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 .
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.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2022/078688, filed 10/26/2022, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/271,983, filed 10/26/2021.
Information Disclosure Statement
The information disclosure statement (IDS) entered 06/12/2024 is considered, initialed and is attached hereto.
Status of the Claims
Claims 1, 8-10, 12, 15-18, 25-27, 29, 32-37, 39, 42, 50, 57-59, 61 and 64-66 are pending; claims 2-7, 11, 13-14, 19-24, 28, 30-31, 38, 40-41, 43-49, 51-56, 60 and 62-63 are canceled; no claims are amended
Claim Objections
Claims 9, 26, 35 and 58 are objected to because of the following informalities:
Claims 9, 26 and 58 recite a typographical error, see at a) it appears the word “to” is missing following “identical” (the claim should read “at least 70% identical to SEQ ID NO: 3”).
Claim 35 is recited as two distinct sentences, as such the claim is objected to for periods in the claims. See MPEP 608.01(m), Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). As such, the claim is objected to for periods in the claim.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The specification at paras [0130] and [0176] each contain typographical errors, see at para [0130], the specification (end of paragraph, second to last line), see “176B” should read as “17B6”, and at [0176] it appears that “conugate” should be “conjugate”.
The specification is objected to because Table 2 at page 38 and Table 4 at pages 39-40, the first letter/number of each entry in the table is missing (e.g., see first column, first row, “lone” should be “clone”).
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.
Claims 8, 9, 25, 26, 57, 58 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.
Claims 8, 25 and 57 each recite “one or more capture antibodies or one or more detection antibodies comprise VH amino acid sequence pair at least 70% identical to any one of SEQ ID NO: 3, SEQ ID NO: 7, or SEQ ID NO: 11, and VL amino acid sequence at least 70% identical to any one of SEQ ID NO: 4, SEQ ID NO: 8, or SEQ ID NO: 12”.
Claims 9, 26 and 58 each recite “a) a VH amino acid sequence at least 70% identical SEQ ID NO: 3 and a VL amino acid sequence at least 70% identical to SEQ ID NO: 4;b) a VH amino acid sequence at least 70% identical to SEQ ID NO: 7 and a VL amino acid sequence at least 70% identical to SEQ ID NO: 8; or c) a VH amino acid sequence at least 70% identical to SEQ ID NO: 11 and a VL amino acid sequence at least 70% identical to SEQ ID NO: 12”.
The claims encompass several genus of antibodies (one for each combination of VH and VL chain), each described by partial structure (at least 70% identity to the claimed VH and VL sequences) and functional ability (antibodies that binds/capture dermatophyte antigen such to achieve detection of a dermatophyte organism).
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.
As noted above, regarding structure, although the claims do recite sequences (referring to the VH and VL sequences noted above), the structures are only somewhat limiting and are still open to substantial variability (at least 70% identical to the claimed sequences) as the scope of the claim language “at least 70% identical” is still quite large and this would encompass various different substitutions, deletions and/or additions to those recited sequences. Neither the claims or the originally filed specification specify which particular residues are necessarily required or essential to binding, there is no clear indication what residues in each of the sequences must be conserved to retain the recited functional language.
Regarding Applicant’s actual reduction to practice (see Examples starting at page 33 of the originally filed specification), at Example 1 Applicant refer to a specific monoclonal antibody, 17B6, which Applicant discloses demonstrates immunoreactivity to T. rubrum as well as lesser common fungal species (Example 1 does not disclose what those lesser common species are, see also para [0130]). See also Example 2 (gold conjugate lateral flow assay), also is an example that relies upon antibody 17B6.
Furthermore, for example, para [0143], Table 3 and Figure 5, applicant demonstrate different antibody species that bind dermatophytes and “unrelated organisms”. Table 2 is a list of specific T. rubrum monoclonal antibodies.
While the originally filed specification supports that there are many specific species of dermatophyte antigen binding antibody, it is not readily clear from the present disclosure and examples therein if any of those recited sequences at claims 8, 9, 25, 26, 57 and 58 are specific to 17B6 or to one of those other antibody clones referenced in the originally filed specification examples. Further, even if it is made clear that one of the referenced antibodies corresponds with two of the claimed sequences (is specific to a particular VH and VL sequences recited), there is no identification of the relevant structure(s) for binding (i.e., which are the conserved residues, or CDRs within these sequences which are necessary for binding/function).
The level of skill in the art is high, and the methods of making and/or screening monoclonal antibodies (with desired binding properties) were well known in the art at the time of the invention. However, knowing how to produce/generate monoclonal antibodies does not support or provide evidence that Applicant is in possession of any and all possible species beyond that/those single disclosed species provided in Applicant’s actual reduction to practice.
Amgen Inc. v. Sanofi further notes, pointing to Ariad Pharms., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed Cir. 2010):
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id.
Amgen at pages 7-8.
In the present case, Applicant has not provided sufficient disclosure to support Applicant was in possession of the entirety of each genus as presently claimed referring to VH and VL represented at the claims by a, b and c, where each has at least 70% identity to the claimed sequences.
It is not within ordinary skill to predict any and all substitutions, additions or deletions that would result in products that retain the functional ability claimed (in terms of binding dermatophyte antigen). Further, as discussed in detail previously above (under 35 U.S.C. 112(b)), it is noted that it is also not readily clear what is encompassed by “dermatophyte antigen”, for example is this something produced/relevant to the presence of the organism (fungi), or is the antigen then organism (a component of the organism’s structure) itself.
As an example provided in order to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (“New Insights in Type I and II CD20 Antibody Mechanisms-Of-Action With a Panel of Novel CD20 Antibodies”, British Journal of Haematology, 2018, 180, 808–820, |https://doi.org/10.1111/bjh.15132). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170ANPS173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170ANPSEKNSP178); however, in contrast to rituximab residues at positions 176–178 contribute the most to binding (see page 809, left col., 2nd full paragraph).
Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170ANPS173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph).
More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2):
“detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure S2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also, for m2, a signal decrease below the WT binding signal occurred within the 168EPANPSEK175 sequence motif but the binding signal to the linear (Figure S2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.” (see ibid). While these antibodies bind within or nearby the rituximab 170ANPS173 epitope they do so with heavy and light chain CDRs non-homologous to those of rituximab.
Thus, even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs.
As further illustration of the unpredictability in the art, Brown et al. (“Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?”, J Immunol. 1996 May;156(9):3285-91), describes how a one amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region (at 3290 and Tables 1 and 2).
Brown et al. further supports that even small changes (for example two residues changed) can completely effect function. This also emphasizes the importance of knowing which residues can tolerate change in order to predict binding, and which cannot.
In the instant case, as noted above, there is no disclosure of a common or necessary structure required of all species of the claimed genus for maintaining the necessary binding (for capture/binding dermatophyte antigen).
Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See AbbVie Deutschland GmbH v. Janssen Biotech. Inc. as well as Amgen v. Sanofi, as discussed above. Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Even further evidence that there is unpredictability, see for example there are antibodies described by the prior art that meet the structural requirements of the claim (at least 70% identical to sequences claimed) but not the functional ability. For example, Karlegis Parra et al., US PG Pub No. 2021/0347856A1 entered describe an antibody, antibody 14F5F6, having heavy chain and light chain sequences indicated as SEQ ID Nos. 1 and 2, this antibody described by Karlegis Parra et al. reads on the “at least 70% identical” to the claimed SEQ ID Nos. 3 and 4, however this prior art antibody is an antibody that recognizes Herpes simplex virus (see title and abstract). This supports the position of the present rejection that not all antibodies that meet the structural requirements of the claim would predictably also meet the functional requirements of the claim.
In summary, there is insufficient evidence that Applicant was in possession of the full scope of the claimed invention in terms of all species having 70% identity with any of the claimed sequence combinations which also bind dermatophyte antigen, as claimed.
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, 8-10, 12, 15-18, 25-27, 29, 32-37, 39, 42, 50, 57-59, 61 and 64-66 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 (see also claims 12, 15-18, 29, 32-34, 50, 61, 64-66) recites “method of differentially detecting one or more dermatophyte organisms” and also recites “dermatophyte antigen”, the claims are indefinite because it is not readily clear if it is the “organisms” (e.g., the fungi) that are the targeted antigen, or rather if the “dermatophyte antigen” is an antigen produced by the organisms. The claims appear to use the language “dermatophyte organisms” and “dermatophyte antigen” interchangeably throughout the claims. See for example, claim 12 recites that the antibodies “do not bind to non-dermatophyte organisms”, suggesting perhaps that the antigen is itself the organism (that antibodies bind the organism). Clarification is necessary.
Claims 8, 25 and 57 recite “VH amino acid sequence pair”, and then proceeds to recite VH sequences by SEQ ID numbers; the language “pair” is indefinite because it is not readily clear what “pair” the language “VH amino acid sequence pair” is in reference to since the VH (heavy chain) structure is not considered itself to be a “pair”.
Claim 18 recites “for the differential detection of one or more dermatophyte organisms”, it is unclear if the language “differential” means differential detection relative to non-dermatophyte organisms, or rather if the claim is intended as differential detection of one or more organisms, as in differentially detecting different dermatophyte organisms.
Claim 35 recites two separate sentences, the second one, “In some embodiments, the nitrocellulose membrane is…” reads as exemplary language. See MPEP 2173.05(d), the claim language is indefinite because it is not clear if the second narrower list of species at the second sentence is considered to be limiting or exemplary/preferred, especially since the first sentence already recites a list of species inclusive of the shorter list recited at the second sentence.
Claim 39 recites “wherein the conjugate pad comprises between about 1 µl/cm to about 20 µl/cm of the one or more detection antibodies”, however, the recited language is indefinite because µl/cm is considered a rate measurement, not necessarily an amount per area (cm is not cm2, for example). It is not readily clear how much detection antibody is present at the conjugate pad based on the recited language.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 18, 27, 29, 32-34 and 37 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by WO2016/172660A1.
Kozel et al. teach detection of mannan from medically relevant fungi by lateral flow immunoassay device (LFIA) (referring to Figure 7 and description of Figure 7 at page 5, para 4, see also pages 31-32, 44-45, referring to lateral flow immunoassay for detection of fungal mannan), see further Table 4, monoclonal antibody 2DA6 for binding/detecting dermatophytosis. Kozel teach their LFIA using mAb 2DA6 to assay for mannans, Kozel teach mannan was readily detectable by LFIA from all invasive fungal infection members tested (see page 44-46, including extracts from infected tissue samples). Kozel describe the lateral flow assay device construction and design at pages 22-27, the assay device comprising a membrane strip (e.g., nitrocellulose, see page 25, para 3) having thereon an unconjugated capture antibody (see page 24, paras 2-3, referring to the test line having binding agents such as analyte specific antibody) that binds the targeted antigen, a conjugate pad comprising detector antibodies (see end of page 23 to page 24), see also Kozel at page 24, end of last paragraph describing control line comprising immobilized detection-reagent-specific binding partner (antibody) that binds the detector reagent (conjugate) in the presence or absence of the analyte.
Regarding the limitation recited at the preamble, “for the differential detection of one or more dermatophyte organism”, see specifically as cited previously above, Kozel is teaching detection of mannan from fungi which cause dermatophyte infection in humans and animals (see page 5, Figure 7 description, the antibody of Kozel binds epitope located on the a-1,6 backbone cell wall of mannan (see page 45). Kozel’s lateral flow assay is structurally the same as that presently claimed, and does specifically detect presence of dermatophyte organisms. Kozel is teaching a device capable of differential detection (see e.g., page20, para 2).
Regarding claim 27, Kozel et al. teach detection antibody conjugated to colloidal gold label (see at page 9, paragraph 3, also page 31, last paragraph).
Regarding claim 29, see Kozel is teaching an assay that specifically binds targeted analyte.
Regarding claim 32, the method of Kozel as modified by the cited prior art detects dermophyte organisms by detecting mannan, organisms including for example Trichophyton, Microsporum, or Epidermophyton fungi (see for example Tables 4, 7 and 11, see also description of Figure 7 at page 5).
Regarding claims 33 and 34, see for example Table 4, Tricophyton rubrum.
Regarding claim 37, regarding the capture line, see Kozel et al. teaching 1 mg/ml (a value that lies inside the claimed range of 0.1 mg/mL to about 5 mg/mL).
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.
Claim(s) 1, 10, 12 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Kozel et al., WO2016172660A1 in view of Tamir, US PG Pub No. 2018/00271771A1 and Reich et al., US PG Pub No. 2007/0092977A1 .
Kozel et al. teach a method of detection of mannan from medically relevant fungi by lateral flow immunoassay device (LFIA) (referring to Figure 7 and description of Figure 7 at page 5, para 4, see also pages 31-32, 44-45, referring to lateral flow immunoassay for detection of fungal mannan), see further Table 4, monoclonal antibody 2DA6 for binding/detecting dermatophytosis. Kozel teach their LFIA using mAb 2DA6 to assay for mannans, Kozel teach mannan was readily detectable by LFIA from all invasive fungal infection members tested (see page 44-46, including extracts from infected tissue samples). Kozel describe the lateral flow assay device construction and design at pages 22-27, the assay device comprising a membrane strip (e.g., nitrocellulose, see page 25, para 3) having thereon an unconjugated capture antibody (see page 24, paras 2-3, referring to the test line having binding agents such as analyte specific antibody) that binds the targeted antigen, a conjugate pad comprising detector antibodies (see end of page 23 to page 24), see also Kozel at page 24, end of last paragraph describing control line comprising immobilized detection-reagent-specific binding partner that binds the detector reagent (conjugate) in the presence or absence of the analyte. Kozel is teaching collecting sample, applying sample to the lateral flow assay device as described above, reading (see end of page 24) the test display to determining if dermatophyte organisms are present (mannan as an indicator of fungal infection related to dermatomycosis).
Kozel describe visualizing test and control lines after 15 minutes (see page 32, para 2), Kozel’s 15 minutes therefore addresses the claimed “at least 10 minutes” (at least 10 is considered a minimum to a range).
Kozel describe samples suitable for their methods/device (see page 20, paragraph 3), and teach sample may be manipulated prior to assay to optimize results (page 20, para 3, suspected, diluted, etc.), teaching samples can be obtained from sheddings, swabs etc. (see also page 12, para 2 of section II.).
Kozel describe a method substantially as claimed (see above), however, fails to recite following collection of sample, incubating sample in a buffer comprising a non-ionic detergent at room temperature before applying to the lateral flow assay device. Rather, see for example, Kozel describe their sample pad (the location where sample is added to the device) comprising solution of BSA and Triton-X (an example of non-ionic detergent, see page 31, last paragraph), Kozel referring to this reagent as a recognized release-reagent that promotes resolubilization of conjugate pad constituents, and for non-specific binding.
Tamir teach embodiments comprising collecting a sample from a subject using a swab (as in Kozel), then transferring the swab to a container comprising extraction reagent to allow reaction of the swab with the extraction reagent solution to extract sample, then contacting the extracted analyte with the lateral flow immunochromatographic assay device (see for example, paras [0017]-[0023]. Regarding extraction reagent, see for example para [0070], Tamir teach solvent comprising reagent such as non-ionic detergents
Reich et al. is another example in the prior art of methods and devices comprising lateral flow immunoassay device, Reich similarly teach obtaining sample using a swab, immersing swabs in extraction buffer (incubating at room temperature, see for example para [0080]) before assaying by immunochromatographic test strip device.
As cited above, Kozel teach collecting sample by collection device such as a swab. It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Kozel et al. in order to have placed the swab in a container comprising extraction buffer (as in Tamir or Reich) that includes a non-ionic detergent, as in Tamir) (thereby incubating in an extraction buffer) in order to extract the sample from the collection swab and sample to be added to the assay test device, the modification an obvious matter of applying a known technique to a known method. In particular, Kozel teach the base method and teach collection of sample by way of collection component such as a swab, further the technique of using a non-ionic detergent containing extraction buffer was a technique known in the art for extraction of analyte (Tamir). One having ordinary skill in the art would have recognized that applying this technique (extraction buffer as in Tamir, Reich, with reagent such as non-ionic detergent as in Ramir) would result in extraction at the swab to accommodate the analyte (transference of the collected sample from swab to the buffer) to be provided at the assay test strip device.
Additionally, one having ordinary skill in the art would have a reasonable expectation of success because Kozel does teach collection, for example by swab, and as such it would be expected there need to be a step of transferring the analyte from the swab to the test device. Additionally, one would have expected success because one would expect the solution to assist in the resolubilization of the reagents and promote flow through the device (consistent with Kozel for example, Kozel recognized detergent such as TritonX-100 assists with resolubilization and reducing non-specific binding).
Regarding claim 10, Kozel et al. teach detection antibody conjugated to colloidal gold label (see at page 9, paragraph 3, also page 31, last paragraph).
Regarding claim 12, see Kozel is teaching an assay that specifically binds targeted analyte.
Regarding claim 15, the method of Kozel as modified by the cited prior art detects dermophyte organisms by detecting mannan, organisms including for example Trichophyton, Microsporum, or Epidermophyton fungi (see for example Tables 4, 7 and 11, see also description of Figure 7 at page 5).
Regarding claims 16 and 17, see for example Table 4, Tricophyton rubrum.
Claim(s) 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Kozel et al. in view of Yuki et al., US PG Pub No. 2013/0244314A1.
Kozel et al. teach a lateral flow assay device substantially as claimed (see above, Kozel et al. also teach detection antibody conjugated to colloidal gold label, see at page 9, paragraph 3, also page 31, last paragraph), however, fails to teach nitrocellulose membrane that is one of those recited at claim 35 (see also claim 36).
However, nitrocellulose membranes known suitable for immunochromatographic test strip assay devices are known in the art, see for example Yuki et al., Yuki is another example of a test strip assay Yuki teach using nitrocellulose that is C140 (see para [0093] for example, UniSart CN140, Satorius).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Kozel et al. to have used CN140, the modification an obvious matter of use of a known material for its art recognized purpose. Specifically one having ordinary skill in the art would have recognized that CN140 is a suitable nitrocellulose membrane material known in the art for immunochromatographic assays and commercially available to those of ordinary skill in the art (and as such, would also have had a reasonable expectation of success).
Claim(s) 39 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Kozel et al. in view of Reich et al. (cited previously above).
Kozel et al. teach a lateral flow assay substantially as claimed and does teach the conjugate pad having a final OD540nm = 10, however, fails to teach conjugate pad comprises between about 1µl/cm to about 20 µl/cm (see however, the rejection under 35 U.S.C. 112(b), set forth above).
Reich et al., cited previously above as another example in the prior art of methods and devices comprising lateral flow immunoassay device, also teaches at para [0062], regarding conjugate pad preparation, producing conjugate pads by dispensing conjugate at a rate of 10µl/cm.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have dispensed the conjugate at the rate taught by Reich (at 10µl/cm) as an obvious matter of applying a known technique, known in the art for conjugate pad preparation, in order to achieve prepared conjugate pad suitable for immunochromatographic assay. One having ordinary skill in the art would have a reasonable expectation of success using a known technique for applying conjugate.
Regarding claim 42, Kozel teach a lateral flow assay substantially as claimed, however, Kozel fails to report a limit of detection for their lateral flow assay, and as such fails to teach the assay capable of detecting one or more dermatophyte organisms in an extract between 20 ng/mL to about 500 ng/mL.
However, see further Reich et al., which is similarly a colloidal gold conjugate based immunochromatographic lateral flow assay device, reports tested limits of detection (para [0080] and Table 8), reporting down to .25 µl/ml (i.e., 250 ng/ml).
It would have been prima facie obvious to one having ordinary skill in the art that the assay of Kozel be capable of the level of detection as recited at claim 42 (capable of detecting concentrations within the claimed range) because Reich, which is structurally similar to that of Kozel (both immunochromatographic devices utilizing gold labeled specific antibody binding), would be expected capable of detecting organisms in an extract samples between 20 ng/mL to about 500 ng/mL. One having ordinary skill would have a reasonable expectation of success given that such immunochromatographic assay devices are recognized as capable of such sensitive detection.
Claim(s) 50, 59, 61 and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Kozel et al. in view of Magaki et al., An Introduction to the performance of Immunohistochemistry, Methods Mol. Biol., 1897, (2019), p.289-298 and Gonda et al., Development of a quantitative diagnostic method of estrogen expression levels by immunohistochemistry using organic fluorescent material-assembled nanoparticles, Biochemical and Biophysical Research Communications, 426, (2012), p.409-414.
Regarding claim 50, Kozel et al. teach the use of their pan reactive antibody for detection of dermatophyte organisms for immunohistopathology (i.e., immunohistochemistry, IHC, referring to immunostaining using fluorescent or enzyme labels, such as with antibody 2DA6 taught by Kozel, see page 47, and also claim 7 of Kozel). However, fail to recite steps or products provided for performing IHC, and as such fail to recite a) one or more unconjugated capture antibodies to a dermatophyte antigen, and b) one or more detection antibodies comprising an antibody-nanoparticle conjugate that binds to a dermatophyte antigen.
However, IHC is a well known technique recognized in the prior art, see for example Magaki et al. teaching IHC is a powerful technique that exploits the specific binding between antibody and antigen to detect and localize specific antigens in cells and tissues (abstract). See at page 2, Magaki list the sequential steps, the steps involving contacting with primary antibody (page 2 paragraph 3), and further secondary labeled antibody against the immunoglobulin species of the primary antibody (paragraph 4).
Further, see Woflbeis, which is an overview of nanoparticles commonly used for fluorescent bioimaging (title, abstract), see at page 4746, col. 1, para 2, Wofbeis teach hydrophilic materials for use in nanoparticle based imaging include various kind of hydrogels, and also natural products like cellulose.
See also Burnham-Marusich et al., teaching antibodies conjugated/linked to labels including colored cellulose nanobeads (see for example, page 19, lines 12-21).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date that the monoclonal antibody of Kozel, for detecting dermatophytes, be provided for IHC as an unconjugated antibody, further provided with secondary an anti-primary antibody labeled conjugate, because Kozel specifically suggest their antibody for immunohistopathology, and it is well known in the prior art that such a technique typically involves primary unconjugated antibody followed by secondary conjugate for visualization of the primary antibody.
Regarding labeled conjugate, it would have been further prima facie obvious to one having ordinary skill in the art to have provided conjugate comprising colored cellulose nanoparticles/beads as an obvious matter of choosing from a finite list of known, suitable and available antibody conjugate particles (see Wolfbeis and Burnham-Marushich). Specifically, the prior art (referring to the cited reference above) disclose a finite list of known nanoparticle conjugates usable and available for detection via antibody binding. One having ordinary skill in the art would have found it obvious to have pursued the known suitable alternatives and have arrived at the claimed cellulose nanobead/particle with a reasonable expectation of success (considering there are only a finite list of known particles/bead materials recognized and utilized for immunodetection in the art).
Regarding claim 61, see Kozel is teaching an assay that specifically binds targeted analyte.
Regarding claim 64, Kozel’s antibodies/methods detect dermophyte organisms by detecting mannan, organisms including for example Trichophyton, Microsporum, or Epidermophyton fungi (see for example Tables 4, 7 and 11, see also description of Figure 7 at page 5).
Regarding claims 65 and 66, see for example Table 4, Tricophyton rubrum.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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