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 .
Priority
This application, Serial No. 17/208,055 was filed on 03/22/2021 and is a Continuation of PCT Application No. PCT/US2020/057636 filed 10/28/2020, and claims benefit to Provisional Application number 62/927,910 filed 10/30/2019.
Information Disclosure Statement
No new Information Disclosure Statement has been submitted
Status of the claims
Claims 12, 18-22, and 24-26 are pending.
Claim 12 is amended.
Claims 12, 18-22, and 24-26 represent all claims currently under consideration.
Withdrawn Rejections
The Indefiniteness rejection of claims 12, 18-22-and 24-26 under 35 U.S.C. 112(b), filed on 02/12/2025, has been withdrawn in view of the amendments filed 08/07/2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 12, 18- 22, 24-26, 30, and 32 remain rejected under 35 U.S.C. 103 as being unpatentable over Millipore Guide and Baumgardner et al. (USP 5186843) in view of
Nabatiyan et al (US 20120015350) and ThermoFisher Antibodies and Barbeau et al. as evidenced by Ho et al (Journal of Chromatography A, 1218 (2011) 1139-1146) for reasons of record which is reiterated below.
In particular, Millipore Guide discloses considerations for product development of rapid lateral flow devices including test strip design, materials and reagents (whole publication), wherein a basic test strip device comprises a housing enclosing a test strip having a sample receiving port and a viewing window for viewing a test line, (page 24, Figs 1,13) wherein the test strip comprises a body having a sample receiving zone and an opposite zone a plurality of sandwiched layers including a top layer and a bottom layer as for example a conjugate pad sandwiched between a sample pad and a capture membrane and an absorbent pad i.e. wick (Fig.1) on top of the membrane opposite the conjugate pad (instant claims 20,25) wherein the membrane can be nitrocellulose (pages 4-6) having for example 10 um thickness (page 4) wherein the conjugate pad is on top of the nitrocellulose membrane (Fig 1) (instant claim 21). Millipore Guide discloses antibodies specific to the analyte of interest can be used as capture reagents at the test line in the membrane and as detector reagents comprising a conjugate on a detector particle to form an immunocomplex at the test line, wherein colloidal gold particles are widely used (page 2). Millipore Guide discloses the detector reagents are comprised in the conjugate pad (page 19 left column). Millipore Guide discloses assembly of test strips in plastic housing comprising viewing windows (page 24, Fig 1, cover page images) which reads on a reader component, wherein the used can distinguish various signal intensities proportional to the bound analyte (instant claim 30). Millipore Guide teaches the lateral flow devices are suitable for a wide target of analytes (page 1), and can accommodate whole blood as the sample by comprising blood filter matrices (page 22). The membrane and layers are mounted on a solid support card, (page 24, Figs 1,13) (instant claims 26) and enclosed in a portable top and base housing. Millipore Guide discloses whole blood filtration matrices and devices were known in the prior art including references i.e., patents relating to whole blood filtration as for example US PAT 5,186,843 to Baumgardner et al. (Appendix page 37).
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Baumgardner et al. teaches throughout the patent whole blood filtration materials for separating plasma or serum from whole blood and comprising glass microfibers (instant claim 18) that can be manufactured in varying thickness typically about 0.175 to 0.65 mm (column 2 lines 39-48) which includes the claimed range (instant claim 19). Advantageously, the single layer media will not denature or bind with the components of plasma or serum and effectively transport the separated plasma or serum from the separation region (column 2 lines 16-32) on solid supports.
While Millipore Guide teaches considerations for product development of rapid lateral flow devices including test strip design, materials and reagents (whole publication) including a plurality of sandwiched layers that can include blood filter pads as taught in Baumgardner et al., wherein such devices can be used for detections of relevant analytes (page 1).
Millipore Guide and Baumgardner et al. are silent the conjugate pad comprises the detector conjugated to gold nanoparticles via the biotin-streptavidin system
Nevertheless, streptavidin gold nanoparticles were known in the art and commercially available as taught in Abcam.
Abcam teaches streptavidin gold nanoparticles wherein a common application is as a detector in lateral flow assays, to label a biotinylated antibody see figure.
Jazayeri et al. disclose throughout the publication chemical and physical approaches commonly utilized for conjugation of gold nanoparticles to antibodies, wherein the chemical interaction between antibodies and nanoparticles is commonly achieved using adaptor molecules like streptavidin and biotin (page 18, right last paragraph, table A1).
It would have been prima facie obvious, before the effective filing of the claimed invention, to modify the basic lateral flow assay test device of Millipore and Baumgardner et al. wherein the detector antibody comprised in the conjugate pad is labelled with colloid gold via the biotin-streptavidin system i.e., biotinylated antibody coupled to streptavidin gold nanoparticles as taught in Abcam and/or Jazayeri et al.
One would be motivated to do so to allow amplification of signal and because the method is conventional as taught in Jazayeri et al. with application in lateral flow devices as taught in Abcam, while gold streptavidin nanoparticles are commercially available as taught in Abcam.
Millipore Guide, Baumgardner et al. in view of Abcam and/or Jazayeri et al. are silent the detector antibody conjugated to gold nanoparticles via the biotin-streptavidin comprised in the conjugate pad is clone E2E3 and wherein the capture antibody is clone 2D11.
However, these antibodies were known, previously used in the art and commercially available along with additional anti-insulin antibodies i.e., total 36 clones, as taught in ThermoFisher Antibodies, at least since 2008 as evidenced by the previously cited references using the antibodies shown in ThermoFisher Antibodies for each of clone E2E3 and clone 2D11. In addition, the instant specification admits the claimed antibodies were commercially available and therefore considered prior art before the filing of the instant application by admission (see MPEP (2129).
In addition, insulin is a clinical analyte that is known in the art and suitable for detection with lateral flow assay devices as taught in Nabatiyan et al or Zhou et al
Nabatiyan et al is relied upon for teaching detection of insulin with a lateral flow assay test device [0010] [0079] wherein an antibody to the analyte of interest coated with detector particles [0051] is comprised in a conjugate pad while a capture antibody for the analyte of interest is deposited at test line in capture membrane comprising nitrocellulose [0050], wherein the detector particles are colloidal gold [0067]. Nabatiyan et al. suggests the sample pad device can be modified to immobilize blood cell prior to flowing into the conjugate pad. [0052]
It would have been prima facie obvious, before the effective filing of the claimed invention, to modify the basic lateral flow assay test device of Millipore and Baumgardner et al. in view of Abcam and/or Jazayeri et al. to include detector and capture anybody reagents specific to insulin wherein the colloid gold labelled insulin detector antibody is comprised in the conjugate pad while the capture antibody is comprised in the nitrocellulose membrane as taught in Nabatiyan et al or Zhou for the detection of insulin in whole blood samples, wherein detector and capture antibodies are selected from commercially available insulin antibodies available as taught in ThermoFisher Antibodies. It would have also been prima facie obvious, before the effective filing of the claimed invention, to match capture/detection insulin antibodies as claimed. as these clones were commercially available and matching antibody pairs is conventionally used in the art to optimize detection of analytes in sandwich immunoassay also taught in Barbeau et al.
Claims 12, 18-22, 24-26, 30, and 32 remain rejected under 35 U.S.C. 103 as being unpatentable over Hennessey et al (WO 2017017314) and Millipore Guide in view of Abcam and/or Jazayeri et al. and in further view of Nabatiyan et al. ThermoFisher Antibodies. and Barbeau et al. as evidenced by Ho et al (Journal of Chromatography A, 1218 (2011) 1139-1146). This rejection stands for reasons of record and is reiterated below.
Hennessey et al. teach throughout the patent and especially in Figs1-2, a typical lateral flow device comprising a housing enclosing a test strip having a sample receiving port and a viewing window for viewing a test line, (Fig.1 ) wherein the test strip comprises a body having a sample receiving zone and an opposite zone (test line element 13) and comprising a plurality of sandwiched layers including a top layer and a bottom layer (Fig 2) whereby allowing a sample fluid as for example whole blood (Abstract) to flow from the sample receiving end toward the opposite end through a conjugate pad (element 16) placed on the analytical membrane 12 (instant claim 21) , at the opposite end there is an absorbent pad 17, see pictures below. The sample receiving pad comprises a blood separation fibrous web material (element 15) on top of the conjugate pad (instant claim 22) and containing glass fibers (Abstract; page 8, lines 15-18) and cotton fibers and having a thickness of for example 340 um (example 1) (instant claims 18-20, 24, 26). The blood separation fibrous web material improves the separation of the red blood cells from the plasma to increase the speed and volume of the sample on the lateral flow device (Abstract).
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Hennessey et al. does not teach the conjugate pad comprising an insulin antibody conjugated to a gold nanoparticle.
Millipore Guide teaches throughout the publication and especially in Fig.1 a schematic view of a lateral flow device that is substantially identical to the lateral flow device depicted in Hennessey et al. In particular, the lateral flow device comprises a sample pad, a conjugate pad each on top of a membrane i.e., nitrocellulose (page 4) and an absorbent pad (see Fig1 of Millipore Guide below).
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Millipore Guide is further relied upon for disclosing details regarding using antibodies as capture reagents as for example antibodies can be used as a capture reagents at the test line and as a conjugate on a detector particle in the conjugate pad (page 2 left second paragraph), wherein the most used materials are colloidal gold and wherein conjugation procedures are well known and published (page 2 right 3rd paragraph;4th paragraph)
Hennessey et al. and Millipore Guide are silent the conjugate pad comprises the detector conjugated to gold nanoparticles via the biotin-streptavidin system as claimed.
Nevertheless, streptavidin gold nanoparticles were known in the art and commercially available as taught in Abcam.
Abcam and Jazayeri et al. are relied upon as in the 103 rejections above.
It would have been prima facie obvious, before the effective filing of the claimed invention, to modify the basic lateral flow assay test device of Hennessey et al. and Millipore Guide wherein the detector antibody comprised in the conjugate pad is labelled with colloid gold via the biotin-streptavidin system i.e., biotinylated antibody coupled to streptavidin gold nanoparticles as taught in Abcam and/or Jazayeri et al. One would be motivated to do so to allow amplification of signal and because the method is conventional as taught in Jazayeri et al. with application in lateral flow devices as taught in Abcam, while gold streptavidin nanoparticles are commercially available as taught in Abcam
Hennessey et al and Millipore Guide in view of Abcam (and/or Jazayeri et al. are silent the detector antibody conjugated to gold nanoparticles via the biotin-streptavidin comprised in the conjugate pad is clone E2E3 and wherein the capture antibody is clone 2D11.
Nabatiyan et al. is relied upon for the detection of insulin using antibodies as a capture reagent as for example antibodies can be used as a capture reagents at the test line and as a conjugate on a detector particle in the conjugate pad antibodies labeled to colloidal gold nanoparticles.
ThermoFisher Antibodies and Barbeau et al. are relied upon as in the 103 rejections above.
It would have been prima facie obvious, before the effective filing of the claimed invention for one of ordinary skill, to incorporate an insulin antibody as taught in Nabatiyan et al. conjugated to the gold nanoparticle as taught in Abcam and/or Jazayeri et al. in the conjugate pad and an insulin capture antibody at the test line of the lateral flow device generic for the detection of blood analytes comprising a plurality of sandwich layers including an analytical membrane and a blood filter pad of Hennessey et al. Millipore in view of Abcam and/or Jazayeri et al. because Millipore Guide teach antibodies can be used as capture reagents at the test line and as a conjugate on a detector particle i.e. colloid gold in the conjugate pad, wherein nitrocellulose is commonly used as an analytical membrane and because Nabatiyan et al. teach detection of insulin with a lateral flow device in a sandwich format wherein the conjugate pad comprises an antibody conjugated to a gold nanoparticle.
One would be motivated to so since insulin is present in blood and has clinical significance and because the lateral flow device of Hennessey et al. comprises a blood filter pad can efficiently separate cells from serum or plasma to advantageously accommodate whole blood as the sample for rapid diagnosis and increased sensitivity and without rupture of the erythrocytes that can cause assay interference while providing increased speed and volume of the separated material (see Hennessey et al. page 4 lines 20-27).
In addition, it would have been prima facie obvious, before the effective filing of the claimed invention for one of ordinary skill, to incorporate a second anti-insulin antibody at the test line to detect insulin in sandwich format since such format is conventionally used as taught in Millipore Guide and Nabatiyan et al. teach detection of insulin with a lateral flow device in a sandwich format wherein a second antibody is placed at the test line.
Selecting insulin antibody pairs would have been within the skill in the art as antibodies were commercially available as taught in ThermoFisher Antibodies or as evidenced by admission in the instant specification and matching antibodies is routinely perfumed for improved sensitivity of sandwich ELISA.
One of ordinary skill in the art would have been motivated to detect for the presence/amount of insulin in blood by optimizing the capture/detection pairs of the antibodies of ThermoFisher Antibodies as these clones were commercially available and matching antibody pairs is conventionally used in the art to optimize detection of analytes in sandwich immunoassay also taught in Barbeau et al to allow for optimal sensitivity in an easy to use simple lateral flow device of Hennessey et al. and Millipore Guide wherein the conjugate pad comprises an insulin antibody conjugated to a gold nanoparticle as taught in Abcam and/or Jazayeri et al. and the test line comprises a second anti-insulin antibody that can capture insulin in a sandwich format as taught in Nabatiyan et al. It would have been with predictable expectation of success that commercial anti-insulin antibody clone E2E3 can be used as a detecting antibody while commercial anti-insulin antibody clone 2D11 can be matched as the capture antibody and suitable for targeting equine insulin as commercial antibodies of the prior are the same as claimed, absent a showing of unapparent differences, and expected to would function in the same manner for the detection of insulin in a sandwich lateral flow device.
Further, as antibodies specific to equine insulin were not commercially available as evidenced by ThermoFisher antibodies, under KSR case law, it is now apparent "obvious to try" may be an appropriate test in more situations. “When there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense”. In that instance the fact that a combination was obvious to try might show that it was obvious under 35 USC 103. See KSR Int'l Co v. Teleflex Inc., 127 S. Ct. 1727; 82 USPQ 1385, 1397 (2007).
In this case, the problem facing those in the art was to develop a specific and sensitive assay with antibody clones that can bind equine insulin for the detection of insulin in whole blood from an equine in a sandwich format using a lateral flow device. A person of ordinary skill would have good reason to pursue the known options within his or her technical grasp as for example select and combine commercially available anti-insulin antibodies that target porcine or human insulin from a finite number of antibodies that were commercially available as taught in ThermoFisher Antibodies to match capture and detection antibodies for optimal detection of insulin with the lateral flow device of Hennessey et al and Millipore Guide wherein the conjugate pad comprises an insulin antibody conjugated to a gold nanoparticle as taught in Abcam and/or Jazayeri et al. and the test line comprise a capture anti-insulin antibody as taught in Nabatiyan et al.
The skilled artisan would have reason to try these antibodies for use as a capture and try these antibodies for use as a detection antibody with reasonable expectation that at least one would be successful i.e., clone E2E3 as detecting antibody and matching clone 2D11 as the capture since insulin is highly conserved across species differing in 1-2 amino acids, due to cross-reactivity as evidenced by Ho et al.
Labeling an antibody with colloid gold was conventional also taught in Nabatiyan et al.
Regarding claim 32, the housing of Hennessey et al appears identical as claimed except for a protrusion in the lateral part of the housing. However, such protrusion and criticality thereof are not disclosed by applicant, and is a matter of shape choice which a person of ordinary skill would have found obvious absence persuasive evidence that the shape of the claimed plastic was significant. MPEP 2144.04 II. IV (b). In addition, as admitted by applicant during the interview of 8/2/2022, the instant device has a generic configuration.
Claims 12, 18-22, and 24-26 remain rejected under 35 U.S.C. 103 as being unpatentable over Mahmoudi et al (Trends in Analytical Chemistry, 2019) and Baumgardner et al (US5186843A) in view of Serebrennikova et al (Moscow University Chemistry Bulletin, 2018), Kolman et al (American journal of physiology, 2009), Oberg et al (Comparative clinical pathology, 2012), Mansfield (Lateral Flow Immunoassay, 2008) and Hurion et al (J Cytol Histol, 2016). This rejection stands for reasons of record and is reiterated below.
Mahmoudi teaches several components of the lateral flow immunoassay (LFIA) claimed including sample pad, mainly from glass fiber; a nitrocellulose (NC) membrane in fluid contact with the conjugate pad containing the test zone, which contains capture antibodies or reagents, and control zone; a conjugate pad in fluid contact with the sample pad comprising the detection antibody or reagent and absorbent pads from cellulose, and a polyvinyl chloride backing card for assembling the components, including the sample pad and NC membrane. In commercial LFAs, the whole assembly was embedded into a housing chamber to allow for sample deposition and provide a viewing window for viewing the test and control lines. The remaining solution flows through the membrane and some of the antibodies will attach to the control line (CL) to show the successful running of the test. The absorbent, or wicking, pad controls the flow rate and ensures the forward movement of fluid and is in fluid contact with the NC membrane opposite the conjugate pad (see Working principle of lateral flow assays, pg. 14, 1st para.; meeting limitations in instant claims 12, 20, and 26). Mahmoudi further teaches the sample pad is on top of the conjugate pad, the wick pad is on top of the NC membrane, and the conjugate pad is on top of the NC membrane (Trends in Analytical Chemistry, 2019; Figure 1 pg. 15), thereby meeting the limitations of instant claims 21-22 and 25).
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Mahmoudi does not teach the use or thickness of a whole blood filter pad, antibodies biotinylated to a streptavidin-coated gold nanoparticle, the specific use of E2E3 and 2D11-H5 antibodies for insulin detection, or the thickness of the NC membrane.
Baumgardner teaches a composite medium for separating plasma or serum from whole blood as a sample pad directly below the sample port in the housing that is a whole blood filter pad that separates whole blood into red blood cells and plasma, said composite comprising glass microfibers (claim 1, meeting limitations in instant claims 12 and 18). Baumgardner further teaches the media of the present invention are manufactured in varying thicknesses, typically about 0.175 to 0.650 mm (175 and 650 micrometers) (summary of the invention, paragraph 2, pg. 2, column 2; meeting limitations in claim 19).
Serebrennikova teaches detection limits can be decreased by a factor of four by using a complex conjugate of gold-nanoparticle-labeled biotinylated antibodies with streptavidin. This approach makes it possible to enhance the sensitivity of conventional LFIA systems based on the standard conjugates with gold nanoparticles. It can be used to create rapid test systems designed, for example, for the early diagnosis of a disease and for monitoring the effectiveness of the treatment without resorting to an instrumental analysis of the test results. They consider a new approach based on the use of an antibody biotinylated to a streptavidin-coated gold nanoparticle that makes it possible to amplify the analytical signal in LFIA. The complex conjugate is formed by the bonding of biotinylated antibodies labeled with gold nanoparticles with streptavidin (Introduction, pg. 131, para. 3; meeting limitations in claim 12).
Hurion teaches avidin-biotin bound to a mix of INS04(E2E3) and INS05(2D11-H5) to facilitate the observation of insulin levels through detection of insulin bound antibodies using the known pairing of E2E3 and 2D11-H5 antibodies for insulin detection (materials and methods, pg. 2, 1st paragraph.).
Kolman teaches that 2D11 is used to bind insulin for immunolabeling (pg. 1230, methods, immunocytochemical controls). Oberg teaches that the insulin molecule is highly conserved between species, human assay, including those with porcine antibodies, have shown to produce good results with equine samples (see Discussion, 1st para. Pg. 1296), thereby meeting the limitations in claim 12.
Mansfield teaches that standard nitrocellulose membranes can be as thin as 100 µm and as thick as 150 µm (pg. 100, Membrane testing, membrane thickness), thereby meeting the limitations in claim 24.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that applying a known technique to a known device, method or product ready for improvement is obvious because a particular known technique is recognized as part of the ordinary capabilities of one skilled in the art; see MPEP 2143. In the instant case, Mahmoudi contains a “base” device of performing a lateral flow immunoassay that can be used to detect an analyte from a biological sample, whole blood in the instant claims, utilizing a detection antibody, a capture antibody comprising a sample pad over a conjugate pad, a conjugate pad over an NC membrane, a wicking pad opposite the NC membrane on top of the NC membrane, and a housing with a sample port and window for viewing test results. Baumgardner teaches the use of a glass fiber pad, as a sample pad, to separate whole blood into red blood cells and plasma. Serebrennikova teaches the increase in detectability of antibodies which are biotinylated to a streptavidin-coated gold nanoparticle. Hurion teaches using an avidin-biotin binding method to detect the presence of insulin using the paired antibodies E2E3 and 2D11-H5. Kolman teaches specifically using 2D11-H5 as an insulin capture antibody. Mansfield teaches the ideal thickness of NC membranes in LFIA devices. Lastly, Oberg teaches that the insulin molecule is highly conserved between species and a human assay using porcine antibodies is shown to produce good results with equine samples. Thus, one of ordinary skill in the art would have recognized that applying the known technique taught by Mahmoudi to the known methods of Baumgardner, Serebrennikova, Hurion, Kolman, Mansfield and Oberg would have yielded predictable results (i.e., the same advantages) and an improved system.
Response to Arguments
Applicant's arguments filed 08/07/2025 have been fully considered but they are not persuasive.
Regarding Applicant argument that there was no reasonable expectation of success, starting on pg. 1, line 12, this has been addressed in the rejections above. Applicant argues there was no reasonable expectation of success when varying even one of the 4 parameters (capture antibodies, detection antibodies, detection antibody conjugation protocol, and whole blood filter pads, pg. 1 lines 21-22), and that evidence on the record is that the result of each variable is not predictable. Applicant argues experiments with 5 different commercially available insulin antibodies requires undue experimentation despite the conservation of the insulin molecule between species. The rejection is addressed above in the rejection with Oberg. In addition, routine experimentation does not have to prove the best device for a problem, only a functional one. Variation of the factors involved in the device which measures equine insulin produces varying degrees of success according to the Applicants own disclosure in figures 3 A&B and 6B. Conclusive proof of efficacy is not required to show a reasonable expectation of success. The reasoning, as elaborated below, is that "the expectation of success need only be reasonable, not absolute")). See MPEP 2143.02(I).
Prior art referenced above teaches the use of E2E3 and 2D11 together for use in binding and detecting insulin. This teaches a reasonable expectation of success when using these antibodies to detect insulin, and presents a reasonable choice when attempting to detect a molecule that is highly conserved between species. This expectation of success is taught in Oberg, cited above, when an assay developed to be optimized for detecting equine insulin have good agreement with human based assays (pg. 1297, l. col., para. 2).
Applicant further argues, starting on pg. 4, line 24, the antibody conjugation protocol used in measuring equine insulin levels would lead to unpredictable results. This is addressed below that the conjugation of a biotinylated antibody to a streptavidin coated gold nanoparticle is routine in the art and using the conjugation protocol would have a reasonable expectation of success.
Applicant further argues, starting on pg. 5, line 21, the choice of blood filter pad would lead to unpredictable results. This is further addressed below, but the choice of whole blood filter pad would be no more than routine experimentation to determine which pad best filters out the solid components of whole blood as disclosed below.
In respect to Applicants’ argument, starting on pg. 6, line 18, that claim 12 is patentable over Millipore Guide and Baumgardner in view of Abcam and/or Jazayeri in further view of view of Nabatiyan or Zhou, ThermoFisher Antibodies and Barbeau as evidenced by Ho, and Claim 12 is also patentable over Hennessey and Millipore Guide in view of Abcam and/or Jazayeri and in further view of Nabatiyan, ThermoFisher Antibodies, and Barbeau as evidenced by Ho, Examiner respectfully disagrees.
Applicant claims, starting on pg. 6, line 29, that ThermoFisher and Abcam are not prior art as previously argued. Examiner maintains the previous response to these arguments that it is noted that a statement by an applicant in the specification or made during prosecution identifying the work of another as “prior art”, as in the remarks submitted 07/19/2023, 02/15/2024, and 06/04/2024 for both ThermoFisher and Abcam, and remarks submitted 07/29/2022, and 12/23/2021 for ThermoFisher alone, is an admission which can be relied upon for both anticipation and obviousness determinations, regardless of whether the admitted prior art would otherwise qualify as prior art under the statutory categories MPEP §2129(I). In this case the subject matter of the claimed antibodies, said antibodies conjugated to a gold nanoparticle, is not inventors own work as the application indicated these antibodies are commercially bought [0050]. Furthermore, the ThermoFisher catalog reference includes published prior references that have used these antibodies.
Applicant argues, starting on pg. 7, line 10, 1) Examiner did not make a finding that there had been a recognized problem or need in the art; 2) Examiner did not make a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; and 3) Examiner did not make a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In response to 1), it is cited above, by Nabatiyan and Zhou, that insulin has a clinical significance, and, as disclosed above, equine insulin antibodies are not commercially available, as evidenced by ThermoFisher above. These citations contribute to previous statement “In this case, the problem facing those in the art was to develop a specific and sensitive assay with antibody clones that can bind equine insulin for the detection of insulin in whole blood from an equine in a sandwich format using a lateral flow device”, not the specification as claimed by Applicant. Examiner further asserted it would have been obvious to try various commercially available antibodies in an immunoassay to detect equine insulin because ““when there is motivation to solve a problem, and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” in this case the motivating factor is of a lack of the commercial availability of antibodies specifically directed towards equine insulin, and more accessible assays, such as LFA, than those as cited by Ho above, detecting equine insulin in urine with LC/MS; and Oberg, detecting equine insulin in serum using ELISA.
In response to 2), it has already been established above that ThermoFisher is considered prior art and may be relied upon.
In response to 3), It has also been recited above by the examiner “The skilled artisan would have reason to try these antibodies for use as a capture and try these antibodies for use as a detection antibody with reasonable expectation that at least one would be successful i.e., clone E2E3 as detecting antibody and matching clone 2D11 as the capture since insulin is highly conserved across species differing in 1-2 amino acids, due to cross-reactivity as evidenced by Ho et al. Labeling an antibody with colloid gold was conventional also taught in Nabatiyan et al.” When combining known and conventional techniques, that are known to work together, as described above in the rejections, there is a reasonable expectation of success by a person of ordinary skill in the art.
Applicant argues, starting on pg. 8, line 11, Examiner cannot use the obvious to try rationale when "what would have been 'obvious to try' would have been to vary all parameters or try each of numerous possible choices, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful. (MPEP 2145 X.B)" The art gives no indication of which choices were likely to be successful to yield a test line that provides a quantitative measure of the insulin concentration in an equine whole blood sample.
Examiner asserts that all parameters would not have been varied. The cited art in the above rejections teach a generic lateral flow assay device, as admitted by Applicant during the interview of 08/02/2022. Applicant states the use of gold labeled antibodies, the specific antibodies, the detection antibody conjugation protocol, and the whole blood filter pad were variables that would not be predictable when testing equine insulin. As explained above, it would have been within a reasonable expectation of success for the person or ordinary skill in the art to select appropriate antibodies from the limited, commercially available selection, and the use of gold nanoparticle conjugation to antibodies is a conventional method, well known in the art. It would have also been obvious to try various whole blood filter pads to account for how the blood would be filtered by a particular material, and where the whole blood is mixed with a reagent or buffer. Baumgartner and Hennessey, cited above, both teach non-species-specific blood filter pads to be used in lateral flow assays which contain various embodiments with different separation qualities as disclosed in the tables of Baumgartner in col. 5 and 6.
In response to Applicants claim that Claim 12 is patentable over Mahmoudi and Baumgardner in view of Serebrennikova, Kolman, Oberg, Mansfield, and Hurion, Examiner respectfully disagrees.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues, starting on pg. 8, line 22, for the base device, the Examiner relies on Mahmoudi. The problem with Mahmoudi is it describes a generic lateral flow assay, which is not designed to quantify equine insulin in an equine whole blood sample. To arrive at claim 12, the Examiner had to modify every feature but the generic lateral flow assay construction of Mahmoudi.
Examiner responds as above that Applicant admitted to the generic nature of their lateral flow assay device design in the interview of 08/02/2022.
Applicant argues Examiner cited Baumgardner for the whole blood filter, but Baumgardner gives no indication it will work on equine whole blood.
Examiner responds as above that the embodiments disclosed by Baumgardner are non-species-specific and provide for the adjustment in quality of blood filtration performed by different materials. The advantage of using the materials of Baumgardner to filter blood is the removal of blood cells and other solid constituents that may interfere with testing (Col. 1, lines 25-45). In addition, this blood filtering prevents hemolysis of the cells which would also interfere with assay results.
Applicant argues Examiner cited Serebrennikova for using antibodies biotinylated to a streptavidin-coated gold nanoparticle, but Serebrennikova give no indication this technique will work with E2E3, 2D11, or equine insulin.
Examiner responds as above that the use of streptavidin gold nanoparticles are well known in the art and commercially available as taught by Abcam, and as taught by Serebrennikova, and as Jazayeri and Nabatiyan taught above, that labelling an antibody with colloidal gold is conventional and well known in the art as taught by Millipore above. It is advantageous to use the biotin-streptavidin system as taught by Serebrennikova because it improves the sensitivity in lateral flow assays (Abstract) and detection limit can be decreased by a factor of four using gold-nanoparticle labelled antibodies (Conclusion).
Applicant argues Examiner cited Hurion as a teaching of "an avidin-biotin binding method to detect the presence of insulin using the paired antibodies E2E3 and 2D11-H5." The problem is Hurion teaches using an antibody mixture of INSO4 and INS05 in a "Discovery XT Full System," not a lateral flow assay system. Hurion does not teach using INSO4(E2E3) biotinylated to a streptavidin-coated gold nanoparticle as the insulin detection antibody and INS05(2D11-H5) as the capture antibody.
Examiner responds that Hurion teaches the practice of using E2E3 and 2D11 antibodies in assays to detect insulin and it would be obvious to improve on a generic lateral flow device as taught by Mahmoudi, to detect insulin using antibodies known to bind insulin as taught by Hurion, and use the known and conventional technique of using streptavidin-coated gold nanoparticles and biotinylated antibodies taught by Serebrennikova because of the advantages recited above.
Applicant argues Kolman teaches using antibody 2D11 on dissected kidney tissues to be able to visualize insulin uptake across the luminal membrane. Kolman does not suggest using 2D11 as an insulin capture antibody on a lateral flow assay.
Examiner responds 2D11 was used in Kolman specifically to indirectly label insulin with a gold conjugate antibody, taught that the antibody corresponds to the full length of porcine insulin, and taught the reaction of the antibody with several species of insulin using several different test methodologies on pg. 1230, r. col., para. 2. This provides evidence that the 2D11 antibody would have a reasonable expectation of success when used to bind insulin from different species, and has the advantage of successfully binding to insulin with differing immunological methods.
Applicant argues Examiner cited Oberg for the concept that the insulin molecule is highly conserved between species, but Oberg also explicitly discusses the unpredictability of measuring insulin in samples from animals with methods developed for human insulin. According to Oberg, "[w]hen measuring insulin in samples from animals with methods developed for a human hormone, cross-reactivity may vary depending on the antibody used (Karol et al. 1978), and antibodies can vary between tests and batches. The advantage with an equine-optimized ELISA is that the antibodies, calibrators, buffer and analytical range have been optimized for equine." Oberg, pg. 1296.
Examiner responds that Oberg also teaches human assays, including those with porcine antibodies, have shown to produce good results with equine samples (see Discussion, 1st para. Pg. 1296) as cited above. Even with the citation above that continues by teaching cross-reactivity may vary, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (MPEP 2144.08 2.A.4.b). It would be obvious to start testing for a highly conserved molecule with tests known to detect said molecule from another species if nothing else is available. Oberg states on pg. 1297 “The equine insulin ELISA validated in this study had good agreement with two earlier-used human assays, an RIA and an ELISA, even if the results of the equine assay are presented with different units.
Applicant argues that even when combined, the cited references do not teach "the conjugate pad comprising insulin detection antibody E2E3 biotinylated to a streptavidin-coated gold nanoparticle." This element specifically places insulin detection antibody E2E3 biotinylated to a streptavidin-coated gold nanoparticle at a specific location, which is on the conjugate pad. The Examiner did not provide a rationale as to why the skilled person would have placed insulin detection antibody E2E3 biotinylated to a streptavidin-coated gold nanoparticle on the conjugate pad.
Examiner responds that the conjugate pad containing the detection antibody is taught in Mahmoudi above, and the use of using a streptavidin coated gold nanoparticle to label a biotinylated antibody to create a detection antibody, which would be in the conjugate pad, is taught by Serebrennikova as above. The use of E2E3 as the detection antibody would be determined using routine experimentation with 2D11 when there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within their technical grasp. It would have been with a predictable expectation of success that commercial anti-insulin antibody clone E2E3 comprised in the conjugate pad while commercial antibody 2D11 comprised as capture antibody.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Warnken et al (BMC Veterinary Research, 2016) teaches different immunoassays for quantification of equine insulin, but none teach the specific use of 2D11 and E2E3 antibodies. Oberg et al (PTO-892, 02/12/2025, REF. U) teaches an equine optimized immunology assay, but does not teach the specific use of 2D11 and E2E3 antibodies, or an LFA.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIM ATWELL, D.Sc., M.S., MLS whose telephone number is (571)272-0890. The examiner can normally be reached Generally Mon-Thurs: 7:30-5:00 EST and every other Fri: 7:30-4:00 EST.
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/JIM ATWELL/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677