anti-AAV5 antibodies which involves using AAV5 capsid proteins to capture and detect anti-AAV5 antibodies (Fig. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by the reference claims to specifically comprise use of a AAV capsid protein or a fragment thereof as the antigen. One of ordinary skill in the art would be motivated to make this modification because one would be motivated to use the proper antigen for the detection of the chosen target antibody. Specifically, one would be motivated to use a AAV capsid protein or fragment thereof for the detection of antibodies against AAV because Falese teaches that detection of antibodies against AAVs is important for uses such as identifying patients who are more or less likely to benefit from gene therapies that use AAV as viral vectors (Abstract). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because the reference claim teaches an immunoassay wherein detection of a target antibody may comprise use of a cognate antigen of that target antibody, wherein the antigen and antibody are not particularly limited, and Falese teaches that antibodies against AAV capsid protein may be detected by immunoassay methods which comprise the use of AAV capsid protein or a fragment thereof.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed 10 March 2026 have been fully considered.
Objections to the specification are overcome by amendment and by corrected filing of a sequence listing.
The previous 112(b) rejections are withdrawn except where repeated above. Applicant’s arguments regarding trademarks and tradenames in claims 8-9 are not persuasive because trademarks and tradenames render the claim scope uncertain since the trademark or trade name cannot be used properly to identify any particular material or product.
The 102 rejection is withdrawn in view of the amendments to the claims and is replaced by new grounds of 103 rejection which address Applicant’s arguments and amendments.
Regarding the 103 rejection of claim 4, Applicant argues that the motivation to combine Vallee-Belisle and Nicolaides provided in the previous rejection is insufficient. This rejection is amended above to better address motivation to combine.
Additionally, applicant argues that Nicolaides teaches a different assay architecture that is not combinable with Vallee-Belisle. This argument is not persuasive. It is noted in the rejection above that Vallee-Belisle teaches a probe comprising two target binding moieties which may be two distinct target binding moieties (i.e. they may specifically bind to different part of the target); Vallee-Belisle teaches that these target binding moieties may be proteins capable of binding to the target; Vallee-Belisle teaches that one of the target binding moieties may be the cognate antigen of a target antibody.
As such, Nicolaides is not relied upon to teach an assay architecture that is combinable as a whole with the assay of Vallee-Belisle. Nicolaides is only relied upon to teach a specific species of protein which can be used as a second target binding moiety to bind to a different part of a target antibody than a first target binding moiety which comprises the cognate antigen of the target antibody. As such, this combination of the prior art does not require the skilled artisan to substantially redesign the probe architecture and the signal transduction mechanism, and the combination is understood to have a reasonable expectation of success, as described in the rejection above.
New grounds of double patenting rejection which address the amendments to the claims are presented above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLIS LUSI whose telephone number is (571)270-0694. The examiner can normally be reached M-Th 8am-6pm ET.
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, Bao-Thuy Nguyen can be reached at (571) 272-0824. 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.
/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
Prosecution Insights